The diabetic foot: a major problem for the new millennium
Andrew J.M. Boulton
Professor of Medicine, University of Manchester, and Department of
Medicine, Manchester Royal Infirmary, Manchester, UK (ajmb@fs1.cmht.nwest.nhs.uk)
Introduction
It has been forced upon me that diabetic gangrene is not heaven sent, but earth born.
— E.P. Joslin, 1934
Early in the last century, soon after the discovery of insulin, Joslin made the important observation noted above: he stated that it was not inevitable that a certain proportion of the diabetic population would develop foot ulceration or gangrene. He concluded that it was something to do with the way that we as health care professionals look after our patients, or the way that patients look after themselves, which results in conditions collectively referred to as ‘the diabetic foot’ [1]. Since then, in the last 70 years, great steps have been taken in diabetes management: these include primary and secondary prevention of complications, the importance of screening all diabetic patients for evidence of long-term complications, improved glycaemic control and measurement thereof, intensified insulin and oral hypoglycaemic agent regimens, and so on. In the area of the diabetic foot, our understanding of the pathogenesis is indeed much improved [2], but little impact has been made in the depressing statistics for rates of amputations and foot ulcers, conditions that have been associated with spiralling health care costs.
This article will review a number of aspects of the diabetic foot at the beginning of this new century; included will be epidemiological and economic statistics, our understanding of pathways to foot ulcerations, different classification systems, and recently introduced new therapeutic agents.
Epidemiological aspects of the diabetic foot
One day everything will be well — that is our hope. Everything is fine today — that is our illusion.
— Voltaire
The words of Voltaire summarize the global situation with regard to the diagnosis and management of diabetic foot problems (the term ‘diabetic foot’ is used in this article to refer to the variety of pathological conditions that may affect the feet of people with diabetes). As discussed below, the vast cost of lower limb complications has been of increasing concern in recent years and this has itself resulted in increasing research into the aetiopathogenesis, management and service provision for diabetic foot problems.
Globally, the diabetic foot is a major medical, social and economic problem that is seen in every continent [3]. Reassuringly, though, it has not only been health care economics that has resulted in an increased awareness of foot problems: there has also been a worldwide increase in the volume of research and presentations in this area. The American Diabetes Association has an active foot council with a large membership, the European Diabetes Association has a new study group on the diabetic foot and its first annual meeting was in 2000. Symposia on the diabetic foot have recently been held at meetings in South Africa, South America, Japan and Australia, and ALFADIEM (French-speaking diabetes group) had a plenary session on the diabetic foot at their 1998 annual meeting.
Foot ulceration
Despite the increase in research activity, foot ulceration remains common in both main types of diabetes and is much more common in neuropathic patients in whom the annual incidence rises from less than 1% in those without neuropathy to greater than 7% in those with estab-
lished neuropathy [4, 5]. A selection of epidemi-
ological data from several countries relating to the major diabetic foot problems of ulceration and amputation is provided in Table I [6–14].
The reported frequencies of ulceration and amputation in Table I do vary considerably and this is not simply due to regional differences but also to differences in the diagnostic criteria used. Problems in epidemiological data on the diabetic foot were recently reviewed by Williams and Airey [15].
Table I: Epidemiological data on diabetic foot problems across the world, indicating the prevalence and incidence of foot ulcers and
amputations in diabetic populations.
Overall it seems likely that 5–10% of all diabetic patients have past or present ulceration, and about 1% have undergone amputation. The most recent epidemiological data from the USA show that the accumulative incidence of foot ulceration was 5.8% over 3 years of observation [10]. This report was of a retrospective cohort analysis of patients in a large health maintenance organization. Of those patients developing ulcers, 15% developed osteomyelitis and 15.6% required amputation. Moreover, survival was
only 72% at 3 years compared with 87% in a
group of age- and sex-matched diabetic patients with no ulcer history. These observations are in keeping with other reports that indicate that diabetic foot ulceration is associated with significant morbidity and mortality [16–18].
Amputation
Diabetes remains the commonest cause of non-traumatic amputation in the Western world [18, 19]. Lower extremity amputation (LEA) was chosen by the St Vincent Task Force [20] as a major endpoint that appears to be clearly definable and easy to measure, and a 50% reduction was the target to be achieved within a 5-year period. Unfortunately, similar difficulties that have affected accurate epidemiological data in diabetic neuropathic foot ulceration have also bedevilled the use of LEA as an outcome measure in diabetic foot disease [21]. More recently, the LEA study group has suggested a common methodology which would in future avoid many of the problems that have affected previous studies [17, 21].
Recent published trends in amputation rates are not encouraging. In the UK, a report from one health care district showed a 50% increase in amputations between 1990 and 1994 [22], whereas a study from Germany found no change between 1990 and 1995 [23]. In contrast, there have been reports of reductions in amputation rates in health districts in both Sweden and Holland [24, 25]. However, the most recent data from the Veterans Administration system in the United States have shown that whereas there was
an average 5% decrease in major and minor amputations per year between 1989–1998, when the diabetic population was looked at separately, the figures remained the same, indicating no significant reduction over a 10-year period in this large health care system [26].
The diabetic foot — economic considerations
One of several reasons that resulted in the American Diabetes Association holding a consensus conference on diabetic foot wound care in 1999 was the vast cost of diabetic foot disease in that country, and the real need to develop cost-effective measures to treat and prevent ulcers [19]. Indeed, just prior to this meeting, Ollendorf et al. [27] published data on the potential economic benefits of strategies to prevent LEAs in diabetes. Using a model to estimate the incidence and costs of LEA in a hypothetical cohort of 10,000 diabetic patients, these authors predicted potential savings of $2–3 million over 3 years for strategies to reduce LEAs, with the greatest benefits being seen in older patients receiving educational intervention. Other data from the USA have estimated the total expenditure for treated diabetic foot ulcers to be $16 million in a database of 7 million US patients followed for 2 years [28].
The recent international consensus document on the diabetic foot [29] has collated data on the costs of foot ulceration. There are enormous variations in the reported cost of foot ulcers depending upon numerous factors including whether the figures comprise hospital costs alone, the involvement of surgery during the ulcer management, the inclusion of rehabilitation, and also, as pointed out by Williams and Airey [15], indirect costs are often neglected. It appears therefore that all economic data should be viewed with caution, remembering that many will be gross underestimates of the likely total costs.
The most recent data from the USA [10] originate from 8905 patients in a 3-year period during which 514 patients developed ulcers (cumulative incidence 5.8%). The attributable costs for a middle-aged diabetic male patient with a new foot ulcer for the 2 years after this diagnosis was almost $28,000.
Turning to the economic consequences of amputation, there is even more variability in the reported data. In the USA, Reiber [30] estimated the total costs (including rehabilitation) for amputation to be $20,000–$25,000. At approximately the same time, Apelqvist et al. [31] estimated the cost to vary between $43,000 and $65,000, depending upon the level of amputation.
Given the undoubted high costs of diabetic foot disease however calculated, to both individuals and society, preventative foot care and low cost interventions are indeed likely to be effective.
Pathways to foot ulceration
An understanding of the contributory factors that ultimately result in foot ulceration is likely to help in the planning of effective preventative strategies. There is no doubt that foot ulcers do not result from a single pathology: the neuropathic foot for example, does not spontaneously ulcerate. It is a combination of insensitivity with other factors that eventually results in ulceration. Such factors may be from extrinsic injury (e.g. walking barefoot and treading on a sharp object or wearing ill-fitting shoes) or intrinsic (such as the patient with insensitivity and high foot pressures who develops callus which results in ulceration [2]). Although there are few reliable population-based data relating to the major risk factors for foot ulceration, neuropathy, which may affect over 40% of older Type 2 diabetic patients [8], has been shown to be a major contributory factor in the pathogenesis of ulcers. In a recent two centre (USA/UK) study assessing causal pathways to foot ulceration [32], neuropathy was the commonest component cause in the pathways. According to this study, the
commonest causal pathway leading to ulceration involves a combination of neuropathy (resulting in insensitivity), deformity (such as claw toes, prominent metatarsal heads) and trauma, most commonly inappropriate footwear. Pecoraro et al. [33] had previously reported similar causal pathways resulting in amputation. Such studies help in the understanding of causation and in the planning of preventative strategies to prevent such component causes from co-existing in our patients. Thus, in the patient with insensate feet, the provision of proper fitting footwear with appropriate orthoses to offload deformities (such as prominent metatarsal head) will do much to protect the feet from unperceived trauma.
Classification of diabetic foot lesions
Wagner ulcer classification system
Many different classification systems have been reported in the literature [2], but the classification system developed by Wagner [34] for the grading of diabetic foot ulcers has been widely used and accepted for many years (Table II).
Table II: Traditional Wagner ulcer classification
system (modified from original Wagner-Meggitt classification [34]).
This classification system is based upon the depth of penetration of the ulcer and the extent of tissue necrosis. Thus a grade 0 foot has no ulcers but is at risk of ulceration (i.e. from neuropathy, vascular disease, deformity, etc.), and regular examination is essential. Wagner grade 1 ulcers are superficial full-thickness ulcers mostly of neuropathic aetiology, and often found under areas of high pressure such as metatarsal heads and toes. Grade 2 ulcers usually have deeper extension often with the presence of infection. Grade 3 ulcers are deeper and involve bone, often with osteomyelitis. Grade 4 lesions involve localized gangrene (forefoot, toes or heel); and grade 5 is gangrene of the whole foot. Although used for many years, this system fails to differentiate between neuropathic and ischaemic ulcers with or without infection.
San Antonio wound classification system
The more recently developed San Antonio University of Texas wound classification system (Table III) [35] also uses grading, but for each grade the ulcer is staged and the presence or absence of infection and ischaemia is noted. A recent prospective study has assessed and
compared these two wound classification systems and concluded that the San Antonio University of Texas system is a better predictor of outcomes than the Wagner classification system [36].
Table III: The San Antonio University of Texas wound classification system (modified from Armstrong et al. [35]).
Two new classification systems
Two other wound classification systems have also recently been proposed: these include the S(AD) SAD system devised by MacFarlane and Jeffcoate [37]. This system includes size (area, depth) and then assesses for sepsis, arterial disease and denervation. The authors claim that this is a robust classification system, but prospective validation requires to be completed before it can be recommended.
Also, Foster and Edmonds [38] have proposed a simple staging system which they have developed to provide a framework for the diagnosis and management of diabetic foot ulcers. This system, which describes six stages, is based upon the natural history of the diabetic foot on the road to amputation. However, as for the previous classification system, published data on prospective validation are awaited with interest.
New therapeutic approaches to foot ulcers
This section on new therapeutic approaches to diabetic foot problems will consider developments and innovations that have been reported in the last 5 years. Treatments that may potentially prevent the development of foot ulcerations will be considered first, followed by specific therapies for the management of patients with active foot ulcers.
Preventative approaches
Therapeutic footwear
The use of footwear is certainly not a new approach: examples of footwear worn by Roman soldiers can be seen at Hadrian’s wall museum in the North of England. It is well recognized that inappropriate footwear is an important
component cause in the pathway to foot ulceration, as noted above. However, although it has been stated for many years that good footwear prevents the development of ulcers, controlled data in this area have been lacking until recently. In a systematic review of foot ulcer prevention for patients with Type 2 diabetes, Mason et al. [39] found only one controlled study that had assessed the efficacy of therapeutic shoes to reduce ulcers. Uccioli et al. [40], in a randomized study of 69 patients with previous ulcerations, reported significantly fewer recurrent ulcers in those wearing therapeutic shoes rather than normal footwear. This study therefore suggests important health benefits from appropriately designed footwear.
Injected liquid silicone
Important predictive factors for the development of foot ulceration include high plantar pressure, which usually occurs at sites with bony prominences such as the metatarsal heads, and the presence of callus, which acts as a foreign body ultimately causing ulceration [41]. Indeed, the removal of plantar callus has previously been shown to reduce abnormally high foot pressures under the metatarsal heads [2]. Previous uncontrolled reports from the United States have suggested that the therapeutic use of liquid silicone injections in the foot to replace fat padding at callus sites, corns and localized painful areas led to a reduction in callus formation and foot ulcer occurrence [42].
A very recent randomized, controlled trial compared the effectiveness of injecting liquid silicone into the diabetic foot with a saline placebo [43]. Those patients who received silicone had significantly increased plantar tissue thickness at the injection sites and correspondingly significantly decreased plantar pressures at 3 months, results that were repeated at 6 and 12 months.
These preliminary data suggest the potential efficacy of plantar silicone injections, which appear to be safe and without side effects. Further larger studies are now indicated.
Therapies for foot ulcers
Platelet-derived growth factors
Several controlled trials of Becaplermin, a recombinant human platelet-derived growth factor B-chain homodimer, have confirmed the efficacy of this topically applied agent in promoting healing of neuropathic foot ulcers. In a combined analysis of four randomized, controlled studies using Becaplermin, Smiell et al. [44] showed that active treatment was associated with a significant increase in the probability of complete healing compared with placebo gel. This topically applied growth factor is now licensed for use in many countries and has mainly been used in difficult to heal neuropathic ulcers that fail to respond to standard treatment such as offloading, treatment of infection and regular debridement. Its widespread use is somewhat limited by its cost, but used selectively, it can accelerate the wound healing of neuropathic foot ulcers.
During the conduct of these growth factor trials, the importance of extensive and regular sharp debridement was confirmed. Steed et al. [45] confirmed that regular sharp debridement is associated with acceleration of normal wound healing. This may be due to the encouragement of platelet migration and the release of platelet-derived growth factor.
Graft skin
The recent development of living human skin equivalents, produced by tissue engineering techniques, has produced new possibilities for wound healing therapies for chronic ulcers such as those caused by venous disease and diabetic neuropathy. Graft skin is a bilayered, cultured skin equivalent which consists of human epidermis and the collagenous dermal layer containing human fibroblast. In a recently presented study, Sabolinski et al. [46] evaluated the efficacy of graft skin in the management of chronic neuropathic diabetic foot ulcers in a randomized, controlled trial. Graft skin or a standard treatment (saline moisturized gauze) was applied to more than 200 patients, who also received standardized good foot care for the diabetic foot ulcer comprising sharp debridement and offloading. After 12 weeks of treatment, 56% of graft skin-treated patients achieved complete healing compared with 38% of the controls.
It appears, therefore, that treatments such as graft skin and possibly Dermagraft [47] might be useful adjuncts to the treatment of diabetic neuropathic foot ulcers. However, it must be pointed out that both living skin equivalents and topically applied growth factors are expensive treatments and must not be seen as a replacement, but as an addition to good wound care that must always comprise adequate offloading and regular debridement.
Larval therapy
Larval therapy, that is the ability of maggots to cleanse wounds, prevent infection and promote healing, like footwear is hardly new. Indeed, an early reference to larval therapy was made during the Napoleonic wars when it was observed that those wounds accidentally infected by maggots did not become infected and appeared to heal better. In recent years the use of sterile larvae has been investigated with encouraging results [48]. It is thought that maggots remove dead tissue by secreting powerful enzymes that break down dead tissue into a liquid form which is then ingested. The mechanisms by which larvae prevent or combat infection are also complex but there is anecdotal evidence that these may help in combating multi-resistant strains of bacteria.
There is a growing body of clinical experience with the use of larval therapy that suggests that it is useful in the management of patients with necrotic, sloughy, and often neuroischaemic ulcers. Clearly, controlled trials are difficult in this area, but the use of this therapy is now quite widespread in diabetic foot care and also in branches of plastic surgery.
Conclusion
This brief review has touched on certain developments in the diabetic foot in the last few years. Unfortunately, despite advances in many areas, we seem to be far from achieving the aims of the St Vincent Declaration, i.e. a significant reduction in amputations secondary to diabetes. However, increased awareness of diabetic foot problems, more effective screening and education and early intervention should eventually result in significant reductions in the incidence of foot ulcers and amputation, which I hope will be seen within the next decade. It might be concluded, therefore, that although we have achieved much, we must do better in order to impact some of the depressing statistics on diabetic foot disease.
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