Unresolved issues in the management of ulcers of the ...

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DIABETICMedicine DOI: 10.1111/j.1464-5491.2008.02573.x

Review Article

Blackwell Publishing Ltd

Unresolved issues in the management of ulcers of the foot in diabetes W. J. Jeffcoate, B. A. Lipsky*, A. R. Berendt†, P. R. Cavanagh‡, S. A. Bus§, E. J. G. Peters¶, W. H. van Houtum††, G. D. Valk** and K. Bakker‡‡ on behalf of the three systematic review working parties of the International Working Group on the Diabetic Foot Foot Ulcer Trials Unit, Nottingham University Hospitals Trust, Nottingham, UK, *VA Puget Sound HCS and University of Washington, Seattle, WA, USA, †Bone Infection Unit, Nuffield Orthopaedic Centre NHS Trust, Oxford, UK, ‡Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA, §Department of Rehabilitation, Academic Medical Center, University of Amsterdam, Amsterdam, ¶Department of Internal Medicine and Infectious Diseases and **Department of Internal Medicine, University Medical Center Utrecht, Utrecht, ††Department of Internal Medicine, Spaarne Hospital, Hoofddorp and ‡‡IWGDF, Heemstede, the Netherlands Accepted 13 August 2008

Abstract Management of diabetic foot ulcers presents a major clinical challenge. The response to treatment is often poor and the outcome disappointing, while the costs are high for both healthcare providers and the patient. In such circumstances, it is essential that management should be based on firm evidence and follow consensus. In the case of the diabetic foot, however, clinical practice can vary widely. It is for these reasons that the International Working Group on the Diabetic Foot has published guidelines for adoption worldwide. The Group has now also completed a series of non-systematic and systematic reviews on the subjects of soft tissue infection, osteomyelitis, offloading and other interventions designed to promote ulcer healing. The current article collates the results of this work in order to demonstrate the extent and quality of the evidence which is available in these areas. In general, the available scientific evidence is thin, leaving many issues unresolved. Although the complex nature of diabetic foot disease presents particular difficulties in the design of robust clinical trials, and the absence of published evidence to support the use of an intervention does not always mean that the intervention is ineffective, there is a clear need for more research in the area. Evidence from sound clinical studies is urgently needed to guide consensus and to underpin clinical practice. It is only in this way that patients suffering with these frequently neglected complications of diabetes can be offered the best hope for a favourable outcome, at the least cost. Diabet. Med. 25, 1380–1389 (2008) Keywords

diabetic foot, infection, osteomyelitis, systematic review, wound healing

EGF, epidermal growth factor; G-CSF, granulocyte colony stimulating factor; HBO, hyperbaric oxygen; IWGDF, International Working Group on the Diabetic Foot; MMPs, matrix metalloproteinases; PDGF, platelet-derived growth factor; RCT, randomised controlled trial; TIMP, tissue inhibitor of matrix metalloproteinases

Abbreviations

Introduction Disorders of the foot affect about 15% of all people who have diabetes [1] and are associated with considerable morbidity, mortality and cost [2,3]. While the spectrum of diabetes-related foot disease comprises chronic ulceration (with or without associated infection of soft tissue or bone), critical ischaemia and acute Charcot foot, most attention is focused on the management of the chronic, non-healing ulcer. This delay in healing is

Correspondence to: William Jeffcoate, Foot Ulcer Trials Unit, Department of Diabetes and Endocrinology, Nottingham University Hospitals Trust, City Hospital Campus, Nottingham NG5 1PB, UK. E-mail: [email protected]

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associated with serious impairment of lifestyle and mood [4] and exposes the patient to limb-threatening complications, such as the development of secondary infection and gangrene. Management is frequently unrewarding: the median time to healing exceeds 2 months [5] and only two-thirds of diabetic foot ulcers will eventually heal without surgery [6– 8]. Unfortunately, few of the interventions available have been shown to enhance ulcer healing [9–13]. Not surprisingly, in the absence of interventions of proven effectiveness, many clinicians resort to a wide variety of unproven remedies. Many treatments for diabetic foot complications are currently promoted and the likelihood of being used may depend on factors other than robust evidence of effectiveness, including

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approval for reimbursement. The weak evidence base for most interventions results in clinical practice that is based largely on clinician opinions and these often differ widely. In 1999, the International Working Group of the Diabetic Foot (IWGDF; a consultative section of the International Diabetes Federation) launched guidelines intended to summarise available evidence and make recommendations for care and these have been recently updated [14,15]. Recognising the need for the guidelines to be based on the available scientific evidence, the IWGDF completed a non-systematic review on the management of infection [16] and, more recently, three systematic reviews covering: footwear and offloading in the prevention and treatment of ulcers; the management of osteomyelitis; and all other interventions that have been reported in the management of established ulcers [17–19]. The conclusions of these reviews echo the work and the conclusions of previous authors; in general, the quality of available research is poor and didactic statements on management are not supported by high-quality evidence. This article is aimed at collating the key findings of these four reviews, augmented by selected papers published since December 2006. We wish to highlight not only what is known, but more importantly the areas in which major uncertainties persist and for which robust evidence is urgently needed to inform good clinical practice.

with colonising flora and fail to identify deep pathogens [20]. Antibiotic regimens should be targeted at the organisms found to be responsible for the infection and should be continued for the minimum duration needed (generally not more than 2 weeks for soft tissue infection) to reduce both the incidence of side effects and the emergence of resistant organisms. Aerobic Gram-positive cocci are the most important pathogens, but numerous studies have shown that, with properly obtained specimens for culture, multiple organisms will be isolated from the majority of clinically infected ulcers [25]. Isolation of these organisms, however, does not necessarily indicate that each is behaving as a pathogen, rather than a coloniser. Current guidelines for the management of newly presenting, acute, mild or moderate infections of soft tissue recommend using agents active against Gram positive cocci (especially Staphylococcus aureus) as these are the most common pathogens. For chronic ulcers in which infection has been unresponsive to primary therapy, a broad spectrum regimen, such as a beta-lactam plus beta-lactamase inhibitor combination or clindamycin plus a quinolone, is recommended. Clinicians should consider covering obligate anaerobes when the wound is ischaemic or gangrenous and covering antibiotic-resistant organisms (especially methicillin-resistant Staphylococcal aureus; MRSA) when local experience or culture results suggest the need [16,20].

Soft tissue infection

Unresolved issues

Accepted practice and available evidence

Soft tissue infection in the foot of a patient with diabetes nearly always represents a complication of a disruption of the skin envelope—occasionally a recent break in the skin, but most often a chronic ulcer—rather than a primary process [20,21]. When infection complicates a pre-existing wound, however, it often triggers a deterioration in that wound, which may be slowly or rapidly progressive. Unchecked infection can precipitate tissue necrosis and gangrene, especially in an ischaemic limb. It follows that, although infection does not cause ulceration, it can impair healing or lead to further tissue loss. Thus, infection is a major precipitating factor leading to limb loss, especially in developing nations [8,22]. The first priority of management of the newly presenting ulcer is, therefore, to diagnose or exclude bacterial infection and to administer appropriate antibiotic therapy when indicated. The diagnosis of infection is essentially clinical, based on the presence of signs of inflammation, not microbiological. Both the Infectious Diseases Society of America (IDSA) and the IWGDF have suggested that it should be graded into mild, moderate and severe [16,20] and some evidence has validated this approach [23,24]. The purpose of obtaining a culture of a wound is not to diagnose infection but to define the identity and antibiotic sensitivity of possible infecting organisms. Wound samples should be obtained by curettage or biopsy to obtain tissue, if possible, as surface swabs are often contaminated

© 2008 The Authors. Journal compilation © 2008 Diabetes UK. Diabetic Medicine, 25, 1380–1389

The significance of colonisation and critical colonisation

Uncertainty persists over the significance of micro-organisms colonising the surface of a wound that is not clinically infected. Some have argued for using systemic antibiotic treatment in the belief that high levels of surface colonisation may inhibit healing or that clinical signs of infection may be obscured by neuropathy or ischaemia [26]. This view is not shared by the majority of experts and there are no supportive published data. Others have suggested using either topical or systemic antimicrobial agents for a wound colonised by more than 105 colony-forming units of organisms—in the belief that this so-called ‘critical colonization’ will inhibit wound healing per se and is likely to evolve into clinical infection of soft tissue. Although there are some data to confirm an inverse association between the level of colonisation of diabetic foot ulcers and healing [27], this does not prove a causal relationship. As it is possible that both poor outcome and the extent of colonisation are themselves the consequence of a third factor (such as ischaemia, wound chronicity or prior antibiotic use), the issue can only be resolved by a prospective study designed to determine the effect of reducing the bacterial load on wound healing. Choice of antibiotic regimen

There is uncertainty about the optimal choice of antimicrobial therapy in the management of clinically overt infection of soft tissue. This includes questions on route of therapy (topical,

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oral, parenteral), specific agents and duration of treatment. Randomised trials are needed to assess the effectiveness and safety of broad spectrum compared with targeted antibiotic regimens. Randomised controlled trials (RCTs) are also needed to determine the optimal route and minimum effective duration of antimicrobial therapy in various types of infection, as well as to assess the relative value of clinical signs, microbiological sampling and biochemical measures such C-reactive protein (CRP) and procalcitonin [24] in determining which wounds are infected and when treatment can be discontinued.

Infection of bone—osteomyelitis Data from several studies show that bone is infected in some 20% of patients with a foot wound attending specialist clinics in both the USA and the UK [28,29]. Because evidence suggests that infection of bone markedly increases the likelihood of lower extremity amputation (either minor or major) [21], it is imperative that clear protocols are developed for defining and treating osteomyelitis of the foot in diabetes. Accepted practice and available evidence

Infection of bone usually occurs by contiguous spread of infection from overlying soft tissue. The diagnosis of osteomyelitis is generally based on the combination of clinical signs of infection with evidence of underlying bone disruption or inflammation on specific imaging tests. Management is based on the use of appropriate antibiotic therapy and, in some situations, on the surgical removal of necrotic bone.

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both are associated with local inflammation and with bone fragmentation [31]. Furthermore, the two entities may coexist, as an ulcerated Charcot foot may be complicated by secondary infection and acute osteomyelitis may also trigger the onset of the Charcot process. Thus, more robust diagnostic criteria are required for these disorders, as the treatments for each are substantially different. The role of early surgery in treatment

As far as treatment of osteomyelitis is concerned, the major continuing controversy centres on the relative roles of surgery and antibiotics. Traditionally, authorities have suggested that the type of contiguous, chronic osteomyelitis seen in the diabetic foot requires that all necrotic bone, and most (if not all) infected bone, should be surgically removed. This was based on the understanding that antibiotics do not penetrate necrotic tissue and early experience that antibiotic treatment of infected bone was frequently unsuccessful [32,33]. Some non-randomised studies suggest a better outcome with surgical than solely antibiotic therapy [34,35]. However, many groups have produced observational evidence that bone infection may be apparently eradicated in the majority of cases following the use of newer antibiotic regimens, such as those including quinolones or beta-lactam plus beta-lactamase inhibitor combinations [36–38]. The optimal treatment will inevitably depend on a judicious combination of non-surgical and surgical treatments, but we do not currently know which patients with which types of infection would benefit from a specific approach. The role of bone biopsy in diagnosis and antibiotic selection

Unresolved issues Diagnosis, including differentiation from acute Charcot disease

Diagnosing osteomyelitis is often difficult. The diagnosis may be unequivocal if pus is observed within bone tissue, but in most circumstances it is based on suggestive evidence, including the clinical appearance of the overlying soft tissue (usually a digit), bone fragmentation on X-ray and oedema of bone marrow on magnetic resonance imaging (MRI). Most believe that a combination of microbiological and histological examination of a bone biopsy sample is the criterion standard for diagnosing osteomyelitis [18], but even this technique is associated with both false positive and false negative results—especially in those who have already been treated with antibiotics (as is commonly the case). Furthermore, most clinicians and many institutions do not have access to bone biopsy. Thus, the IWGDF has proposed a scheme based on combinations of clinical, imaging and laboratory results to classify the likelihood of osteomyelitis in individual cases as ‘definite’, ‘probable’, ‘possible’ or ‘unlikely’ [18]. This scheme remains to be validated. The greatest diagnostic difficulty lies in differentiating osteomyelitis from acute Charcot disease, as both disorders are most commonly observed in a similar patient population and

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Bone can be sampled either at the time of an open procedure or percutaneously (usually under imaging guidance), but must be obtained without traversing microbially contaminated tissue. Data are urgently needed to determine the place of bone biopsy, for both histological and microbiological analysis, in the diagnosis and directed therapy of osteomyelitis. We need to determine the meaning of a bone biopsy obtained in a patient with a non-healing ulcer who has no clinical signs of bone infection but a positive bone culture. A number of authors interpret this finding as diagnostic of osteomyelitis, whereas other possibilities, such as non-infective colonisation of bone, may need to be considered. Finally, while bone biopsy appears to be safe, at least in the hands of those experienced in the procedure, we need to ensure it remains safe when the use of the technique becomes more widespread. Choice of antibiotic regimen

There are limited data on which to establish the best choice of antibiotic therapy for diabetic foot osteomyelitis. The usual recommended duration of antibiotic therapy for bone infection is about 6 weeks, but most of the reports of using antibiotics alone for diabetic foot osteomyelitis have treated for about 3 months or longer. Some evidence suggests the outcome may be improved when the antibiotic choice is based on the results

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of culture of bone [39], but this needs to be validated in a randomised study.

the use of dressing products that incorporate or release such an agent.

Debridement

Unresolved issues

Accepted practice and available evidence

Once the issue of infection has been dealt with, the next priority is to ensure that the surface and edges of the wound are prepared in such a way as to encourage healing. The main purpose of this wound bed management is to remove necrotic and highly bacterially contaminated tissue from the surface and edges of the wound. This can be accomplished most quickly and most effectively by sharp (i.e. surgical) debridement. Other methods of debridement include using larvae (maggots), chemical agents, antiseptics (see below) and some newer technologies.

There are some data suggesting a significant benefit for hydrogel dressings in wound healing but these derive from studies of relatively poor quality [19]. A more robust study has reported benefit from using a carboxymethylcellulose dressing [44]. No other trial data indicate that the use of any other topical antiseptic, wound preparation or dressing has a beneficial effect on the healing of diabetic foot ulcers [19]. A single RCT on the use of a silver impregnated dressing showed no difference between groups for the primary endpoint [45] and a systematic review of the use of silver-containing products concluded that there was insufficient evidence to recommend their use [46].

Unresolved issues Sharp debridement

Only two published studies have attempted to demonstrate the effectiveness of sharp debridement and both were of weak design, i.e. subset analyses of patients included in other studies [40,41]. A robust prospective assessment is required because various clinical teams differ in their approach: in the extent to which debridement is primarily directed at the wound margin or the wound bed, the regularity with which they will pare the surface of the wound to leave freely bleeding soft tissue and the frequency with which debridement is repeated. Many providers do not have the training, the equipment or the time during an outpatient visit to perform the sharp debridement that other specialists would regard as important. Other methods

Two controlled studies have addressed the effectiveness of larvae [42,43] but both had methodological weaknesses and more data are required to assess benefit. No controlled trials using other methods of debridement have been published. If the effectiveness of either larvae or other methods in cleaning the wound bed is confirmed, it will be important to know how long the effect remains and whether the change is associated with an improved rate of eventual healing.

Topical antiseptics, applications and dressings Accepted practice and available evidence

Open wounds require regular inspection, repeated cleansing and re-dressing. The main purposes of dressings are to provide a warm moist environment which is believed to be optimal for wound healing, as well as to absorb excess exudate and to protect the wound bed from trauma. Clinicians also hope that both the speed and success of healing will be improved by applying specific agents to the surface of the wound or by

© 2008 The Authors. Journal compilation © 2008 Diabetes UK. Diabetic Medicine, 25, 1380–1389

Growth factors and other agents designed to correct abnormalities of wound bed metabolism Accepted practice and available evidence

A number of approaches that attempt to modify the biochemistry of the wound bed or surrounding cells have been described, but many are experimental and there is no consensus on their place in clinical practice. These approaches include applying or injecting various types of platelet-derived products, granulocyte-colony stimulating factor (G-CSF), platelet-derived growth factor (PDGF, becaplermin) and epidermal growth factor (EGF). Some advocate dressing products designed to correct imbalances in the wound of the expression of matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases, TIMPs) [19]. Although a variety of platelet-derived products have been advocated over the last two decades [47–51], the effectiveness and cost-effectiveness of this approach has yet to be established in rigorous trials. Several randomised trials have explored the use of G-CSF in treating diabetic foot ulcers complicated by infection and the results suggest the possibility of an overall improvement in limb salvage [52]. Because, however, of the small size of these studies, the various G-CSF preparations and regimens used and the variable quality of the study designs, this possibility needs to be confirmed. An apparent benefit of PDGF was observed in one large RCT conducted on neuropathic foot ulcers in diabetes [53], but the results of a follow-up US study were inconclusive [54]. The results of an equivalent European study were not published, suggesting that the promise of the first study was not confirmed. Early work on EGF has suggested that it may hasten healing, but this remains to be confirmed in appropriately powered studies. The results of a single large trial designed to demonstrate an effect of a dressing product aimed at modulating expression of MMPs and TIMPs (Promogran®) were essentially negative [55], although a recent

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study by Kakagia and colleagues has suggested that this product exhibited a synergistic effect when used in combination with PDGF [56]. Unresolved issues

There are currently insufficient data to support the use of growth factor preparations in routine clinical practice.

Bioengineered skin substitutes Accepted practice and available evidence

Healing of clean, neuropathic ulcers may be enhanced by the application of bioengineered skin substitutes, comprised of sheets of cultured cells derived from neonatal skin. Of five randomised controlled studies on skin substitutes, three involved dermal fibroblast culture and one each fibroblast/keratinocyte co-culture and culture of keratinocytes alone. One RCT of the use of dermal fibroblasts reported a significant difference from control patients, although control subjects responded very poorly with only 18% of neuropathic ulcers healing by 12 weeks [57]. The performance of fibroblast/keratinocyte co-culture was better [58], but was still inferior (in both control and intervention groups) to results obtained in offloading studies of a similar group of patients [59]. The fibroblast/keratinocyte co-culture was also assessed in a large, non-US, study but the results were never published. The study on keratinocytes did not report full results [60]. A single report of the use of a skin substitute for patients with relatively large ulcers based on autologous cells reported no benefit overall, but a weakly significant benefit in a subgroup [61]. Another recent systematic review of the evidence to support the use of bioengineered skin substitutes concluded that identified trials were of questionable quality and that recommendations for the use of skin substitutes could not be made until further high-quality studies were performed [62]. Unresolved issues

The place of bioengineered skin substitutes has yet to be established and we need further evidence of both the effectiveness and cost-effectiveness of this approach. Such studies should select appropriate populations, excluding those most likely to heal with less costly interventions [19].

Negative pressure wound therapy

Management of diabetic foot ulcers • W. J. Jeffcoate et al.

cantly enhanced healing in the intervention group, although they were limited by being necessarily non-blinded, as well as by including patients who had surgical closure in the ‘healed’ group. Compression therapy has also been shown to be of benefit in one single trial [65]. Unresolved issues

While there is evidence to support the use of negative pressure therapy [66], especially in clean post-operative wounds, a more recent systematic review has emphasized that it is not strong [67]. Its place in the management of non-surgical wounds, including those with less good blood supply, is far from clear. The most widely available commercial equipment is relatively expensive and it is not known if the intervention should be reserved for a particular subgroup that is less likely to heal with simpler measures. More information is needed on patient (and wound) selection, the duration of treatment and its optimal combination with other approaches, such as grafting or surgical closure. Rozen et al. [68] have recently reported successfully using a form of negative pressure wound therapy that is cheaper than commercially available devices.

Hyperbaric oxygen Accepted practice and available evidence

Hyperbaric oxygen (HBO) has been promoted for the management of non-healing wounds for decades, but is endorsed mainly by those with ready access to (and often ownership of) the necessary facilities. An earlier systematic review concluded that there are insufficient data to justify the routine use of systemic HBO [69]. Most reported studies have been anecdotal reports, leaving many sceptical of the need for this expensive intervention [70], but there have been a number of RCTs undertaken to examine the effectiveness of HBO, including one which was double-blinded, although unfortunately rather small [71]. All of these suggest possible clinical benefit. There are no data to support the use of topical, as opposed to systemic, HBO. Unresolved issues

More data are required from larger, controlled trials to confirm the effectiveness of HBO for diabetic foot wounds and to define which types of lesion may benefit. These trials must, such as that by Abidia et al. [71] be double-blinded and use hyperbaric air in the control group to eliminate the possible beneficial effect of compression. Formal cost–benefit analyses are also needed.

Accepted practice and available evidence

The application of negative pressure to the surface of wounds (especially of those which are post-operative or newly debrided) has been shown to improve healing [63,64]. This technique has been heavily marketed and is being widely adopted. Both of the published large trials of this technique reported signifi-

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Revascularisation Accepted practice and available evidence

Revascularisation should be considered in patients with clinical evidence of impaired lower limb blood flow resulting from

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macrovascular disease that is amenable to intervention, but this practice is based on clinical experience rather than evidence from controlled trials. Observational data have shown that the benefit of attempted revascularisation is much reduced in patients with chronic renal failure [72–74]. Unresolved issues

The lack of evidence results in continuing uncertainty over case selection, with many centres attempting intervention only for occlusions of the larger arteries of the leg, while others advocate angioplasty for arteries of the calf and foot. The benefit of distal revascularisation procedures should be established in controlled trials but clinical circumstances and ethical issues make this difficult (but not impossible), and most data derive from observational series. Many such series report the apparent benefit of an intervention in terms of ‘limb salvage’, but this term should be used and interpreted with caution. The term implies that the limb would have been inevitably lost if the intervention had not been adopted, but this can only be conclusively demonstrated if there was a control population.

Offloading in the management of chronic wounds Accepted practice and available evidence

One of the factors responsible for the failure of chronic ulcers to heal is continued mechanical trauma to the bed of the healing wound, often occurring during the normal activities of daily life. This occurs because the area is insensate as a result of underlying distal symmetrical neuropathy. The regenerating wound bed can, however, be protected by a variety of pressure offloading methods, including casting, bracing, footwear and surgical offloading. Compared with other methods, the use of non-removable devices, such as a plaster or fibreglass total contact cast or a walking brace that has been rendered non-removable, results in a higher proportion of plantar ulcers being healed and in a shorter time [75–78]. Remarkably, ulcer patients have been shown to take an average of 72% of their daily steps unprotected when given a device which they can remove [79]. Other forms of footwear, such as cast shoes or half shoes, may result in rates of healing that are better than standard care [80–84], but this remains to be substantiated in controlled studies. Surgical procedures, such as excision of bony prominences, joint arthroplasty and Achilles tendon lengthening do not improve the proportion of ulcers that eventually heal when compared with total contact casting, but may reduce healing time [85–90]. The benefit, cost–benefit and safety of surgical interventions has yet to be demonstrated, especially as relatively little is known of their long-term consequences, and of the incidence of associated transfer ulcers.

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No studies on the effects of bed rest, crutches, canes, wheelchairs, offloading dressings and soft midsole plugs on ulcer healing were located in the literature. Unfortunately, there is also little evidence for the effectiveness of low technology approaches to offloading, such as felted foam dressings [91] or other techniques that may be suitable for use in less-developed parts of the world [92]. Unresolved issues

While effective offloading is largely recognized as a cornerstone of management of the chronic wound, uncertainties surround the optimal means of implementing this strategy. The application, and repeated replacement, of casting devices has historically been an expensive and time-consuming task and further information is needed on the minimum training and optimal setting required to ensure delivery of safe and effective offloading. Additional investigations should also be directed at establishing what place special footwear has in ulcer healing and on the effectiveness of surgical procedures in accelerating the healing of ulcers overlying bone deformity or joints with reduced mobility. Other issues that need to be addressed are the relative advantages and disadvantages of non-removable vs. removable offloading devices. While non-removable devices appear to be more effective [59,75], they may be associated with secondary ulceration on both the affected and contralateral foot, as well as with inconvenience and distress (caused by immobility and reduced ability to wash), and with muscle wasting and backache. Removable devices are more convenient, but less effective because of issues relating to patient non-adherence. Simple, reliable, unobtrusive and reasonably priced methods to monitor adherence to offloading interventions are urgently needed to inform the results of future clinical trials.

Discussion Disease of the foot remains a major complication of diabetes, one that is difficult and expensive to treat and which is associated with potentially devastating medical, social and psychological consequences [2–4]. Thus, a climate of evidencebased intervention is imperative, notwithstanding the fact that design of trials in this field is difficult. Studies designed to assess the management of infection—whether of soft tissue or bone—pose particular problems. These derive from (i) the need to rely mainly on clinical signs to make the diagnosis and the lack of objective measures of these signs, (ii) the importance of surgical interventions in many infections, (iii) the difficulty in objectively defining the eradication of infection and (iv) the fact that placebo-controlled trials are almost always unethical once the diagnosis of infection is made. Trial design is also made difficult by the multiplicity of factors involved in the pathogenesis of chronic ulcers and which underlie the failure to heal. The condition of an ulcer may vary with time and treatment and this means that the

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relative contribution made to delayed healing by different pathological processes will also vary. It may therefore be hard to demonstrate that any one intervention has on its own an effect on the desired clinical outcome, which is ulcer healing, with improved function and well-being. The absence of a demonstrable clinical benefit does not necessarily mean that the intervention is ineffective. The choice of appropriate outcome measures requires special care. Careful consideration must also be given to definition of the selected study population (both of ulcers and patients) because the effectiveness of interventions will vary depending on the type of ulcer (as characterized by area, depth, site and the presence of infection, peripheral arterial disease, neuropathy) as well as in different groups of people (characterised by age, co-morbidities, glycaemic control, social factors and access to effective primary health care). The issue of population selection is especially relevant to the assessment of newer, more costly, interventions. Many such interventions are currently assessed in patients in whom the likelihood of healing is relatively high: those with uncomplicated neuropathic ulcers of relatively well-perfused feet. However, this population is one in which healing can be readily achieved with proper attention to simple issues, such as offloading, and is not the one for which most clinicians will select newer, and generally more expensive, advanced wound therapies. Such therapies will generally be reserved for patients who have proved unresponsive to established methods and it is in this group that they should properly be tested. Clinicians have to be cautious in extrapolating into routine practice the results of some commercially funded studies. Investigators should consider other options if the complexity of the presentation of diabetic foot ulcers, or their variability over several months of management, is such that it is not possible to design a robust randomised trial that will reasonably assess the effectiveness of an intervention. One of these is to compare outcomes (of ulcers or people: healed, unhealed, amputation, death) between centres, whilst acknowledging the many factors that may differ between them [8,93]. If one service is associated with a substantially better outcome, using clinically meaningful and patient-centred measures [5], a search should be undertaken for the specific aspects of care which may make that service superior. Ultimately, the aim is to demonstrate that the adoption by a specialist unit of protocols of care linked to a battery of interventions of proven efficacy is associated with improved long-term clinical outcome, at justifiable cost, in a carefully defined population. Because the current paucity of robust scientific evidence to inform treatment choices, and of validated protocols for management of diabetic foot ulcers, is unacceptable, we challenge all those involved in the care of the diabetic foot to work together to resolve these issues. The absence of evidence has allowed a culture to develop in which clinical management is determined primarily by professional opinion and belief, and in which attempts are made by industry to influence these by the promotion of new, usually more expensive, inter-

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ventions of unproven efficacy. Properly designed trials are needed to demonstrate effectiveness of recommended interventions. Until effectiveness has been demonstrated in this way, it is the responsibility of professional groups, as well as of those authorising reimbursement, to favour the use of the simplest, most economical and most acceptable therapies in the treatment of this serious and much neglected complication of diabetes.

Competing interests None of the authors has a duality of interest relevant to the content of this review to declare, although ARB has received honoraria from Pfizer and Merck for advisory board membership and speakers’ bureau, and BAL has received research funding from or served as a consultant to: Merck, Pfizer, Wyeth-Ayerst, Bayer, Cubist, Ortho-McNeill/Johnson & Johnson, Oculus. PRC owns stock in DIApedia LLC and is an inventor on US patents 6 610 897 6 720 470 and 7 206 718 which elucidate a load-relieving dressing and a method of insole manufacture for offloading diabetic feet. DIApedia receives royalties from a licensing agreement with Acor Orthopaedic. PRC has also received honoraria from Merck, Eli Lilly and ConvaTec and is a recipient of grants from the National Institutes of Health.

Acknowledgements

Systematic review working parties for the international working group on the diabetic foot. Footwear and off-loading: Peter Cavanagh, Chair, Seattle, USA; Sicco Bus, Secretary, Amsterdam, the Netherlands; David Armstrong, Chicago, USA; Karel Bakker, Heemstede, the Netherlands; Carlo Caravaggi, Milano, Italy; Robert van Deursen, Cardiff, UK; Petr Hlavacek, Zlin, the Czech Republic; Gerlof Valk, Utrecht, the Netherlands. Wound management: William Jeffcoate, Chair, Nottingham, UK; William van Houtum, Secretary, Hoofddorp, the Netherlands; Jan Apelqvist, Lund/Malmö, Sweden; David Armstrong, Chicago, USA; Karel Bakker, Heemstede, the Netherlands; Fran Game, Nottingham, UK; Agnès Hartemann-Heurtier, Paris, France; Rob Hinchliffe, Nottingham, UK; Magnus Löndahl, Lund, Sweden; Patricia Price, Cardiff, UK; Gerlof Valk, Utrecht, the Netherlands. Osteomyelitis: Tony Berendt, Chair, Oxford, UK; Edgar Peters, Secretary, Leiden, the Netherlands; Karel Bakker, Heemstede, the Netherlands; Magnus Eneroth, Malmö, Sweden; John Embil, Winnipeg, Canada; Rob Hinchliffe, Nottingham, UK; William Jeffcoate, Nottingham, UK; Benjamin Lipsky, Seattle, USA; Eric Senneville, Tourcoing, France; James Teh, Oxford, UK; Gerlof Valk, Utrecht, the Netherlands.

References 1 Reiber GE, Lipsky BA, Gibbons GW. The burden of diabetic foot ulcers. Am J Surg 1998; 176: 5S–10S.

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