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Practical Diabetes Care, 3rd Ed., Excerpt #22: Diabetic Neuropathy Part 2 of 5

David Levy, MD, FRCP     

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Foot ulceration
The ulcerated, infected and possibly gangrenous foot is a common reason for hospital admission. Anatomically, diabetic foot ulceration is restricted to the region distal to the ankle; proximal lesions are more likely ischemic, vasculitic, venous, or to have another underlying cause. Most ulcers are predominantly neuropathic, but ischemia from large-vessel lower limb disease must be carefully excluded. Ulceration always has three components: neuropathy, tissue ischemia, and infection.

Tissue ischemia is due to large-vessel occlusion or local trauma. ‘Large vessel’ includes arteries as small as digital vessels, which can become involved in septic thrombophlebitis and lead to gangrene of one or more digits. True microangiopathic (capillary) involvement as seen in the retina and kidney does not occur in the foot, so the common clinical description of ‘small-vessel disease’, while aptly referring to vessels that are too small in calibre to be amenable to interventional radiology or arterial surgery, suggests a diffuse process that does not occur. Additional risk factors include deformity, callus and edema….

 Neuropathy
The usual sequence of events leading to ulceration can be summarized as follows:

  1. loss of protective sensation (pain and thermal sensation), leading to
  2. areas of maximum pressure in the foot exposed to repeated trauma, leading to
  3. callus at pressure sites, frequently the ball of the great toe or fifth toe (compare ischemic ulcers which often occur at acute pressure sites (e.g. tips of the toes, sides of the feet), resulting in
  4. ulceration (neuropathic ulcers are usually deep, clean and punched-out, the ulcer margin often being surrounded by callus).

Although any neuropathic patient can develop an ulcer, it characteristically occurs in tall overweight white men with type 2 diabetes. In the UK it is much less frequent in South Asians, the 75% lower risk of amputation partly accounted for by lower rates of smoking, peripheral vascular disease and of neuropathy itself [6]. However, in the USA, black and Hispanic patients have notably higher rates of lower-extremity disease, and social deprivation and lack of access to foot care are likely additional factors. Although amputations in type 1 patients have decreased over the past decade, and are very rare in the under thirties, there is a still an 80-fold increased risk compared with the non-diabetic population, and by age 65, men have a cumulative risk of about 20%, women 11%. Foot ulceration carries a 40% increased mortality compared with non-ulcer diabetes patients, and a twofold increased risk compared with non-diabetes, differences that are only partly explained by conventional cardiovascular and other risk factors, including depression [7]. Ulceration requires specialist podiatrist management, but even a superficial wound to a vulnerable foot needs vigilance since infections can spread very rapidly. This is a situation where prophylactic antibiotics are justified. Heel ulceration usually has causes in addition to neuropathy (e.g. ischemia, prolonged bed rest without adequate heel protection) but is always serious and can lead to rapidly progressing osteomyelitis of the calcaneum (Fig. 10.2).

Ischemia
If foot pulses are present, there is no significant peripheral vascular disease. However, pulses are often absent or questionably present, especially where there is oedema. Doppler studies are routinely used. If the pulse is monophasic, significant peripheral arterial disease is likely. As with ischemia generally in diabetes, symptoms are atypical: short proximal iliofemoral stenoses causing classical claudication are uncommon, and multivessel infrapopliteal disease is the usual culprit.

Ankle–brachial pressure index
This is the systolic pressure at the ankle (12-cm sphygmomanometer cuff just above the ankle and inflated until the posterior tibial pulse is obliterated) divided by the systolic pressure in the brachial artery measured conventionally. The ratio is usually over 1.0. Values below 0.6–0.7 signify severe occlusive vascular disease; where there is ulceration, patients should be referred for a vascular opinion, and will require more detailed Doppler studies and magnetic resonance angiography. Medial arterial calcification is widespread in diabetes, occurring in distal vessels of the foot and hand. It commonly leads to falsely elevated systolic foot pressures (though is also associated with systemic systolic hypertension) and an apparently normal ankle–brachial pressure index. A normal index in an ulcerated pulseless foot indicates critical limb ischemia that requires urgent investigation and treatment.

Infection (see Chapter 7)
Describe carefully what you see and seek permission to take a digital photograph, which will help communication. Although intended for research, the PEDIS system summarizes key elements of diabetic foot ulcers and is useful as a descriptive scheme [8].

  • Perfusion (presence of peripheral vascular disease)
  • Extent/size
  • Depth/tissue loss
  • Infection
  • Sensation (neuropathy).

Probe-to-bone test
It used to be thought that if a sterile probe hits bone at the base of an ulcer, osteomyelitis was likely. Another view has been proposed: it has low positive predictive value and its main benefit is excluding ostyeomyelitis if the test is negative [9]. The two contrasting views are still held, but positive or negative, it is a useful contributory test in a condition that is difficult to diagnose.

Radiography
Always request a plain foot radiograph for osteomyelitis. Help the radiologists by describing the site of the ulcer. X-ray changes are unlikely within 2 weeks of the onset of osteomyelitis, cortical changes are difficult to distinguish from degenerative joint disease, and abnormalities around the joint spaces can also be found in Charcot neuroarthropathy (see below). Unsuspected fractures, especially involving the metatarsals, are commonly found, and may be precipitants of Charcot joints. MRI (see Chapter 7) is increasingly helpful in detecting the early signs of osteomyelitis and, importantly, its resolution with treatment. Routine blood tests should include CRP, which can help distinguish no infection from mild infection (see Chapter 7); however, where there is no systemic upset, CRP may be quite low, and it is not clear whether antibiotic treatment can be guided by it more reliably than using radiography and clinical examination.

Management
Podiatrists with a special interest in diabetes are the key professionals, and should always be involved. Deep infections, abscesses and spreading infection associated with tissue necrosis require early liaison with surgeons.

The mainstay of treatment is relieving pressure from the ulcer, and complete bed rest will heal most ulcers in 6–12 weeks. In practice this is rarely possible, and total contact casting, where available, allows patients to remain mobile. The technique is simple, but requires fully trained personnel who understand that the methods, precautions and aims differ from those used in fracture management. Poorly applied casts can themselves cause ulceration in these insensitive feet. Casts require changing at least weekly. Off-the-shelf removable casts (e.g. Aircast) are useful where individual casting is not available, or if precautionary immobilization pending further tests or specialist evaluation is required.

Ulcers require meticulous care, including frequent débridement. Adherent fibrinous material at the base of ulcers can delay healing and needs sharp removal with a scalpel. Dressings are important, but should be kept simple where possible. Ulcers should be dressed daily after thorough cleaning with sterile saline. Practice varies widely, but a simple technique uses (i) an antimicrobial dressing such as povidone iodine (Inadine) or nanocrystalline silver (Acticoat), or a simple non-adherent dressing, covered by (ii) a thick protective layer of non-adherent foam (e.g. Allevyn), with (iii) a firmly but not tightly applied conforming stretch bandage. Use minimal amounts of tape, and wherever possible avoid applying it to skin. Many patients have thin skin, and heavily applied tape left for several days can cause skin damage if not carefully removed.

Special dressings designed to liquefy or absorb exudate are widely used and each has their advocates, but the liquefied products are sometimes not easy to remove and can obscure the appearance of the ulcer base. Trial evidence is woefully inadequate here, but it seems that regular simple cleaning and dressing of ulcers is more important than the type of dressing used.

Vascular interventions

Proximal iliofemoral lesions can easily be managed with angioplasty, and bypass surgery is almost never required. Distal disease is more difficult, because of involvement of multiple smaller-calibre vessels, especially those below the knee and and in the ankle and foot. Improving techniques in endoluminal angioplasty and subintimal angioplasty (for total occlusions) may also be improving the outcome in critical limb ischemia, but RCTs are needed. Outcomes for distal reconstructive surgery in diabetes are worse than in non-diabetic subjects, with a 50% increased risk at 2 years of death or amputation, even when adjusted for factors such as renal and cardiac disease. Intensive multidisciplinary input is likely to improve outcomes in patients where, by definition, risk factors have not been addressed in the past [10].

Adjunctive treatments for non-healing ulcers
Larval treatment
Where there is a lot of adherent exudate, sterile larval (maggot) treatment can give impressive results, especially when there is MRSA infection [11]. This treatment is more readily accepted by patients than clinical staff.

Growth factors
In vogue a few years ago, recombinant human platelet-derived growth factor (becaplermin 0.01% gel) may accelerate healing of chronic ulcers not responding to standard treatment. Extended use may increase risk of malignancy.

Tissue-engineered skin
Preparations of dermis/epidermis are available, for example Apligraf, living bilayered cell therapy secreting growth factors found in normal skin, and Dermagraft, a fibroblast-derived dermal substitute. As with all studies in diabetic foot ulcers, sufficiently powerful trials are difficult to carry out, but both these agents may help heal full-thickness diabetic foot ulcers more quickly than standard treatment alone.

Hyperbaric oxygen treatment

Systemic hyperbaric oxygen (HBO) is widely used in the USA and Europe, but is available in only a few centres in the UK. HBO promotes wound healing through several mechanisms, including improved oxidative killing of bacteria, and it is speculated that it may increase production of bone marrow-derived endothelial progenitor cells. HBO significantly reduces the risk of major (though not minor) amputations and in an RCT (using hyperbaric air as placebo), over 50% of ulcers remained healed at a year, compared with 30% treated with air [12]. There is reasonable evidence for the use of HBO in refractory osteomyelitis, and arterial ulcers and those associated with calciphylaxis may also benefit. The level of hyperoxygenation achieved at the wound or ulcer site detected by transcutaneous oximetry correlates reasonably well with positive outcomes of HBO. Case selection is continually improving, and where available the advice of a hyperbaric team is valuable.

Negative-pressure wound therapy (e.g. vacuum-assisted closure therapy system)
Widely used in general surgery, negative-pressure wound therapy increases the likelihood of wound healing, but is designed for large ulcers and large soft-tissue deficits, especially after partial foot amputations.

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David Levy, MD, FRCP, Consultant Physician, Gillian Hanson Centre, Whipps Cross University Hospital; Honorary Senior Lecturer
Queen Mary University of London London, UK

This edition first published 2011, © 2011 by David Levy. 1st edition 1998 (Greenwich Medical Media/Cambridge University Press) 2nd edition 2006 (Altman Publications)