13.7 The diabetic foot

At some time in their life, 15% of people with diabetes develop foot ulcers, which are highly susceptible to infection. This may spread rapidly leading to overwhelming tissue destruction and amputation: indeed, 85% of amputations are preceded by an ulcer and there is an amputation in a person with diabetes every 30 seconds throughout the world (1). Evidence-based protocols for diabetic foot ulcers have been developed (2), and diabetic foot programmes that have promoted a multidisciplinary approach to heal foot ulcers with aggressive management of infection and ischaemia have achieved a substantial decrease in amputation rates (3, 4). Furthermore, a reduction in amputations has been reported nationwide in diabetic patients throughout the Netherlands (5). Recently, a decrease in major amputation incidence has been reported in diabetic as well as in nondiabetic patients in Helsinki (6). These reports have stressed the importance of early recognition of the ‘at-risk’ foot, the prompt institution of preventive measures, and the provision of rapid and intensive treatment of foot infection and also evascularization in multidisciplinary foot clinics. Such measures can reduce the number of amputations in diabetic patients.

Systematic reviews on prevention and treatment have been carried out, e.g. see Eldor et al. (7), and national guidelines have recently been formulated (8, 9). An International Consensus developed in 1999 was re-launched in revised form as an interactive DVD (10, 11) in 2007.

This chapter outlines a simple classification of the diabetic foot into the neuropathic and neuroischaemic foot. It then describes a simple staging system of the natural history of the diabetic foot and a treatment plan for each stage. Successful management of the diabetic foot needs the expertise of a multidisciplinary team which should include physician, podiatrist, nurse, orthotist, radiologist, and surgeon working closely together, within the focus of a diabetic foot clinic.

An important prelude to proper management of the diabetic foot is the correct diagnosis of its two main syndromes;

The significance of structural abnormalities of the skin microcirculation is not fully understood, although there are numerous functional abnormalities which may be important. These include increased blood flow, widespread vascular dilatation, increased vascular permeability, impaired vascular activity and limitation of hyperaemia (12).

Infection is rarely a sole factor but often complicates neuropathy and ischaemia and is responsible for considerable tissue necrosis in the diabetic patient. Effective neutrophil microbial action depends on the generation of several oxygen-derived free radicals. These toxic species, which include the superoxide anion, are formed during the respiratory burst activated after chemotaxis and phagocytosis. In diabetes, especially poorly controlled diabetes, deficiencies in neutrophil chemotaxis, phagocytosis, superoxide production, respiratory burst activity, and intracellular killing have all been described (13).

This is a warm, well-perfused foot with sensory deficit and autonomic dysfunction leading to arteriovenous shunting and distended dorsal veins. Peripheral auto-sympathectomy damages the neurogenic control mechanisms which regulate capillary and arteriovenous shunt flow and loss of precapillary vasoconstriction. The pulses are palpable. Sweating is diminished and the skin may be dry and prone to fissuring. Motor neuropathy results in paralysis of the small muscles of the foot and may contribute structural deformities such as a high arch and claw toes. This leads to prominence of the metatarsal heads (Fig. 13.7.1). The neuropathic foot has two main complications, the neuropathic ulcer and the neuropathic (Charcot) foot.

This is a cool, pulseless foot with poor perfusion. It also has neuropathy. Ischaemia results from atherosclerosis of the leg vessels. This is often bilateral, multisegmental, and distal, involving the arteries below the knee. Intermittent claudication and rest pain may be absent because of coexisting neuropathy and the characteristic distal distribution of the arterial disease.

The natural history of the diabetic foot can be divided into six stages.

Every diabetic patient can be placed into one of these stages and then managed appropriately. In stages 1 and 2, the emphasis is on prevention of ulceration. In stage 3 the presentation and management of foot ulceration is critical. Finally, in stages 4 and 5, the complications of foot ulceration, notably, cellulitis and necrosis must be managed. By developing an understanding of these stages and appropriate interventions, complications can be identified and risk of problems minimized. One of the most important principles in the care of diabetic patients is early diagnosis and then rapid intervention.

At each stage, it is necessary to take control to prevent progression. Management will be considered under the following headings:

Metabolic control is important at every stage. Tight control of blood glucose, blood pressure, and blood cholesterol and triglycerides should be achieved to preserve neurological and cardiovascular function. Advice should be given to stop smoking. In stages 4 and 5, metabolic decompensation may occur in the presence of infection and intensive management of the diabetic state is often required.

By definition, the foot does not have the risk factors for foot ulcers, namely, neuropathy, ischaemia, deformity, callus, and swelling. Neuropathy and ischaemia are the two most important risk factors for the diabetic foot. Deformity, swelling, and callus do not commonly lead to ulceration in patients with intact protective pain sensation and a good blood supply, but when they are found in combination with neuropathy or ischaemia, they significantly increase the risk of ulceration The diagnosis of stage 1 is made by screening patients and excluding these factors. The low risk is simply from trauma to a normal foot. The American Diabetes Association has recently described a Comprehensive Assessment Foot Examination and Risk (15).

A simple technique for detecting patients with loss of protective pain sensation is to use a nylon monofilament, which, when applied perpendicular to the foot, buckles at a given force of 10 g. The filament should be pressed against several sites including the plantar aspect of the first toe, the first, third and metatarsal heads, the plantar surface of the heel, and the dorsum of the foot. It is recently recommended that four sites (1st, 3rd, and 5th metatarsal heads, and plantar surface of distal hallux (15)) be tested on each foot. The filament should not be applied over the callus until that has been removed. If the patient cannot feel the filament at any of these sites, then significant neuropathy is present with loss of protective pain sensation. Caution is necessary when selecting the brand of monofilament to use, as many commercially available monofilaments have been shown to be inaccurate. Single-use disposable monofilaments or those shown to be accurate by Booth and Young’s study are recommended (16). After using monofilaments on 10 consecutive patients there should be a recovery time of 24 hours before further usage. Prospective studies have shown that the inability to perceive the 10 g monofilament at the toes or the dorsum of the foot predicts future development of an ulcer (15).

Alternatively, vibration perception threshold can be measured using a neurothesiometer although this is more suitable for research purposes. It assesses large fibre function. A vibration threshold greater than 25 V is strongly predictive of foot ulceration. Recently, the vibration perception threshold has been shown to be more sensitive than the 10 g monofilament for assessment of individuals at risk for foot ulcers (17).

The most important manoeuvre to detect ischaemia is the palpation of the foot pulses, namely the dorsalis pedis pulse and the posterior tibial pulse. If either of these foot pulses can be felt then it is highly unlikely that there is significant ischaemia. A small hand-held Doppler probe can be used to confirm the presence of pulses and to quantitate the vascular supply. Used together with a sphygmomanometer, the brachial systolic pressure and ankle systolic pressure can be measured. The pressure index, which is the ratio of ankle systolic pressure to brachial systolic pressure, can be calculated. In health, the pressure index is usually more than one, but in the presence of ischaemia it is below one. Thus, absence of pulses and a pressure index of less than 1 confirms ischaemia. Conversely, the presence of pulses and a pressure index over 1 rules out ischaemia and further vascular investigations are not necessary.

Many diabetic patients have medial arterial calcification, giving an artificially elevated systolic pressure, even in the presence of ischaemia. It is thus difficult to assess the diabetic foot when the pulses are not palpable, but the pressure index is more than 1. It is then necessary to use other methods to assess flow in the arteries of the foot, such as examining the pattern of the Doppler arterial waveform or measuring transcutaneous oxygen tension or toe systolic pressures. The value of performing Doppler pressures on asymptomatic patients has been questioned. However, the American Diabetes Association has recommended that the ankle–brachial pressure should be measured in all diabetic patients above 50 years of age (18). Indeed, a recent study showed a prevalence of peripheral arterial disease in 21% of newly diagnosed diabetic patients (19).

Deformity often leads to bony prominences, which are associated with high mechanical pressures on the overlying skin. This leads to ulceration, particularly in the absence of protective pain sensation and when shoes are unsuitable. Common deformities that should be noted include claw toes, pes cavus, hallux valgus, hallux rigidus, hammer toe, and nail deformities and Charcot foot (see below).

This is a thickened area of epidermis which develops at sites of high pressure and friction. It should not be allowed to become excessive as this can be a forerunner of ulceration in the presence of neuropathy.

Oedema is a major factor predisposing to ulceration, reducing skin oxygenation and often exacerbating a tight fit inside poorly fitting shoes.

This stage by definition does not have any evidence of skin breakdown or ischaemia. However, mechanical and educational control are important to prevent the development of ulceration.

Mechanical control is based on wearing sensible footwear. Shoes should have broad rounded or square toes, adequate toe depth, low heels to avoid excessive toe pressure on the forefoot and laces, Velcro, or buckle straps to prevent movement within the shoe.

Advice should be given on basic foot care including nail cutting techniques, the treatment of minor injuries, and the purchase of shoes. Educational programmes involving behavioural contracts and organizational intervention for health care providers have shown a significant reduction in foot ulceration at 1-year follow-up.

The diabetic foot enters stage 2 when it has developed one or more of the following risk factors for ulceration: neuropathy, ischaemia, deformity, swelling, and callus. It is important to detect these by a regular screening examination. If symptoms do develop in the foot with ischaemia, there are three main clinical presentations:

The classical site of claudication is the calf, although it may occur in the thigh and buttocks in aortoiliac disease. Claudication is less common in diabetic patients compared with nondiabetic patients because of peripheral neuropathy and the very distal site of atherosclerosis in the tibial vessels of the diabetic leg. Those patients who do present with claudication should be referred for a vascular opinion and undergo Doppler studies for pressure index measurement and sonograms and duplex angiography. Patients with claudication rarely have vascular intervention and operative intervention is required in only 1% of diabetic patients per year although it may be indicated when the claudication is severe, i.e. pain comes on within a few yards of walking and the site of the arterial disease is in the iliac arteries. Patients with claudication should enter an exercise programme. Pharmacological treatment with cilostazol can now be prescribed at a dosage of 100 mg twice daily but it should not be prescribed in patients with heart failure.

With increasing severity of occlusive arterial disease, patients may develop a pink, painful, pulseless foot. The colour of the skin is a strikingly bright pink and the foot is cold. The amount of pain is related to the severity of the disease and the degree of peripheral neuropathy. When neuropathy is mild, patients will have classic rest pain, which is a constant pain, often worse at night and it can be relieved by hanging the leg down outside the bed. It is important not to mistake the pink painful ischaemic foot for an infected cellulitic foot. The pink painful ischaemic foot is usually cool and the infected cellulitic foot is usually hot. If the leg is elevated the pinkness of ischaemia will fade, while the erythema of cellulitis will remain.

Patients who present with ischemic feet may also have peripheral painful neuropathy, when it can be difficult to know how much pain is due to ischaemia and how much pain is due to neuropathy. It may be necessary to treat the ischaemia by revascularization with angioplasty if possible, as well as managing the painful neuropathy.

The pink painful ischaemic foot is an indication of severe arterial disease. Urgent vascular investigations will be necessary with a view to vascular intervention. The ankle–brachial pressure index will nearly always be less than 0.5, although medial calcification may give an erroneously high value. It is wise to proceed to further investigations including transcutaneous oxygen tension and toe pressure measurements. A level below 30 mmHg confirms severe ischaemia in both tests and patients should proceed to urgent angiography.

A sudden occlusion of a major artery, usually popliteal or superficial femoral, will result in a pale, painful cold foot with purplish mottling. Initially the skin is intact but if treatment is delayed digital necrosis will develop.

Acute ischaemia is a rare complication of the stage 2 diabetic foot and can present very suddenly in:

Unless the patient is profoundly neuropathic, he or she will complain of sudden onset of pain in the leg and foot. If a hand is run down the leg a ‘cut-off’ point will be found where the temperature of the skin suddenly decreases. Symptoms may include pain, numbness, paraesthesiae, and weakness, and signs are pallor, bluish-grey discoloration with mottling or a ‘bruised’ appearance. Acute ischaemia is a clinical emergency associated with severe morbidity and mortality. If the leg is to be saved it is necessary to achieve reperfusion as a matter of urgency.

Recent studies have demonstrated the value of foot protection programmes including education and footwear intervention. A large randomized controlled trial (RCT) demonstrated that amputation rates among people at high risk of ulcers could be significantly reduced by a foot protection programme, and such a programme is cost-effective (20). Patients with foot deformities, history of foot ulceration, and significant vascular or neuropathic disease were randomized to the intervention (weekly clinics providing chiropody, hygiene, hosiery, protective shoes, and education) or usual care. At 2 years the ulcer rate in the intervention group was nonsignificantly reduced to 2.4% compared with 3.5% in the usual care group (p = 0.14). Amputations, however, were reduced threefold with 7 in the intervention group and 23 among controls (p <0.04).

The foot risk classification system of the International Working Group divided patients into four groups: subjects without neuropathy, patients with neuropathy but without deformity or peripheral vascular disease, patients with neuropathy and deformity or peripheral vascular disease, and patients with a history of foot ulceration or a lower extremity amputation. This system has been shown to be effective in predicting clinical outcomes of ulceration and amputation (21). A similar foot risk classification system incorporating the Scottish foot ulcer risk score has been shown to predict foot ulcer healing in a regional specialist foot clinic (22).

Mechanical, vascular, and educational control are important.

Deformity must be accommodated and callus, dry skin, fissures, and oedema must be treated.

Deformities in the neuropathic foot render the plantar surface vulnerable to ulcers, best prevented by using special insoles, whereas in the neuroischaemic foot the foot margins need protection and appropriately wide shoes should be advised. Footwear can be divided into three broad types: sensible shoes (from high street shops) for patients with minimal sensory loss; readymade stock (off the shelf) shoes for neuroischaemic feet that are not greatly deformed but that need protection along the foot margins; and customized or bespoke (made to measure) shoes containing cradled, cushioned insoles, necessary to redistribute the high pressures on the plantar surface of the markedly neuropathic foot.

With regard to the prevention of ulcers, most studies have examined the effect of therapeutic shoes on ulcer recurrence. The majority have been positive, but not all. In a recent review of studies, assessing the association between therapeutic footwear and re-ulceration, risk ratios in all of them were below 1.0, suggesting some protective footwear benefit. In patients with severe foot deformity or prior toe or ray amputation, observational studies suggested a significant protective benefit from therapeutic shoes. However, this issue remains equivocal (23).

Patients should never trim their own callus or use callus removers. Callus should be removed regularly by sharp debridement.

Dry skin should be treated with an emollient such as E45 cream or Calmurid cream.

Oedema may complicate both the neuropathic and the neuroischaemic foot. Its main cause will be impaired cardiac and renal function, which should be treated. Oedema may rarely be secondary to neuropathy, and this will respond to ephedrine (initial dose 10 mg thrice daily and increasing up to 30–60 mg three times daily).

Patients with absent foot pulses should have their pressure indices measured to confirm ischaemia and to provide a baseline, so that subsequent deterioration can be detected. If the patient has rest pain or disabling claudication, or the pressure index is below 0.5, then severe ischaemia is present and the patient should be referred for a vascular opinion. All diabetic patients with evidence of peripheral vascular disease may benefit from antiplatelet agents: 75 mg aspirin daily, or clopidogrel 75 mg daily. Diabetic patients with peripheral vascular disease should also be given statin therapy. The Heart Protection Study has shown that simvastatin reduced the rate of major vascular events in a wide range of high-risk patients including those with peripheral arterial disease or diabetes (see Chapter 13.6.3). Patients should be encouraged to stop smoking and blood pressure should be tightly controlled. Patients who are above 55 years and have peripheral vascular disease should also benefit from an angiotensin-converting enzyme (ACE) inhibitor to prevent further vascular episodes (as indicated by the Heart Outcomes Prevention Evaluation (HOPE) and micro-HOPE study). ACE inhibitors protect the vasculature in diabetic patients who have evidence of atherosclerotic disease (see Chapter 13.5.3).

The above recommendations are also discussed in a consensus document which has been produced by the American Diabetes Association on the management of patients with diabetes and peripheral vascular disease (18).

Patients who have lost protective pain sensation need advice on how to protect their feet from mechanical, thermal, and chemical trauma. They should establish a habit of regular inspection of the feet so that problems can be detected quickly and they should always seek help early. Education and podiatry may improve knowledge of foot care and in some studies have led to improvements in the condition of the feet (24). A recent review of the role of patient education in preventing diabetic foot ulceration concluded that there was poor methodology and conflicting results (25). However, weak evidence suggests that education may have positive but short-lived effects on foot care and on the knowledge and behaviour of patients in the short term. Malone reported significantly reduced ulcer rates in high-risk patients. Patients who had ulcers or who had undergone amputation were randomized to a one-off hour-long class (intervention group n = 103 or usual care control n = 100) (26). The intervention group were shown slides of infected feet and amputations and given a simple checklist of foot care instructions. After 1 year, there were 8 ulcers and 7 amputations in the intervention compared with 26 ulcers and 21 amputation among controls (p = 0.005 and 0.025 for each outcome respectively). In an observer-blind RCT designed to determine the effect of a foot care education programme in the secondary prevention of foot ulcers, there was no evidence that this programme of targeted education was associated with clinical benefit in this population when compared with usual care (27).

The term Charcot foot refers to bone and joint destruction that occurs in the neuropathic foot. It is extremely important to have a high index of suspicion for Charcot’s osteoarthropathy and to encourage early presentation of the patient. This should be followed by a rapid diagnosis and early intervention, and with such a modern approach many Charcot feet can now be healed and deformity prevented (28).

Charcot’s osteoarthropathy can be divided into two phases:

The acute active phase includes those patients presenting early with normal X-ray and those presenting later with deformity and radiological changes of Charcot’s osteoarthropathy. The acute phase is characterized by unilateral erythema and oedema. The foot is at least 2°C hotter than the contralateral foot (Fig. 13.7.3). Cellulitis, gout and deep vein thrombosis may masquerade as a Charcot foot. Later on in the active clinical phase, the signs are swelling, warmth, and deformities, including the rocker bottom deformity and medial convexity of the foot as well as hind for deformition (Fig. 13.7.4). X-ray reveals fragmentation, fracture, new bone formation, subluxation, and dislocation. Deformity in a Charcot foot can predispose to ulceration, which may become infected and lead to osteomyelitis. This may be difficult to distinguish from neuropathic bone and joint changes, as on X-ray, bone scan or MRI, appearances may be similar. However, if the ulcer can be probed to bone, osteomyelitis is the more likely diagnosis.

Early diagnosis of the charcot foot is essential. Patients should have initially an X-ray examination which may be normal. It is then possible to proceed to two investigations. A technetium methylene diphosphonate bone scan will detect early evidence of bone damage and also locate the site of this damage. If the result of the bone scan is positive an MRI examination will describe in more detail the nature of the bony damage

The aim of treatment is immobilization in a plaster cast until there is no longer evidence on X-ray of continuing bone destruction, and the foot temperature is within 2°C of the contralateral foot. An alternative treatment is a prefabricated walking cast, such as the Aircast. Bisphosphonates may be helpful in the treatment of the Charcot foot but are not yet fully established therapy (29). An RCT of a single 90 mg pamidronate infusion has shown a significant reduction of the markers of bone turnover and skin temperature in treated compared with control subjects although the fall in skin temperature was similar in both groups. There was a similar finding in a recent study with alendronate (30). Calcitonin has also been used in the acute stage and there was a more rapid transition to the stable chronic phase in the treated group compared with controls (31).

The foot is no longer warm and red. There may still be oedema but the difference in skin temperature between the feet is less than 2°C. X-ray shows fracture healing, sclerosis, and bone remodelling. The patient can now progress from a total contact or Aircast to an orthotic walker, fitted with cradled moulded insoles. However, too rapid mobilization can be disastrous, resulting in further bone destruction. Extremely careful rehabilitation should be the rule. Finally, the patient may progress to bespoke footwear with moulded insoles.

The rocker bottom Charcot foot with plantar bony prominence is a site of very high pressure. Regular reduction of callus can prevent ulceration. If ulceration does occur, an exostectomy may be needed. The most serious complication of a Charcot foot is instability of the hind foot and ankle joint. This can lead to a flail ankle on which it is impossible to walk. Reconstructive surgery and arthrodesis, with a long-term ankle foot orthosis, have resulted in better outcome and limb salvage (32).

It is essential to differentiate between ulceration in the neuropathic foot from that in the neuroischaemic foot.

Neuropathic ulcers result from mechanical, thermal, or chemical injuries that are unperceived by the patient because of loss of pain sensation. The classical position is under the metatarsal heads, but they are more frequently found on the plantar aspects of the toes. Direct mechanical injuries may result from treading on sharp objects but the most frequent cause of ulceration is the repetitive mechanical forces of gait, which result in callosity formation, inflammatory autolysis and subkeratotic haematomas. Tissue necrosis occurs below the plaque of callus resulting in a small cavity filled with serous fluid which eventually breaks through to the surface with ulcer formation.

Ulceration in the neuroischaemic foot usually occurs on the margins of the foot and the first sign is a red mark which blisters and then develops into a shallow ulcer with a base of sparse pale granulations or yellowish closely adherent slough. Although ulcers occur on the medial surface of the first metatarsophalangeal joint and over the lateral aspect of the fifth metatarsophalangeal joint, the commonest sites are the apices of the toes and also beneath the nails if these are allowed to become overly thick.

Mechanical, wound, microbiological, vascular, and educational control are important.

In the neuropathic foot the aim is to redistribute plantar pressures, while in the neuroischaemic foot, it is to protect the vulnerable foot margins.

The ulcer is managed by off-loading, by which means there is a redistribution of load bearing on the plantar surface of the foot. The most efficient way is by the immediate application of some form of cast, including the removable cast walker such as the Aircast Walker, the Scotchcast boot, and the total contact cast. The Aircast is a removable bivalved cast. It is lined with four air cells, which can be inflated with a hand pump to ensure a close fit. The Scotchcast boot is a simple removable boot made of stockinet, felt, and fibreglass tape. The total contact cast is a close fitting plaster cast applied over minimum padding. It is useful in patients with recurrent foot ulceration. Nonremovable fibreglass casts have been also used. Recently, standard removable cast walkers have been modified by wrapping plaster around them to make them non-removable and to increase patient compliance. This is just as successful in healing diabetic foot ulcers as the total contact cast (33). If casting techniques are not available, accommodative sandals such as half shoes can off load the site of ulceration. However, a comparative study showed that total contact cast healed a higher proportion of wounds in a shorter time than the removable cast and the half shoe (34).

Heel ulcers can be off-loaded by a foam wedge or pressure relief ankle–foot orthosis (PRAFO), which suspends the heel to protect against further breakdown and allow the ulcer to drain. The PRAFO has a washable fleece liner with an aluminium and polypropylene adjustable frame and a non-slip walking neoprene base (35).

Ulcers in neuroischaemic feet are often associated with tight shoes which lead to frictional forces on the foot margins. A high street shoe that is sufficiently long, broad, and deep, and fastens with a lace or strap high on the foot, may be sufficient. Alternatively, a readymade stock shoe which is wide fitting may be suitable or a Scotchcast boot.

Wound control consists of three parts: debridement, dressings, and stimulation of wound healing.

Debridement is the most important part of wound control and is best carried out with a scalpel. It allows removal of callus and devitalized tissue and enables the true dimensions of the ulcer to be perceived. It reduces the bacterial load of the ulcer even in the absence of overt infection, restores chronic wounds to acute wounds and releases growth factors to aid the healing process. It also enables a deep swab to be taken for culture. The larvae of the green bottle fly are sometimes used to debride ulcers (36) especially in the neuroischaemic foot (37). Maggot debridement therapy has recently been shown to reduce short-term morbidity in non-ambulatory patients with diabetic foot wounds, decreasing antibiotic use and risk of amputation (38).

Although moist wound healing is generally carried out in the management of chronic wounds, the situation with diabetic foot ulcers is more complex. Indeed, a fine balance is needed to avoid maceration of tissues whilst on the other hand encouraging conditions that prevent eschar formation and assist cell migration within the wound (39).

There is no firm evidence that any dressing is better or worse than any other. A review that assessed 10 randomized trials and two controlled trials concluded that there was no evidence to support the effectiveness of any one type of protective dressing over any other for treating diabetic foot ulcers (40). Sterile, nonadherent dressings should cover all ulcers to protect them from trauma, absorb exudate, reduce infection, and promote healing. Wounds should be inspected frequently to ensure that problems or complications are detected quickly, especially in patients who lack protective pain sensation. The following dressing properties are essential for the diabetic foot: ease and speed of lifting, the ability to be walked on without suffering disintegration and good exudate control. Dressings should be lifted every day to ensure that problems or complications are detected quickly, especially in patients who lack protective pain sensation.

When ulcers do not respond to basic treatment, advanced products to stimulate wound healing may have to be put into practice (41). These are expensive treatments and should only be used when basic treatments have failed. Clinical decisions about when to use advanced or more experimental therapies may be based on healing rates. Studies in venous and diabetic ulcers suggest that advancement of more than 0.7 mm per week is 80% sensitive and specific for eventual wound closure. Advanced wound healing products include growth factors, skin substitutes, extracellular matrix protein, protease inhibitors, and vasoactive compounds.

Platelet-derived growth factor (PDGF; REGRANEX stimulates fibroblasts and other connective tissue cells located in the skin and is beneficial in enhancing wound healing processes of cell growth and repair. Four placebo-controlled trials of PDGF-BB in neuropathic ulcers have been carried out. The pivotal study of 382 patients demonstrated that Regranex gel (100 μg/g) healed 50% of chronic diabetic ulcers, which was significantly greater than the 35% healed with a placebo gel (42).

Dermagraft is an artificial human dermis manufactured through the process of tissue engineering. Human fibroblast cells obtained from neonatal foreskin are cultivated on a three-dimensional polyglactin scaffold. This results in a metabolically active dermal tissue with the structure of a papillary dermis of newborn skin. A multicentre RCT of 281 patients with neuropathic foot ulcers demonstrated that at 12 weeks, 50.8% of the Dermagraft

group experienced complete wound closure which was significantly greater than in the controls, of whom 31.7% healed (43). In another 12-week randomized study with living foreskin fibroblasts in a Vicryl mesh, incidence of complete wound closure of neuropathic foot ulcers was 30% in the active group and 18% in the control group (44).

Apligraf consists of a collagen gel seeded with fibroblasts and covered by a surface layer of keratinocytes (45). In another multicentre, 12-week RCT of 208 patients with neuropathic ulcers, the bilayered construct Apligraf led to complete wound closure in 56% of patients, compared with 38% in controls (p = 0.0042). There was a reduced the time to complete closure (65 days vs 90 days, p = 0.0026) (45). Bilayered cellular matrix (BCM, OrCel) is a porous collagen sponge containing co-cultured allogeneic keratinocytes and fibroblasts harvested from human neonatal foreskin. Patients with chronic, diabetic, neuropathic foot ulcers were randomized in a multicentre, parallel-group pilot RCT to receive either standard care (moist saline gauze cover for up to 12 weeks (n = 20)) or to active treatment (n = 20) of standard care plus an application of bilayered cellular matrix at each weekly visit for up to six total applications, followed by standard care alone for an additional 6 weeks or until complete healing. By 12 weeks, 7 of 20 wounds (35%) treated with BCM showed complete healing compared with 4 of 20 wounds (20%) treated with standard care (46).

There has also been considerable interest in the application of ECM proteins to accelerate healing of diabetic foot ulcers, including hyaluronic acid and collagen. Hyaff is an ester of hyaluronic acid, which is a major component of the extracellular matrix. Hyaff -based autologous grafts both dermal and epidermal have been used to treat two groups of diabetic foot ulcers: plantar ulcers and postoperative wounds located on the dorsum of the foot. Patients in both groups had offloading which was total contact casting for plantar ulcers and a rigid-sole shoe for dorsal ulcers. After 11 weeks there was no difference in the rate of healing in patients with plantar ulcers but in the dorsal ulcers, the autologous bioengineered graft showed increased rate of ulcer healing compared with control group (67% vs 31%, p = 0.049) (47). OASIS wound matrix (Cook Biotech, Lafayette, IN) is derived from the pig small intestine submucosa. This consists of a natural collagenous, three-dimensional extracellular matrix that acts as a framework for cytokines and cell adhesion molecules for tissue growth. In a comparative trial healing occurred in 49% of OASIS (reared diabetic foot ulcers) versus 28% treated with becaplermin p < 0.055 (48).

Promogran is a protease inhibitor that consists of oxidized regenerated cellulose and collagen. It inhibits proteases in the wound and protects endogenous growth factor. In a 12-week study of 184 patients, 37% of Promogran-treated patients healed compared with 28% of saline gauze treated patients, a non-significant difference (49).

The effect on dalteparin on ulcer outcome in diabetic patients with peripheral arterial occlusive disease has been investigated in a prospective, randomized, double-blind, placebo-controlled trial. A total of 87 patients were randomized to treatment with subcutaneous injection of 5000 units of dalteparin (n = 44) or an equivalent volume of physiological saline (n = 43) once daily until ulcer healing or for a maximum of 6 months. There was a better ulcer outcome (p = 0.042) and a greater number of patients healed with intact skin or decreased ulcer area ≥50% in the dalteparin group compared with the placebo group (50).

Some preliminary work suggests that topically applied autologous bone-marrow cultured cells can heal human chronic wounds that are recalcitrant to other treatments, including growth factors and bioengineered skin (51).

In this technique, the VAC pump applies gentle negative pressure to the ulcer through a tube and foam sponge which are applied to the ulcer over a dressing and sealed in place with a plastic film to create a vacuum. Exudate from the wound is sucked along the tube to a disposable collecting chamber. The negative pressure improves the vascularity and stimulates granulation of the wound. In the most recent multicentre RCT of 342 patients, a greater proportion of foot ulcers achieved complete ulcer closure with the VAC pump (73 of 169, 43.2%) than with standard care (48 of 166, 28.9%) within the 112-day active treatment phase (p = 0.007) (52).

Adjunctive systemic hyperbaric oxygen therapy has been shown to reduce the number of major amputations in ischaemic diabetic feet. Studies involving relatively small groups of patients have shown that hyperbaric oxygen accelerates the healing of ischaemic diabetic foot ulcers. It is reasonable to use hyperbaric oxygen as an adjunctive in severe or life-threatening wounds. In a systematic review evaluating published clinical evidence of the efficacy of hyperbaric oxygen therapy for wound healing and limb salvage it was concluded that there is a high level of evidence that it reduces risk of amputation in the diabetic foot ulcer population by promoting partial and full healing of problem wounds (53).

To speed healing of ulcers which have a clean granulating wound bed, a split skin graft may be harvested and applied to the ulcer. If chosen from within the distribution of sensory neuropathy, the donor site will be less painful.

In a systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes, no data were found to justify the use of any other topically applied product or dressing (54).

When the skin of the foot is broken, the patient is at great risk of infection as there is a clear portal of entry for invading bacteria. At every patient visit, the foot should be examined for local signs of infection, cellulitis or osteomyelitis. If found, antibiotic therapy is indicated. However, a uniformly agreed practice on the place of antibiotics in clinically noninfected ulcers has not been established. A controlled trial was conducted in patients with neuropathic ulcers who were randomized to oral amoxicillin plus clavulanic acid or matched placebo. At 20 days follow-up, there was no significant difference in outcome (55). However, in a further study, 32 patients with new foot ulcers were treated with oral antibiotics and 32 patients without antibiotics (56). In the group with no antibiotics, 15 patients developed clinical infection compared with none in the antibiotic group (p <0.001). Seven patients in the nonantibiotic group needed hospital admission and three patients came to amputation (one major and two minor). Seventeen patients healed in the nonantibiotic group compared with 27 in the antibiotic group (p <0.02). When the 15 patients in the nonantibiotic treated group who developed clinical infection were compared to the 17 who did not, there were significantly more ischaemic patients in the former. Furthermore, out of the 15 patients who became clinically infected, 11 had positive ulcer swabs at the start of the study compared with only 1 patient out of 17 in the non-infected group (p <0.01). From this study, it was concluded that diabetic patients with clean ulcers associated with peripheral vascular disease and positive ulcer swabs should be considered for early antibiotic treatment. Thus for the neuropathic ulcer, at the first visit, if there is no cellulitis, discharge or probing to bone, then debridement, cleansing with saline, application of dressing and daily inspections will suffice. For the neuroischaemic ulcer, at the initial visit, if the ulcer is superficial, oral amoxycillin 500 mg thrice daily and flucloxacillin 500 mg four times daily may be prescribed (or erythromycin 500 mg four times daily or cefadroxil 1 g twice daily if the patient is penicillin allergic). If the ulcer is deep, extending to the subcutaneous tissue, trimethoprim 200 mg twice daily and metronidazole 400 mg thrice daily may be added. The patient is reviewed, preferably at 1 week, together with the result of the ulcer swab. If the ulcer shows no sign of infection and the swab is negative, treatment is continued without antibiotics. However, in the cases of severe ischaemia (pressure index below 0.5), antibiotics may be prescribed until the ulcer is healed. If either the neuropathic or neuroischaemic ulcer has a positive swab, the patient may be treated with the appropriate antibiotic according to sensitivities until the repeat swab, taken at weekly intervals, is negative.

If an ulcer has not responded to optimum treatment within 4 weeks and ankle–brachial pressure index is less than 0.5 and the Doppler waveform is damped, or transcutaneous oxygen is less than 30 mmHg or toe pressure is less than 30 mmHg, then angiography is indicated. This can be performed by a Duplex examination, which combines the features of Doppler waveform analysis with ultrasound imaging to produce a picture of arterial flow dynamics and morphology. If the Duplex angiogram indicates stenoses or occlusions, antegrade transfemoral angiography can be performed, together with digital subtraction angiography and angioplasty can then be carried out. Angioplasty is a valuable treatment to improve arterial flow in the presence of ischaemic ulcers and is indicated for the treatment of isolated or multiple stenoses as well as short segment occlusions less than 10 cm in length. If lesions are too widespread for angioplasty, arterial bypass may be considered. However, this is a major, sometimes lengthy, operation, not without risk, and is more commonly reserved for the foot with severe tissue destruction which cannot be managed without the restoration of pulsatile blood flow.

Patients should be instructed on the principles of ulcer care stressing the importance of rest, footwear, regular dressings, and frequent observation for signs of infection.

Infection is caused by bacteria that invade the ulcer from the surrounding skin. Staphylococci and streptococci are the most common pathogens (35). However, infection due to Gram-negative and anaerobic organisms occur in approximately 50% of patients and infection is often polymicrobial. The most common manifestation is cellulitis. However, this stage covers a spectrum of presentations, ranging from local infection of the ulcer to spreading cellulitis, sloughing of soft tissue and finally, vascular compromise of the skin. This is seen as a blue discolouration, when there is an inadequate supply of oxygen to the soft tissues. This spectrum occurs in both neuropathic and neuroischaemic feet, although in the presence of severe neuropathy and ischaemia, signs of inflammation are often diminished. Infection of the soft tissues may be complicated by underlying osteomyelitis.

Local signs that an ulcer has become infected include colour change of the base of the lesion from healthy pink granulations to yellowish or grey tissue, purulent discharge, unpleasant smell and the development of sinuses with undermined edges or exposed bone. There may also be localized erythema, warmth, and swelling. In the neuroischaemic foot, it may be difficult to differentiate between the erythema of cellulitis and the redness of ischaemia. Although the redness of ischaemia is usually cold, it is not always so. It is most marked on dependency. The erythema of inflammation is warm.

When infection spreads there is widespread intense erythema and swelling. Lymphangitis, regional lymphadenitis, malaise, ‘flu-like’ symptoms, fever, and rigors may develop. In the presence of neuropathy, pain and throbbing are often absent, but, if present, usually indicate pus within the tissues. Palpation may reveal fluctuance, suggesting abscess formation, although discrete abscesses are relatively uncommon. Often there is a generalized sloughing of the ulcer and surrounding subcutaneous tissues, which liquefy and disintegrate. Subcutaneous gas may be detected by direct palpation of the foot and the diagnosis is confirmed by the appearance of gas in the soft tissue on the radiograph. Although clostridial organisms have previously been held responsible for this presentation, nonclostridial organisms are more frequently the offending pathogens. These include Bacteroides, Escherichia coli, and anaerobic streptococci. Only 50% of episodes of severe cellulitis will provoke a fever or leucocytosis. A substantial number of patients with a deep foot infection do not have severe symptoms and signs indicating the presence of deep infection. However, when increased body temperature or leucocytosis is present, it usually indicates substantial tissue damage.

The diagnosis of osteomyelitis is strongly suggested if a sterile probe, inserted into the ulcer, reaches bone. In the initial stages, plain X-ray may be normal. Localized loss of bone density and cortical outline may take at least 14 days to develop. Radionuclide bone scanning using technetium-99m diphosphonate is very sensitive but not specific for osteomyelitis. Gallium or indium scans may improve specificity but MRI may be most helpful in demonstrating loss of bony cortex. Chronic osteomyelitis of a toe has a swollen, red, sausage-like appearance (57).

Infection in the diabetic foot needs full multidisciplinary treatment. It is vital to achieve microbiological, wound, vascular, mechanical and educational control, for if infection is not controlled it can spread with alarming rapidity, causing extensive tissue necrosis and taking the foot into stage 5.

At presentation, the organisms responsible for infection cannot be predicted from the clinical appearance. The wound should be swabbed for culture and broad spectrum antibiotics prescribed without delay in all stage 4 patients. Deep swabs or tissue should be taken from the ulcer after initial debridement and further deep tissue samples taken for culture if the patient undergoes operative debridement. Ulcer swabs should be taken at every follow-up visit. Bacterial species not normally pathogenic can cause true infection in a diabetic foot when part of a mixed flora. As the diabetic patient has a poor immune response even bacteria regarded as skin commensals may cause severe tissue damage. This includes Gram-negative organisms such as Citrobacter, Serratia, Pseudomonas, and Acinetobacter. Gram-negative bacteria isolated from an ulcer swab should not be automatically regarded as insignificant. If there is fever and systemic toxicity, blood should be cultured. Close contact with the microbiologist is advised and it is helpful to do laboratory bench rounds to discuss management.

Infection in the neuroischaemic foot is often more serious than in the foot which has a good arterial blood supply; a positive ulcer swab in a neuroischaemic foot has serious implications, which influence antibiotic policy. Antibiotic treatment is discussed both as initial treatment and at follow-up: dosage should be determined by the level of renal function and serum levels when available. No single agent or combination has emerged as most effective. Lipsky et al. randomized 56 patients with an infected lesion to oral clindamycin or oral cephalexin in an outpatient setting and at 2 weeks, there was no difference in outcome (58). Grayson et al. randomized 93 patients to intravenous imipenem/cilastatin or IV ampicillin/sulbactam and, cure had been effected after 5 days in 58% and 60%, respectively (59). Recently the treatment of diabetic foot infections, with a focus on extapenem has been reviewed (60)

The regimen outlined in Box 13.7.1 has been developed in our practice, based on many years of treating the diabetic foot, with a significant reduction in amputations.

Diabetic foot infections are almost always more extensive than would appear from initial examination and surface appearance. Initial debridement is indicated to determine the true dimensions of the lesion and obtain samples for culture. Callus often overlies the ulcer and must be removed, to reveal the extent of the ulcer, and allow drainage of pus and removal of infected, sloughy tissue.

Cellulitis should respond to IV antibiotics, but the patient needs daily review to ensure that erythema is resolving. In severe episodes of cellulitis, the ulcer may be complicated by extensive infected subcutaneous soft tissue. At this point, the tissue is not frankly necrotic but has started to break down and liquefy. It is best for this tissue to be removed operatively. The definite indications for urgent surgical intervention are a large area of infected, sloughy tissue, localized fluctuance and expression of pus, crepitus with gas in the soft tissues on X-ray, and purplish discolouration of the skin, indicating subcutaneous necrosis.

The role of hyperbaric oxygen in the management of wounds is not yet established but two small RCTs found that systemic hyperbaric oxygen reduced the absolute risk of foot amputation in people with severely infected ulcers compared with routine care (53).

It is important to explore the possibility of revascularization in the infected neuroischaemic foot. Improvement of perfusion will not only help control infection but will also promote healing of wounds after operative debridement.

Patients should be on bed rest with heel protection using foam wedges.

The patient should be advised about the importance of rest in severe infection. If the patient has mild cellulitis and is treated at home he or she should understand the signs of advancing and progressing cellulitis so as to return early to clinic. Patient education provided after the management of acute foot complications decreases ulcer recurrences and major amputations.

This stage is characterized by the presence of necrosis. It is classified as either wet necrosis due to infection (Fig. 13.7.5) or dry necrosis due to ischaemia (Fig. 13.7.6). In wet necrosis, the tissues are grey or black, moist and often malodorous. Adjoining tissues are infected and pus may discharge from the ulcerated demarcation line between necrosis and viable tissue. Dry necrosis is hard, blackened, mummified tissue and there is usually a clean demarcation line between necrosis and viable tissue.

Necrosis presents in both the neuropathic and the neuroischaemic foot and the management is different.

In the neuropathic foot, necrosis is invariably wet, and is usually caused by infection complicating an ulcer, leading to a septic vasculitis of the digital and small arteries of the foot. The walls of these arteries are infiltrated by polymorphs leading to occlusion of the lumen by septic thrombus.

Necrosis can involve skin, subcutaneous and fascial layers. In the skin, it is easily evident but in the subcutaneous and fascial layers it is not so apparent. The bluish-black skin discolouration may be the ‘tip of an iceberg’ of deep necrosis in subcutaneous and fascial planes, so-called necrotizing fasciitis.

Both wet and dry necrosis can occur in the neuroischaemic foot. Wet necrosis is also caused by a septic vasculitis. However, reduced arterial perfusion to the foot resulting from atherosclerotic disease of the leg arteries is an important predisposing factor.

Dry necrosis is usually secondary to a severe reduction in arterial perfusion and occurs in three circumstances: severe chronic ischaemia, acute ischaemia, and emboli to the toes. In the first, a gradual but severe reduction in arterial perfusion results in vascular compromise of the skin, leading to blue toes which usually become necrotic unless the foot is revascularized. Acute ischaemia is usually caused either by thrombosis in the superficial femoral or popliteal artery or by emboli from proximal atherosclerotic plaques to the iliac, femoral, or popliteal arteries. It presents as a sudden onset of pain in the leg associated with pallor of the foot, quickly followed by mottling and slate-grey discolouration. Blue discolouration of the toes followed by necrosis can also occur. Paraesthesiae and ischaemic pain may be reduced or absent because of sensory neuropathy and this may delay presentation. Emboli to the digital circulation results in a bluish or purple discolouration of the toes which is quite well demarcated but which quickly proceeds to necrosis. If it escapes infection, the toe will dry out and mummify. Microemboli present with painful petechial lesions in the foot that do not blanch on pressure.

Digital necrosis is a relatively common problem in patients with advanced diabetic nephropathy. It may result from a septic neutrophilic vasculitis but can occur in the absence of infection. It may be precipitated by trauma.

Patients should be admitted for urgent management to achieve wound, microbiological, vascular, mechanical, and educational control.

Operative debridement is almost always indicated for wet gangrene. It is important to remove all necrotic tissue, down to bleeding tissue, and to open all sinuses. Deep necrotic tissue should be sent for culture. Although necrosis in the diabetic foot may not be associated with a definite collection of pus, the necrotic tissue still needs to be removed. In the neuropathic foot, with good arterial circulation, the wound always heals as long as infection is controlled. Wounds should not be sutured. Skin grafting may be the best way to accelerate healing of large tissue deficits. When there is extensive loss of tissue, modern reconstructive surgical techniques have proved useful.

In the neuroischaemic foot, wet necrosis should also be removed when it is associated with severe spreading sepsis. This should be done whether pus is present or not. In cases when the limb is not immediately threatened, and the necrosis is limited to one or two toes, it may be possible to control infection with intravenous antibiotics and proceed to urgent revascularization with digital or ray amputation at the same operation. Wounds in the neuroischaemic foot may be slow to heal even after revascularization, and wound care needs to continue as an outpatient procedure in the diabetic foot clinic. With patience, outcomes may be surprisingly good.

If revascularization is not possible for digital necrosis, then a decision must be made to either amputate the toe in the presence of ischaemia or allow the toe, if infection is controlled, to convert to dry necrosis and autoamputate. Recently, VAC therapy has facilitated healing of the post amputation wound especially when revascularization cannot be carried out.

Wound swabs and tissue specimens and deep tissue taken at operative debridement must be cultured. IV antibiotic therapy (amoxycillin, alternatively, piperacillin-tazobactam flucloxacillin, metronidazole, and ceftazidime) should be given. Erythromycin or vancomycin (dosage adjusted according to serum levels) may be used instead of amoxycillin and flucloxacillin. IV antibiotics can be replaced with oral therapy after operative debridement and when infection is controlled. When the wound is granulating well and swabs are negative then the antibiotics may be stopped.

When dry necrosis develops secondary to ischaemia, antibiotics should be prescribed if discharge is present or the wound swab is positive, and continued until there is no evidence of clinical or microbiological infection.

When toes have gone from wet to dry necrosis and are allowed to autoamputate, antibiotics should be stopped only if the necrosis is dry and mummified, the foot is entirely pain-free, and there is no discharge exuding from the demarcation line. Daily inspection is essential. Regular swabs should be sent for culture and antibiotics should be restarted if the demarcation line becomes moist or swabs grow organisms.

After operative debridement of wet necrosis, revascularization is often essential to heal the tissue deficit. In dry necrosis, which occurs in the background of severe macrovascular disease, revascularization is necessary to maintain the viability of the limb. When dry necrosis is secondary to emboli, a possible source should be sought. In some patients, increased perfusion following angioplasty may be useful. However, unless there is a very significant localized stenosis in iliac or femoral arteries, angioplasty rarely restores the pulsatile blood flow to the foot which is necessary to keep the limb viable in severe ischaemia or restore considerable tissue deficits secondary to necrosis. This is best achieved by arterial bypass.

Peripheral arterial disease is common in the tibial arteries, and distal bypass with autologous vein has become an established method of revascularization. A conduit is fashioned from either the femoral or popliteal artery down to a tibial artery in the lower leg, or the dorsalis pedis artery on the dorsum of the foot. Patency rates and limb salvage rates after revascularization do not differ between diabetic patients and nondiabetic patients, and an aggressive approach to such revascularization procedures should be promoted (61).

During the peri- and postoperative period, bed rest with elevation of the limb will relieve oedema and afford heel protection. After operative debridement in the neuroischaemic foot, nonweight-bearing is advised until the wound is healed especially when revascularization has not been possible. In the neuropathic foot, non-weight bearing is advisable initially and then off-loading of the healing postoperative wound may be achieved by casting. Autoamputation can take several months, during which the patient needs a wide fitting shoe to accommodate the dressings.

For patients in hospital, advice is similar to that given for severe cellulitis. For patients undergoing autoamputation at home, it is important to rest the foot and keep it dry and covered with a dressing and bandage. Patients should be advised to return to the clinic immediately if the foot becomes swollen, painful, develops an unpleasant smell or discharges pus.

This chapter has outlined a simple classification of the diabetic foot into the neuropathic and neuroischaemic foot and defined six specific stages in its natural history. It has described a simple plan of management for each stage which requires a well-organized, multidisciplinary approach that provides continuity of care between primary and secondary sectors (35).

Secondary care should be focused on a diabetic foot clinic to which rapid referrals should be possible. Such clinics have reported a reduction in amputations and should be available to all diabetic patients (4).