NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

School of Health and Related Research (ScHARR), University of Sheffield. Clinical Guidelines for Type 2 Diabetes: Prevention and Management of Foot Problems [Internet]. Sheffield (UK): University of Sheffield; 2003. (NICE Clinical Guidelines, No. 10.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Clinical Guidelines for Type 2 Diabetes

Clinical Guidelines for Type 2 Diabetes: Prevention and Management of Foot Problems [Internet].

Show details

7Care of people with foot ulcers

Caring for people with foot ulcers

Recommendations

For a new foot ulcer, urgent (within 24 hours) assessment by an appropriately trained health professional should be arranged. (D)

Ongoing care of an individual with an ulcerated foot should be undertaken without delay by a multidisciplinary foot care team. (D)

The multidisciplinary foot care team should comprise highly trained specialist podiatrists and orthotists, nurses with training in dressing of diabetic foot wounds and diabetologists with expertise in lower limb complications. They should have unhindered access to suites for managing major wounds, urgent inpatient facilities, antibiotic administration, community nursing, microbiology diagnostic and advisory services, orthopaedic/podiatric surgery, vascular surgery, radiology and orthotics. (D)

Patients who may benefit from re-vascularisation should be referred promptly. (D)

Introduction

The morbidity associated with diabetic foot ulcers is considerable. Apelqvist and Agardh (1992) report a prospective study of 314 consecutive patients with diabetes with foot ulcers referred to a multi-disciplinary foot team in a university hospital. Healing was affected in 62% of patients, amputation in 25% of patients, and 13% of patients died with unhealed ulcers. The traditional (although inadequately evaluated) approach to diabetic foot ulcers includes debridement, and antibiotic treatment. In addition, new treatments include the proposed use of hyperbaric oxygen therapy, growth factors, ketanserin, cultured human dermis and total contact casting.

Meijer et al (2001) reported significant differences in the perceived quality of life in patients with diabetes and foot ulcers and those without foot ulcers. Using the SF36 on 38 people with diabetes who had been hospitalised, 14 for diabetic foot ulcers and 24, who had no foot problems but were admitted for diabetic dysregulation. Those patients with foot ulcer problems had poorer scores for physical functioning (p<0.001), social functioning (p<0.05), physical roles (p<0.001) and health experience (p<0.05). There were no differences between the two groups in emotional role scores, mental health, vitality and pain.

Trials of ulcerated feet commonly class ulcer severity according to the Wagner system:

Grade 0intact skin
Grade Isuperficial ulcer
Grade IIdeep ulcer
Grade IIIosteomyelitis and/or deep abscess
Grade IVforefoot gangrene
Grade Vhindfoot gangrene(Wagner 1983).

Trials reported in the following sections are characterised (with a few notable exceptions) by small patient numbers, a lack of common approach, inadequate reporting of methods and lack of repetition of any one method. To illustrate the point, suppose a 50% improvement in an outcome is considered worthwhile (i.e. a new treatment achieving 60% success at some endpoint instead of 40%). To adequately power a trial to detect this improvement (i.e. an 80% chance of correctly detecting a real effect with a 5% chance of incorrectly rejecting a null hypothesis of no effect) would require randomising approximately 100 patients to each treatment. Seldom in any of the trials reported in the following sections is a rationale given for sample size or for the difference between treatments investigators expected to find. Few of the trials randomised 50 patients to each treatment arm.

Many trials have the characteristics of pilot studies and thus were never intended to inform treatment policy but to inform areas for further research. Most trials are generally industry funded. The value of treatments can sometimes be misrepresented due to publication bias.

A further problem in interpreting these trials arises from the unsatisfactory classification and enrolment of patients into studies. Treatments may be expected to achieve variable effects for cellulitis of different extent and appearance, e.g. localised cellulitis around an ulcer, ulcers with relatively little cellulitis but underlying osteomyelitis, and those with considerable cellulitis. It may be valuable, when trying to understand the influence of a particular treatment on disease, to conduct studies on much better defined ulcer types.

Most aspects of the treatment of diabetic foot ulcers appear in need of a comprehensive and coordinated trial programme.

Comment

The guideline development group also felt that good overall glycaemic control was likely to assist wound healing in people with diabetic foot ulcers.

The ulcerated foot references (with evidence grades where appropriate)

Antibiotic treatment for diabetic foot complications

Recommendation

Patients with non-healing or progressive ulcers with clinical signs of active infection (redness, pain, swelling or discharge) should receive intensive, systemic antibiotic therapy. (C)

Evidence statements

There is inadequate evidence to address the relative effectiveness of different antibiotic regimens for treating serious diabetic foot infections (spreading cellulitis and osteomyelitis). (Ib)

There is inadequate evidence to demonstrate whether antibiotics are more effective than placebo and standard wound care in healing superficial or skin deep ulcers. (Ib)

Introduction

Polymicrobial, mixed aerobic/anaerobic infections are common in diabetic foot wounds, suggesting the use of antibiotics with a broad spectrum of activity and low rate of toxic reactions in patients with diabetes who are often nephrologically impaired. Trials generally differentiate between infections uncomplicated by deep soft tissue involvement and ulcers which have become colonised by invasive penetrating infection (cellulitis), or where osteomyelitis is present. Only 4 randomised trials have assessed the efficacy of antibiotic therapy specifically in patients with diabetes with infected ulcers (for details see Appendix 7), although a number of other studies have addressed broader groups of patients. Two of the 4 trials addressed the treatment of non-limb threatening infection, 1 addressed non-limb-threatening but treatment-resistant infection, and 1 concerned treatment of invasive infection (cellulitis or osteomyelitis). An ongoing trial may provide more substantive evidence about the role of antibiotic treatments in foot ulcer care.

Evidence

Chantelau et al (1996) randomised 44 patients to evaluate the efficacy of oral amoxicillin plus clavulanic acid against matched placebo. Patients had purely neuropathic ulcers of severity 1A (superficial with or without cellulitis) to 2A (deeper, reaching to joints and tendons) on the Wagner and Harkless classification (a modified Wagner scale). At 20 days follow-up, no significant differences were apparent between treatment and placebo in number of ulcers healed or mean reduction in ulcer size. Completely closed lesions occurred in 32% of patients receiving antibiotics and 50% of patients receiving placebo. Mean reduction in ulcer radius was 0.27 mm2/day (95% C.I: 0.15–0.39) in the antibiotic group and 0.41 mm2/day (95% C.I: 0.21–0.61) in the placebo group.

Lipsky et al (1996) randomised 88 patients to intravenous ofloxacin (400 mg) followed by oral ofloxacin (400 mg, 12 hourly) or intravenous ampicillin (1–2 g) sulbactam (0.5–1 g) followed by amoxicillin (500 mg) clavulanate (125 g, 8 hourly). Enrolled patients were hospitalised for soft tissue infections which had not responded to outpatient management but which were not limb threatening. Therapy lasted between 14 and 28 days according to clinical need. In the ofloxacin group, cure occurred in 49% of patients, and improvement in 36%. In the amino-penicillin group, 56% of patients were cured and 27% were improved. There were no statistical differences in the efficacy of the 2 therapies.

Grayson et al (1994) randomised 93 patients with diabetes to imipenem/cilastatin (500 mg every 6 hours) and ampicillin/sulbactam (3 g every 6 hours). Patients had severe infections of the lower extremities, threatening to the lower limbs (the presence of cellulitis with or without ulceration or purulent discharge). Osteomyelitis was diagnosed in 59 (63%) patients. For the first 5 days treatment followed randomisation, but following this period treatment could be adaptive in the instance of inadequate response. There were no significant differences between the 2 treatment groups in terms of clinical improvement at 5 days, or cure at the end of definitive treatment. In the ampicillin/sulbactam group 81% of episodes of infection were cured (mean length of therapy 13±6.5 days), while in the imipenem/cilastatin group, 85% of episodes of infection were cured (mean length of therapy 15±8.6 days).

Lipsky et al (1990) randomised 56 patients, with an infected lesion regardless of type or duration, to oral clindamycin or oral cephalexin in an outpatient setting with assessment after 2 weeks. No statistically significant differences were found between treatments either for response to infection or for wound healing. With clindamycin 78% were cured of infection and 40% of wounds healed during follow-up, for cephalexin 72% were cured of infection and 33% of wounds healed.

A number of other randomised trials of intravenously administered antibiotics have been conducted on groups of patients, including a proportion with diabetic foot ulcer. Hughes and colleagues (1987) compared ceftizoxime and cefoxitin for lower extremity infections in 63 patients with diabetes or peripheral vascular disease. File and Tan (1983) compared amdinocillin plus cefoxitin and cefoxitin alone in 45 patients with bacterial soft tissue infections. Tan and colleagues (1993) compared piperacillin-tazobactam and ticarcillin-clavulanate in the treatment of complicated skin infections requiring hospitalisation. Bradsher and Snow (1984) compared ceftriaxone and cefazolin in 84 hospitalised patients with skin and soft tissue infections. No differences in clinical response were found in any of these studies (at p<0.05).

The two outpatient trials for non-invasive infections found no difference between antibiotic regimens and no improvement relative to placebo. It is uncertain whether all antibiotics are ineffective in this group of patients or just the particular regimen used by Chantelau and colleagues. The outlook for patients with cellulitis is not encouraging. Despite the apparent treatment success reported by Grayson and colleagues (1994), 66% of patients had an amputation affecting part of the lower limb in the following year, although the operation was foot sparing in most cases.

Cost effectiveness

McKinnon et al (1997) reports a cost-effectiveness study of ampicillin/sulbactam (A/S) versus imipenem/cilastatin (I/C) for the treatment of limb-threatening foot infections in patients with diabetes (type not stated). The study was supported by Pfizer. Analysis was based on an RCT although the economic data were collected retrospectively, see Grayson et al. (1994) for details of the trial. Ninety of 93 patients had data collected for use in the economic evaluation.

It is not clear from the paper the measure of outcome that was intended for use in cost effectiveness analysis. However, it is stated later in the paper that since “success rates were identical between each treatment group” (p.59) no cost-effectiveness ratios are required. No statistically significant difference in terms of antibiotic related length of stay and total length of stay were identified.

Resource use data were collected on drug use, treatment of adverse events and hospitalisations. These were costed in 1994 US dollars. Resource use that was not included includes items such as laboratory tests, or intensive care use. It is claimed that the average cost of a hospitalisation includes “unaccounted resources”. However, this is not an acceptable method for identifying differential resource use between intervention groups. No discounting was applied since the model is only short term.

It is also stated that the perspective of the CEA is the institution and therefore it is appropriate to exclude physician charges and outpatient visits.

Base case results indicate that A/S costs less than I/S and a limited number of one-way sensitivity analyses do not change that conclusion.

The study however, is not a cost-effectiveness study as claimed. It is a partial cost or cost-minimisation study. It is poorly conducted and is of little relevance to the UK NHS.

Eckman et al (1995) is a US cost-effectiveness study that compares a range of approaches to the diagnosis and treatment of patients with Type 2 diabetes with foot infections and suspected osteomyelitis. The options compared are

  1. treatment for presumed soft-tissue infection
  2. culture-guided empiric treatment for presumed osteopmyelitis
  3. 71 combinations of diagnostic tests preceding antibiotic therapy for osteomyelitis
  4. 71 combinations of tests preceding amputation
  5. immediate amputation

Analysis is based on a Markov model, run over the lifetime of patients, with data taken from existing literature. The base case analysis involved a 56 year old man who had had Type 2 diabetes. Results are presented in terms of cost per QALY with a discount rate applied to costs and benfits of both 0% and 5%.

QALYs are based on “the judgements of experienced physicians.” It is also stated that the SF-36 Physical Functioning Index is used for quality of lfie adjustments in the sensitivity analysis. However, insufficient details are provided of this procedure and since the SF-36 does not provide a measure of preference the validity of this method is questionable.

Inpatient cost data are derived from Medicare records for seven Boston teaching hospitals. Other relevant cost items are derived from a variety of accounting systems the validity of which is difficult to judge.

Results are not presented in an easily interpretable form, since total costs and benefits are presented separately. However, the interventions are grouped according to these costs and benefits. Those options grouped as “Tier 1” dominate those in other tiers. Within that tier the differences between strategies are very slight and, although some sensitivity analyses are performed, it is difficult to be confident that one option is preferable to another. Furthermore, given the US setting and the source of the QALY data, it is unlikely that the case for distinguishing between options within tier 1 at least could be made in the UK NHS.

Comment

Intravenous antibiotics were agreed by the guideline development group to be appropriate care in patients with cellulitis, although adequate evidence from placebo-controlled or comparative trials is lacking.

Antibiotic treatment for diabetic foot complications references (with evidence grades where appropriate)

Dressings and topical agents for foot ulcers

Recommendations

In the absence of strong evidence of clinical or cost effectiveness, health care professionals should use wound dressings that best match clinical experience, patient preference, and the site of the wound and consider the cost of dressings. (D)

Wounds should be closely monitored and dressings changed regularly. (D)

Evidence statement

There is insufficient evidence to support the effectiveness of any type of protective dressing, or topical application, over any other for treating diabetic foot ulcers. (Ib)

Introduction

In many cases, foot ulcers in people with diabetes are not infected and protective bandaging is appropriate. A number of characteristics for a good dressing have been proposed (Foster et al, 1994). It should perform well in the closed environment of the shoe; not take up too much space; be capable of absorbing large quantities of exudate without plugging the wound and preventing drainage; withstand the pressures and shear forces of walking without failing; not cause side effects; and be easily lifted or removed for regular inspection without adversely affecting the wound. Whilst simple gauze dressings are often employed by clinicians, there are newer forms of dressing available. Alginate, foam, hydrogel and hydrocolloid dressings have been designed to absorb wound exudate and control the level of wound hydration.

An ongoing HTA multicentre trial, which is due to report in about 3 years time, may provide more information about the role that different dressings have in the care of foot ulcers. NICE guidelines on wound care management are also being developed and may be of use in this area of care (see Appendix 23).

Evidence

The trials identified can broadly be grouped into trials comparing newer dressings or gels with gauze dressings and trials comparing the newer dressings with one another. From a meta-analysis of control groups (six used saline gauze, two used gel, and one used both), in nine studies that looked at healing of diabetic foot ulcers, Margolis et al (1999), concluded that after 20 weeks of good wound care 31% of diabetic neuropathic ulcers heal. After 12 weeks of good care, 24% of neuropathic ulcers have attained complete healing.

Dressings

Jensen et al (1998) compared two moist wound healing protocols for patients with non-infected foot ulcers 1 cm in diameter. All patients in a Diabetic Foot and Wound Centre, Denver, USA were treated initially with debridement to remove nonviable tissue in and around the ulcer and were also given custom-made sandals to redistribute plantar pressures, reduce trauma, and prevent weight-bearing over the ulcer. Patients were then randomised to sixteen weeks with a 1/8 to ¼-inch layer Carrasyn® Hydrogel Wound Dressing containing Acemannan hydrogel (n=14) or a standard wet-to-moist saline dressing (control group, n=17). Other care and bandaging was identical in the two groups. Dressings were changed daily. Outcomes were time to ulcer closure and wound area. Wound closure rate was greater (84.6%) in the treatment group than in the control group (46.1%, p<0.05) and quicker, 10.3 weeks in the treatment group compared with 11.69 weeks in the control group (not significant). Patients in the control group also had more adverse events ( 4 vs 2) and patients dropping out of the study (4 vs 1).

Blackman et al (1994) randomised 18 people with diabetes, with partial or full thickness foot ulcers of Wagner stage I or II, to a semipermeable polymeric membrane dressing or a conventional wet-to-dry saline gauze dressing with primary analysis after 2 months. The polymeric dressing combined a urethane prepolymer with water soluble and hydrophilic components and additionally glycerol as a bacteriostatic agent and a non-ionic surfactant as a cleansing agent. At 2 months follow-up the polymeric dressing group ulcer size compared to baseline was significantly smaller than with gauze dressing (35 ± 16% vs. 105 ± 26%) (p<0.03). Complete healing occurred in 3 ulcers (27%) in the polymeric dressing group and none in the gauze.

Ahroni et al (1993) randomised 39 people with diabetes with superficial foot ulcers, in an American outpatient setting, to a calcium alginate dressing or to dry sterile gauze. After 4 weeks, there were no significant differences between the 2 groups in number of ulcers healed (alginate: 25%; gauze 37% p=0.65). There was also no significant difference between the rate of healing per day of the area of ulcer (p>0.99) or by linear measurement (p=0.87).

Two new studies evaluated the impact of a collagen wound dressing on the healing or reduction in wound area of foot ulcers in people with diabetes (Donaghue et al 1998, Veves et al 2002). Collagen is a structural protein component of connective tissue and may serve as a mechanical support and this lattice may be a stimulus to the migration of fibroblasts and to promote metabolic activity of granulation material and fibronectin. Donaghue et al’s study was in a single centre in Boston, USA. Seventy-five patients with foot ulcers 1 cm2 were assigned randomly, in a 2:1 ratio to have a collagen-alginate wound dressing (FIBRACOL, Johnson and Johnson) (n=50) or conventional treatment with saline moistened gauze (n=25) and followed up for eight weeks. No statistically significant differences were found in wound area reduction or in complete healing although multivariate analysis indicated that the overall treatment effect on ulcer areas was significantly in favour of the collagen-alginate dressing compared with the gauze dressing, when ulcer duration was included in the analysis (p=0.0401). More study dropouts occurred in the control group compared with the treatment group (8 vs 6) although the analysis was on the basis of intention to treat. Limited power could explain some of the non-significant differences in this study but similar findings were reported in the larger study by Veves et al which took place in 11 centres and involved 276 subjects with diabetes and similar ulcer characteristics, foot ulcers ≥1 cm2. Treatment was a primary dressing of Promogran (collagen: oxidised regenerated collagen, 55:45) (Johnson and Johnson) or an isotonic sodium chloride solution-moistened gauze in the control group, with additional bandaging similar in the two groups. Dressings were changed when clinically necessary, off-loading was used with all subjects, and patients were followed up weekly for 12 weeks. No significant differences were seen between the two groups for complete wound closure, percentage reduction in ulcer size, or time to complete healing. There were also no differences in adverse events or dropouts between the two groups. Thus collagen dressings do not appear to promote better ulcer healing than saline-moistened dressings.

Donaghue et al (1996) randomised 75 patients (in a 2:1 ratio) to a combination collagen-alginate dressing or regular gauze moistened in saline with a follow up period of 8 weeks. No statistically significant differences were found between the groups in any outcome: complete healing, percentage with 50% or greater reduction in wound size, mean time to 50% healing, mean reduction in wound size. Analysis is based on patients completing treatment; significantly more patients withdrew from the gauze dressing arm than the collagen-alginate arm (32% vs. 12%).

Di Mauro et al (1991) randomised 20 NIDDM patients to a lyophilised type I collagen dressing or hyaluric acid medicated gauze. Patients had glycaemia (>250 mg%; also HbA1>10%) and were subject to strict alimentary regimen and insulin therapy. There was a significant difference in the mean time to wound healing with the collagen dressing compared to the medicated gauze (mean time 32.4 days vs. 49.0 days, p=0.001).

Foster et al (1994) randomised 30 patients with foot ulcers to a polyurethane foam dressing or a calcium-sodium alginate dressing, with treatment over an 8-week period or until the ulcer was healed. Patients were over 18 years of age, had uninfected, non-sloughy or non-necrotic foot ulcers, were prescribed preventative antibiotics, and were seen weekly at a clinic where ulcers were debrided and progress monitored. No significant differences in ulcer healing were apparent at 8 weeks (foam 60%; alginate 53%).

Baker et al (unpublished) randomised 20 patients to a polyurethane foam dressing or a calcium alginate dressing with treatment and follow-up over a 12-week period. Patients had palpable pedal pulses with no history of intermittent claudication or pain at rest. Ulcer healing at 10 weeks was significantly better with the foam dressing group (90% vs. 44%). Similarly, median time to healing was 28 days with the foam dressing and 84 days with the alginate dressing.

Clever and Dreyer (1996) randomised 40 patients to 1 of 2 polyurethane gel dressings in addition to standard care. Patients had pure, superficial neuropathic ulcers, size 1–5 cm in diameter. There were no differences between the 2 groups in terms of time to healing, reduction in wound size at 4 weeks, or frequency of change of dressing.

The effectiveness of a hydrophilic dressing made of carboxyl-methyl-cellulose (Aquacel®, Convatec) for foot ulcers was investigated by Piaggesi et al (2001). However this was another small study with only ten patients in each of two groups. In the control group, ulcers were treated with a saline-moistened gauze, renewed twice a day with saline to prevent dehydration. Patients were followed up weekly for eight weeks in the clinic and then to complete re-epithelialisation. Dressings were changed at home every second or third day for the treatment group and every one to two days in the control group. Healing time in the treatment group was shorter than that in the control group (127±46 vs 234±61 days, p<0.001). Other variables chosen to monitor the development of the lesion healing process also scored significantly better in the treatment group. There were no differences in adverse events or dropouts between the two groups.

Finally, in an interim analysis of 20 patients, Alvarez et al (2003) report the outcome of a randomised open label trial examining the efficacy of a non-contact normothermic wound therapy for healing diabetic neuropathic foot ulcers. The non-contact thermal wound care system maintains the wound environment at a skin surface temperature of 37ºC using a double layer polyurethane film and a heating element. Warming treatments were performed three times daily, for one hour each time, with a minimum of one hour between treatments until the wound healed or for a maximum of 12 weeks. The placebo group received standard wound care of weekly debridement, moist saline gauze dressings changed daily and elastic stockinet. Both groups received initial debridement, were fitted with therapeutic healing sandals and told to avoid weight-bearing activity. Differences in healing rates between the treatment and placebo groups were not significant (p>0.05 at weeks 2,4,6,8,10 and 12) although the mean percent wound closure was higher in the treatment group at each follow-up point. There was also no difference in the numbers of ulcers healed at six (p=0.11) or 12 weeks (p=0.069). This is an interim analysis of an ongoing trial, but it is not clear whether the authors intend to recruit more participants or to follow-up those already recruited for a longer period.

Cost effectiveness

Ghatenakar et al. (2002) undertook a cost-effectiveness study. It compares Promogran®, a dressing (collagen and oxidised regenerated cellulose matrix), plus “good wound care” (GWC), defined as sharp debridement (if necessary) and wound cleansing, against GWC alone for patients with non-superficial diabetic foot ulcers in four countries: France, Germany, Switzerland and the UK. The basis of the cost-effectiveness analysis is a trial which showed non statistically significant benefits in terms of 12 week healing rates.

A Markov model based on different Wagner grades of ulcer severity plus death was developed and run over a one year period with monthly transitions. Extrapolating still further than the original trial was not considered feasible. Transition probabilities were derived from a prospective study of US patients (Amato et al. 1999) and healing rates from the RCT applied to the uninfected health state. Costs were derived from existing literature and from physician interviews combined with country specific unit costs. No further details of the costing methodology are supplied but readers are referred to Ghatnekar et al. (2001). Results are presented in 2000 Euros. A 5% discount factor is claimed to be applied but this was only a one year model.

It is unclear why the frequency of changes of Promogran® was below that suggested by the manufacturers.

Base case results show that Promogran® dominates GWC in all four countries, generating savings of between €169 and €1079 per patient. A small number of sensitivity analyses are performed, the majority of which result in even greater cost savings.

The whole difference between the intervention and standard care is generated by non statistically significant differences in healing rates from one RCT and are therefore highly uncertain.

Ointments and gels

Apelqvist and Tennvall (1996) evaluated topical treatment with cadexomer iodine ointment dressing in addition to standard treatment. Forty-one patients were randomised with ulcers of Wagner stage I or II and surface area greater than 1 cm2. After 12 weeks there were no significant clinical differences between the groups in completely healed ulcers or clinical improvement. An analysis of costs was conducted including materials and drugs, staff and transportation (of patients and health professionals) which purported to show significant cost savings due to reduced staff costs and transportation. The cost savings arise predominantly because of the more frequent need for dressing changes in the standard care group. However, substantially more patients were withdrawn from the ointment group due to deteriorating disease or protocol violation (removing high cost patients) making it uncertain that patients evaluated are comparable. It is unclear whether dressing changes occurred on the basis of the protocol or of need, or how need was assessed.

Mulder et al (1994) evaluated the use of a topical gel: a GHK-Cu complex (glycyl-L-histidyl-L-lysine peptide, copper complex). Patients with neuropathic full thickness ulcers were randomised into 4 groups. Following immediately after debridement, 2 groups were randomised to GHK-Cu gel or vehicle. Significantly better plantar ulcer healing was observed in the GHK-Cu gel group (median area percentage wound closure, 98.5% vs. 60.8% p<0.05), although most benefit was seen in patients with large ulcers who did not respond well to the control treatment. Two further groups were randomised to different concentrations of GHK-Cu gel after a 4-week delay after debridement and no significant differences were seen in these groups compared with each other or the control group. This leads the authors to suggest that the gel interacts with the process of debridement. The dressing used in all patient groups was plain gauze.

Muthukumarasamy et al (1991) conducted a prospective matched case-control study, with 100 patients comparing daily topical phenytoin powder with a dry sterile occlusive dressing, in a total of 100 patients (50 in each group). Patients’ ulcers were debrided at baseline, and antibiotics were provided as necessary. Groups were matched for age, sex, ulcer area and depth and chronicity at baseline, although there is a non-significant trend to small ulcer size in the phenytoin group. Ulcers with gross cellulitis, deep slough, ischaemic gangrene or tropic ulcers were excluded. Ulcers were assessed using an impression scale A-E, where A denotes deterioration and E denotes complete healing. At 35 days, ulcer healing was significantly better with phenytoin on the impression scale. The mean tine to complete healing in the phenytoin powder group was 21 days compared to 45 days in the occlusive dressing arm (p<0.05). The overall percentage reduction in ulcer area was also greater in the phenytoin group (p<0.005).

Lishner et al (1985) allocated 40 patients in a prospective controlled study where, in addition to conventional care, the treatment group received a foot bath containing dimethylsulfoxide (DMSO) solution for 20 minutes, 3 times a day. Patients enrolled had not responded to previous treatment and had deep, or perforated, ulcers. Gentamicin was added to the solution when infection occurred and the concentration of DMSO was doubled and if no healing occurred by the sixth week. The ulcers of 14 patients in the DMSO group healed by 15 weeks compared to 2 patients in the control group. Overall improvement was significantly better in the treatment group (p<0.001). It is unclear to what extent improvement was due to the active therapy or to the process of regular foot bathing in the treatment group.

Comment

Trials comparing newer dressing or gels with gauze dressing cannot provide clear messages because of their small size and lack of common method. Polymeric membrane dressing, GHK-Cu complex dressing, lyophilised collagen dressing, and proprietary moist dressing suggests improved performance over gauze, but, in each case, one small trial does not provide an adequate evidence base. The findings of dimethylsulfoxide foot-bathing and topical phenytoin powder are similarly problematic and these were not randomised. The lack of efficacy of cadexomer iodine ointment, calcium alginate dressing, and collagen-alginate dressing is inconclusive. The stated importance of the newer dressings and the inappropriateness of gauze (see for example Appendix 8 and the British National Formulary) does not appear substantiated by the available evidence from randomised controlled trials.

Although the available evidence from trials is inadequate, the guideline development group felt it was good practice to ensure that appropriate wound monitoring practices were observed, including close monitoring and regular dressing changes.

Debridement

Recommendation

Dead tissue should be carefully removed from foot ulcers to facilitate healing, unless revascularisation is required. (B)

Evidence statement

Limited clinical trial data suggest that healing is improved by the use of hydrogel to debride diabetic foot ulcers. (1b)

Introduction

Debridement is the removal of necrotic (dead) tissue by either surgical, chemical or other (eg larval therapy) means. Types of debridement include:

  • autolytic debridement: this occurs naturally in healthy, moist wounds when arterial perfusion and venous drainage are maintained
  • enzymatic debridement: using topical, proteolytic enzymes
  • mechanical debridement: includes, wet to dry dressings and high pressure irrigation
  • sharp (surgical) debridement: usually using a scalpel but may also involve tissue nippers, and/or curettes

Saap and Falanga (2002) developed a Debridement Performance Index to assess the adequacy and performance of any surgical debridement undertaken. The Index was shown to be an independent predictor of wound closure (odds ratio 2.4, 95% confidence interval 1.0–5.6) making it potentially a useful predictive tool for determining ulcer healing outcome following debridement.

Evidence

A recent systematic review (Smith 2002) looked at the effectiveness of debridement as a treatment for diabetic foot ulcers in Type 1 or Type 2 patients. Of the five randomised controlled trials included in this review, all published between 1997 and 2000, none of the earlier ones had been included in the original foot care guideline evidence (Hutchinson et al 2000). Three of the studies assessed the effectiveness of a hydrogel as a debridement agent, one considered surgical debridement and the final one evaluated larval therapy. Sample sizes were predominantly small (<22 per group in three studies, approximately 70 per group in the other two studies) with a full description of age, sex and type of diabetes provided by a single study only. From a meta-analysis of the three hydrogel studies, the absolute risk difference was 0.23, 95% CI 0.10, 0.36) with hydrogel being more effective than gauze or standard care in healing diabetic foot ulcers. Surgical debridement and larval therapy showed no significant benefit, but both trials were small.

Debridement references (with evidence grades where appropriate)

Off-loading

Recommendation

Total contact casting may be considered for people with foot ulcers unless there is severe ischaemia. (B)

Evidence statement

Evidence from several small trials suggests that total contact casting may substantially improve ulcer healing in diabetic foot ulcers with Wagner grades I and II. (Ib)

Total contact casting is associated with unacceptable risk of inducing ulcers in people with severe ischaemia. (IV)

Introduction

Pressure is a causal factor for neuropathic foot ulcers. Therefore removal or relief from pressure should facilitate healing of foot ulcers. The removal of pressure on affected feet or joints can be achieved by avoidance of weight bearing, known as off-loading. However, achieving effective offloading of pressure on the foot while the patient remains ambulant remains a challenge. One way of addressing the problem is the use of therapeutic shoes.

Evidence

Footwear and total contact casting

Armstrong et al (2001) looked at the effects on wound healing of patients with diabetes and neuropathic foot ulcers randomised to three different off-loading systems: total contact casts, a half shoe (Darco) and a diabetic walker (Aircast). Sample sizes (n=19, 24 and 20 respectively) were small but the proportion of healing was significantly higher in the total cast group (89.5%) compared with the two other groups combined (61.54%) (p=0.026, odds ratio 5.4, 95% CI 1.1, 26.1) at 12 weeks. Mean time to healing was also shorter in the total cast group (33.5±5.9 days) compared with the half shoe group (61.0±6.5) (p=0.005) but similar to that for the walker (50.4±7.2) (p=0.07). There were also some differences in daily activity with those with the total cast taking significantly less steps daily than the half shoe group (p=0.04), but a similar number to the walker group (p=0.67) which also did not differ from the half shoe group (p=0.15).

Caravaggi et al (2000) compared a non-removable total off-loading cast made with fibre glass bandages against cloth therapeutic shoes with rigid rocker-bottom soles and unloading insoles in a randomised trial of 50 patients with diabetes and neuropathic foot ulcers. There were no differences in baseline characteristics between the 26 cast and 24 shoe patients but at 30 days follow-up, ulcers had healed in 13 of the cast patients compared with 5 shoe patients (p=0.032). Similarly, the reduction in ulcer size was faster in the cast group compared with the shoe group (p=0.0004). There were no adverse effects in either group. There were no differences in patient acceptance of the two treatments.

Mueller et al (1989) randomised 40 people with diabetes with foot ulcers (without gross infection, osteomyelitis or gangrene) to either total contact casting (TCC) or standard treatment. Accommodative footwear was provided to the control group. Both groups were told to reduce weight bearing; follow-up was for 3 months or until ulcer healing occurred. Complete skin closure with no drainage occurred in 19 of 21 patients in the TCC group (90%) and 6 from 19 in the standard treatment group (32%). The proportion difference was thus 58.9% (95%CI: 30.3% to 78.3%). Mean time to ulcer healing and infections requiring hospitalisation also significantly favoured TCC. The results of this trial need confirmation.

Oedema can be reduced with the application of compression. Armstrong et al (2000) randomised 115 patients with diabetes and foot infections requiring incision and debridement to treatment with a pulsatile pneumatic foot compression system (n=52) or a placebo device, which was similar with the exception that it did not inflate and provide compression (n=45). Eighteen patients did not complete the study. Patients received treatment for eight hours per day and were followed up weekly for 12 weeks. All patients also received an off-load walker. A higher proportion of healing occurred in the active treatment group (75%, 39) compared with the placebo group (51%, 23) (p<0.02, OD 2.9, 95% CI 1.2, 6.8) and time to healing was shorter (p=0.04). Following treatment, oedema reduction, as measured by foot circumference, was greater in the treatment group (p<0.001). Compliance (treatment for >50 hours/week) with active treatment resulted in more patients healed than non-compliance (p=0.03).

Silicone

Reduced plantar thickness is associated with high plantar foot pressure and risk of foot ulceration. Increasing local plantar thickness by injecting silicone may reduce plantar pressure and result in reduced callus formation, another risk factor for foot ulceration. Van Schie and colleagues (2000) enrolled 28 patients with diabetes attending a Diabetic Foot Clinic (Manchester, UK) who had established neuropathy and a callus under at least one metatarsal head, in a randomised controlled trial. In the treatment group, 14 patients received six silicone injections per site (1–5 sites) at two-weekly intervals, whilst the 14 placebo subjects received saline injections in a similar manner. Patients were all treated similarly in skin preparation and bandaging and were followed up at 3,6 and 12 months after baseline. Outcomes included dynamic plantar pressures, plantar tissue thickness at each injected site, and callus formation as assessed by scored photographs. No statistical differences were present between the two groups at baseline. The median plantar thickness increased in the silicone-treated group from baseline to follow-up but no change was seen in the placebo group (p<0.005). Similarly decreases in plantar pressure from baseline to follow-up were seen in the silicone group but no change or a slight increase was seen in the placebo group (p<0.05). An intention to treat analysis found a similar relationship in tissue thickness changes at 3, 6 and 12 months (p<0.008) and in peak plantar pressure changes, significant at 12 months (p<0.02) although not at 3 ( p=0.06) or 6 months (p=0.09). Trends were seen in reduction of callus formation in the silicone group compared with the placebo group but these were not significant (p=0.3). Adverse events were similar in the two groups, with three patients developing foot ulcers in the silicone group and four in the placebo group and no significant side effects were reported.

Comment

Although there is reasonable data about the effectiveness of total contact casting, for individuals with severe ischaemia the friction that may be caused by the wearing of a cast may in itself cause injury in terms of skin breaks and thus this must also be considered when decisions are being taken about total contact cast use.

Offloading references (with evidence grades where appropriate)

Other treatments for foot ulcers

Recommendation

Currently, there is a lack of trial evidence on the use of the following interventions in the treatment of foot ulcers and they are not recommended: cultured human dermis (or equivalent), hyperbaric oxygen therapy, topical ketanserin, or growth factors. (D)

Evidence statements

The value of cultured human dermis, and equivalents, is not clear from the evidence of available trials. (Ib)

The value of hyperbaric oxygen therapy is not clear from the evidence of 2 available trials. (Ib)

Evidence from 2 trials suggests that topical ketanserin (2%) in addition to conventional care may improve the rate of healing of diabetic foot ulcers, of Wagner grades II and III. (Ib)

Available trials indicate that growth factors CT-102 (dilution 0.01), RGDpm and rhPDGF in addition to conventional care may improve healing in diabetic foot ulcers with Wagner grades I and II with transcutaneous oxygen tension TcPO2 30 mmHg. (Ib)

Cultured human dermis and cultivated equivalents

Cultured human dermis consists of neonatal dermal fibroblasts cultured in vitro onto a bioabsorbable mesh to produce a living, metabolically active tissue containing normal dermal matrix proteins and cytokines (Gentzkow et al, 1996). Human skin and cultured equivalents have been used to treat venous ulcers. The effectiveness of these as a treatment for diabetic foot ulcers is also being examined.

Cultured human dermis

Note: Dermagraft® is currently not commercially available in the UK.

Naughton et al (1997) randomised 281 patients with neuropathic full-thickness foot ulcers in a multi-centre trial comparing cultured human dermis and conventional care. Conventional care included debridement, infection control, saline-moistened gauze dressings and special shoes and inserts. Cultured human dermis was applied every week for 8 weeks in the treatment group, in addition to the conventional therapy. At 12 weeks, ulcer healing had occurred in 38.5% of patients receiving cultured human dermis and 31.7% of patients receiving conventional care (p=0.14). Differential loss to follow-up occurred (22% from cultured human dermis vs. 11% from control) making interpretation of findings problematic. The study suggests a dose-response effect with patients receiving all grafts doing better than those who did not; however, ability to receive full treatment may be confounded with underlying disease.

Gentzkow et al (1996) randomised 50 patients to 3 different dose regimens of cultured human dermis or standard care alone. Treatment groups received for 8 weeks: 1 piece of cultured human dermis applied weekly, 2 pieces applied every 2 weeks or 1 piece of cultured human dermis applied every 2 weeks. Ulcers were full thickness with area >1 cm2 at enrolment; assessment was at 12 weeks. Only the first, maximally treated, group (1 piece of cultured human dermis per week) demonstrated healing significantly better than control although a dose-response effect was apparent. In the first treatment group 50% of ulcers healed, compared to 8% in the control group (p=0.03). The mean ulcer duration before enrolment was 50 weeks in the first group and 87 weeks in the control group raising a question mark about comparability at baseline. No adverse reactions to cultured human dermis were reported or differences in the rate of infection of the wound between groups.

Cost effectiveness

A cost effectiveness study by Allenet et al (2000) assessed Dermagraft® vs. standard treatment in the treatment of foot ulcers. A Markov model is developed and transition probabilities extrapolated from a clinical trial conducted in the USA (Naughton et al. 1997) although it is doubtful that the trial was powered to detect differences across the range of health states used in the model. No indication of the uncertainty around these values is provided. No description of standard treatment is given.

Costs are presented in “current” French francs (2000) and are based on expert opinion. The assessment was over a 52 week period and no discounting was therefore applied. Cost effectiveness is presented in terms of cost per ulcer healed. Dermagraft® generates additional benefits by reducing the average time to heal and, additionally, ulcers that recur heal faster if they were originally treated with Dermagraft®. The additional cost of dermagraft is not recouped by lower ulcer treatment costs. The incremental cost per additional ulcer healed is 38,784 ff. A small number of one-way sensitivity analyses are performed which vary the ICER between 34,000 and 53,000ff. No indication of the likelihood of these ranges is given.

Cultured skin equivalents

Note: Apligraf® is currently not commercially available in the UK.

Veves et al (2001) used Graftskin (Apligraf®), an allogenic bilayered cultured skin equivalent, in a multicentre randomised trial. Participants had diabetes, either Type 1 or Type 2, were aged 18–80 years and had full thickness neuropathic ulcers of 2 weeks duration and 1 - 16 cm2 post debridement, which had not responded (any reduction in size was <30%) to a screening 7 day treatment with saline-moistened gauze. One hundred and twelve people were randomised to the Graftskin treatment and 96 to a control treatment of saline-moistened gauze. Patients were followed up for twelve weeks, with dressing changes made routinely in each of the first four weeks in both groups plus other changes as necessary. All patients were fitted with customised sandals and instructed to avoid bearing weight on the affected foot. Unhealed ulcers at week five, in both groups were subsequently treated with saline-moistened gauze. Withdrawals and adverse events were similar in the two groups, but analysis was on intention to treat. Complete wound healing occurred in 56% (63) of the treatment group and 38% (36) of the control group (p=0.0042) (OR 2.14, 95% CI 1.23, 3.74). Time to complete healing was also shorter in the treatment group, with a median time of 65 days compared with 90 days in the control group (p=0.0026). Significant differences in time to closure were maintained in a regression analysis model (p=0.0001) and the estimated hazard ratio indicated that an average patient treated with Graftskin had a 1.59-fold better chance for closure per unit time that a patient in the control group (95% CI 1.26, 2.00).

Hyperbaric oxygen therapy

Hyperbaric oxygen (HBO) treatment involves immersing the wound in a pure oxygen atmosphere, either with steady or cyclical raised pressure, in a leg chamber or by placing the whole patient in a chamber. A number of possible mechanisms form the rationale for this treatment including improved oxygen supply promoting the proliferation of granulation tissue (although the case for this comes from studies of ischaemic leg ulcers) and antibacterial effect on anaerobic organisms.

One new randomised controlled study has been published since the original guideline literature survey was conducted. Heing et al (2000) carried out a trial of topical hyperbaric oxygen at 1.004 to 1.013 atmospheres on newly admitted non-ambulatory residents with life-threatening gangrene, uncontrolled diabetes and untreated sepsis in a long-term care facility in Los Angeles, USA. Patients were randomly assigned, by drawing lots, to receive oxygen for four hours/day, four days/week for four weeks (n=13 with 29 ulcers of which 21 were diabetic) or standard wound care for four weeks (n=27 with 50 ulcers of which 16 were diabetic). Numbers between the groups were unbalanced, because only two patients could be treated with oxygen therapy at any one time and any ‘over-flow’ new patients were included in the standard care group. Oxygen was administered topically via a 84 × 48 inch pleated polythene bag taped at chest level. Patients were similar at baseline in all parameters tested and the study was powered (89%) to treat at least 10 patients (20 wounds) with either treatment. In the oxygen therapy group, 26 (90%) of the 29 ulcers healed within 2 to 16 weeks, whereas in the standard care group, 8 had healed by 7 months, a further 3 by 15 months (22% in total). Ulcer size was significantly smaller after four weeks with the oxygen therapy, down from 11.9 ± 7.8 cm2 to 3.0 ± 11.8 cm2 compared with 7.8 ± 8.8 cm2 increased to 11.8 ± 11.9 cm2 in the standard care group (p<0.001). Subgroup analysis of diabetic ulcers only, found no difference between diabetic and nondiabetic necrotic ulcers in improvement per day (p=0.203). For diabetic ulcers classified by stage of ulceration, changes in size over four weeks between the two treatment groups, mirrored those for the total patient groups and showed that, in the oxygen therapy group, ulcer mean size reduced, whatever the stage, whilst in the standard wound care group, ulcer mean size increased, in all stages, although no statistical tests were reported.

Faglia et al (1996) randomised 70 patients to HBO or standard care alone. Patients had full thickness gangrene (Wagner grade IV), abscess (Wagner grade III), or persistent large and infected ulcer (Wagner Grade II). Standard treatment included radical debridement, antibiotic therapy and provision of orthopaedic devices. Patient groups appear comparable at baseline, except that the control group had more claudication (p=0.07). Treatment group patients sat in a hyperbaric chamber breathing pure oxygen pressurised at 2.5–2.2 atmospheres in 90-minute daily sessions. The study was powered to detect a reduction of ⅓ in major amputation rate. The treatment group received an average of 38 sessions and patients were followed until discharge. Major amputation was significantly lower in the treated group (8.6%) than the control group (33.0%), (p=0.016). There were no significant differences in minor amputations.

Leslie et al (1988) randomised 28 patients to HBO treatment (90 minutes, twice daily for 2 weeks) or to clinical management alone. All patients had well demarcated foot ulcers without gangrene or other major complications and received debridement, intravenous antibiotics, wet-to-dry dressings and bed rest. HBO was topically applied using a leg chamber and cycled pressure (up to 1.04 atmospheres every 20 seconds). Ulcers in both groups improved significantly; however, there were no statistically significant differences between groups at 2 weeks follow-up. No significant differences were found in ulcer area or depth (as a percentage of baseline) between the HBO group and the control group at 2 weeks.

The study by Leslie and colleagues did not involve severe grade ulcers, did not use breathed but topical oxygen therapy, and did not use substantially raised or sustained pressure. It is unclear which of these effects may be important in achieving benefit from HBO therapy. Further evaluation of effectiveness, and consideration of cost-effectiveness is required.

Ketanserin

Note: this is not listed in BNF, included for completeness of review only.

Ketanserin is a 5HT2 serotonergic receptor antagonist reported to inhibit platelet aggregation, block vasoconstriction, improve tissue perfusion and increase granulation tissue formation. It can be administered orally or topically.

Martinez-de Jesus et al (1997) randomised 140 people with diabetes with neuropathic foot ulcers (<100 cm2, Wagner grade II or III) to topically applied ketanserin (2%) or (unmatched) normal saline. A sample size calculation of 65 per arm is presented, assuming an improvement in healing from 50% to 75%, when conventionally powered. All patients enrolled were hospitalised for debridement, parenteral antimicrobial treatment, foot rest and correction of fasting hyperglycaemia caused by sepsis. Patients received outpatient care after discharge. Groups were comparable in all important characteristics except smoking, which was more common in the ketanserin group (p=0.043). By 2 weeks, 21 patients (13%) had withdrawn and are not included in the numbers presented: it is not reported whether dropout was equivalent between groups. At 12 weeks, the average percentage reduction in ulcer area was 87.0% for intervention and 62.8% for placebo (p<0.001): this equated to average daily reductions in ulcer areas of 4.5 mm2/day and 2.88 mm2/day respectively.

Apelqvist et al (1990) randomised 40 patients to ketanserin (oral, 20 mg tid for 1 month, then 40 mg tid for 2 months) or placebo. Otherwise, all patients were offered the same treatment for their ulcers. Patients enrolled had a deep or superficial ulcer, with an area of 1 cm2 or more, and a systolic toe pressure below 45 mmHg. At 3 months, no statistically significant difference was found in wound healing (defined as either intact skin or 50% wound reduction in ulcer size).

Janssen et al (unpublished) randomised 299 patients, including 45 people with diabetes with chronic ulcers, to ketanserin (2% ointment) or vehicle placebo. Both groups otherwise received conventional care, and follow-up was for 8 weeks. The study reports the initial velocity of healing to be 3-fold faster with ketanserin ointment than placebo (p<0.001), in the sub group of people with diabetes. No detailed presentation of results is given for the diabetic foot ulcer sub group. Patients were not randomised into strata by wound type and baseline comparability of the people with diabetes unknown.

These trials report different endpoints making comparison between studies problematic. It is unclear what the respective bioavailabilities are of topical or oral ketanserin. The (relatively) large study by Martinez-de Jesus and colleagues indicates a clinically important benefit from topically applied ketanserin when applied in addition to comprehensive care in relatively severe ulcers, but requires further confirmatory evaluation.

Growth factors

Growth factors are applied directly to the wound surface with the intention of stimulating cellular movement, replication and matrix synthesis leading to healing in chronic non-healing wounds. We identified 6 randomised controlled trials, in which 4 types of growth factor have been used in the treatment of people with diabetes with foot ulcers (see Appendix 11 for details). CT-102 is derived from a thrombin-induced human platelet process; rhPDGF is a recombinant platelet derived growth factor; rbFGF is a recombinant basic fibroblast growth factor using Escherichia coli type β; and RGDpm is an arginine-glycine-aspartic acid peptide matrix.

Wieman et al (1998) randomised 382 patients to receive either 100 μg/g or 30 μg/g rhPDGF once daily or placebo (vehicle gel) in a multi-centre trial. All patients had chronic neuropathic foot ulcers free of infection, received sharp debridement of ulcers at baseline and subsequent debridement of callus and necrotic tissue as required. Patients attended as outpatients and were followed for 20 weeks or until healing. After 20 weeks, 50% of ulcers healed with 100 μg/g rhPDGF compared with 35% in the placebo group, p=0.007. No differences in outcome were found between 30 μg/g rhPDGF and placebo groups. Variation of treatment effect across centres was not reported. No differences in adverse events or withdrawals were observed between groups. This study found no benefit for 30 μg/g rhPDGF, contrasting with Steed et al (1995b) which found significant benefits. The investigators suggest this may be due to better infection control, and the use of a relatively small number of experienced centres for treatment, in the latter study.

Steed et al (1995a) randomised 65 patients, with chronic full-thickness neurotrophic foot ulcers, to RGDpm or placebo (normal saline) in a multi-centre trial. RGDpm was applied topically twice weekly for up to 10 weeks in patients who otherwise received conventional care, including twice-weekly clinics. Ulcers were 1–15 cm2 in area, of at least 1 month duration, penetrating the skin without exposing the bone or tendon and free of infection. At 10 weeks, the percentage of patients whose ulcers completely healed was significantly greater in the RGDpm group, 35% (14/40) vs. 8% (2/25) in the control group, p=0.02. A significantly greater proportion had achieved >50% ulcer closure (75% RGDpm vs. 48% placebo), p=0.03. No significant difference in adverse events between groups was observed.

In a French pilot study, Richard et al (1995) randomised 17 patients, suffering from chronic neuropathic foot ulcers of Wagner grade I to III without infection, to receive rbFGF or placebo (normal saline) daily for 6 weeks and then twice weekly for 12 weeks. After 18 weeks, 3 of 9 ulcers healed with rbFGF and 5 of 8 in the placebo group, p=NS. There was no significant change in rate of healing or percentage of area healed at 18 weeks. No drug-related adverse events were observed.

Steed et al (1995b) randomised 118 patients to receive rhPDGF (30 μg/g) once daily or placebo (vehicle gel) in a multi-centre trial. All patients had chronic neuropathic foot ulcers free of infection, received sharp debridement of ulcers at baseline and subsequent debridement of callus and necrotic tissue as required. Patients attended as outpatients and were followed for 20 weeks or until healing. After 20 weeks, 48% of ulcers healed with rhPDGF compared with 25% in the placebo group, p=0.01. The treatment effect was consistent across centres. Adverse events were not reported.

Holloway (1993) randomised 97 patients to 3 different dilutions of CT-102, (CT-102: 0.1, 0.033 and 0.01) or matched placebo (normal saline solution or isotonic platelet buffer) in a multi-centre trial. Some 27 patients were removed from the analysis due to protocol violation, 11 after randomisation. Wounds were chronic, diabetic non-healing ulcers of at least 8 weeks' duration and volume 500 mm3 to 50,000 mm3. All patients received debridement of ulcers at baseline, subsequent debridement of callus and necrotic tissue as required, and were seen weekly for 2 weeks and then bi-weekly. The best results were seen in the lowest dilution: 80% of wounds with CT-102–0.01 healed versus 29% in the placebo group (p=0.01). However, this group contained 6 of the 11 patients removed from the analysis. The mean volume reduction for CT-102 (all dilutions) was 94.9% versus 82.7% in the placebo group (p=0.005) and this showed no significant variation by dilution. A similar finding occurred in ulcer area reduction. No differences in adverse events were reported between groups.

Steed et al (1992) randomised 13 patients to receive CT-102 (dilution 0.01, applied twice daily with dressing change) or matched placebo (normal saline). Patients had diabetic neuropathic ulcers of >8 weeks duration and no wound infection. Wounds were debrided at baseline, had volumes 700 mm3 to 50,000 mm3, had areas <100 cm2 and involved subcutaneous tissue. Patients agreed to be totally non-weight-bearing and were evaluated as outpatients weekly then fortnightly. In the CT-102 group, 5 of 7 ulcers were healed at 20 weeks compared with only 1 of 6 in the placebo group (p<0.05). Average reduction in area was 94% for CT-102 compared with 73% for placebo. Adverse events were not reported.

The available trials of growth factors indicate clinically important benefits from 3 growth factors applied in addition to conventional care: CT-102 (dilution 0.01), RGDpm and rhPDGF. On the basis of 1 small pilot study there is no evidence for the use of rbFGF. When reported, growth factors appear well tolerated with no drug-related side effects. All findings need confirmation from further trials and assessment of cost-effectiveness.

Granulocyte-colony stimulating factor

Granulocyte-colony stimulating factor (G-CSF) increases both the production and release of neutrophils from the bone marrow enhancing the ability to fight infection in the blood. Recombinant G-CSF has been shown to reduce neutropenia in vulnerable patients undergoing chemotherapy treatment for a number of cancers, and thus reduce infections and their sequelae. While people with diabetes are not neutropenic, diabetes represents an immunocompromised state secondary to neutrophil dysfunction: it is hypothesised that improved neutrophil production and function will improve bactericidal activity in foot ulcers (Gough et al, 1998).

A small study by de Lalla et al (2001) found no differences in reduction in foot infection between 40 Italian adults with diabetes and severe limb-threatening foot infection randomised to receive G-CSF with local treatment and systemic antibiotic therapy (n=20) or local treatment and systemic antibiotic therapy only (n=20). G-CSF was given subcutaneously at a dosage of 263 μg daily for 21 days and reduced or discontinued if the neutrophil count exceeded certain defined values. All patients required insulin. There were no differences between the two groups of patients upon recruitment and no patient’s infection was cured during the three weeks of treatment although improvement was seen in 60% (12/20) of the G-CSF group and 45% (9/20) of the standard treatment group (p>0.05). After three weeks of treatment, one amputation was required (5%) in the G-CSF group and 5 (25%) in the conventional treatment group (P=0.08). In further follow-up six months after recruitment there were no differences in infection, cure, or deterioration between the two groups.

In a randomised controlled study of 30 Turkish hospital patients with diabetes and infection of the skin and subcutaneous tissue (pedal cellulitis) or a foot lesion, patients either received 0.5–0.2.5μg/kg recombinant human G-SFF (filgrastim) subcutaneously once daily or every two days dependent upon neutrophil count plus local wound care and parenteral antibiotherapy, or local wound care and parenteral antibiotherapy only (Yonem et al 2001). All patients were on daily multiple-dose injections of short-acting insulin and the study interventions were given for ten days. Outcomes were time to resolution of infection and time to hospital discharge and neither of these differed statistically between the two groups. Duration of hospitalisation was 26.9±2.0 versus 28.3±2.2 days and time to resolution of infection was 23.6±1.8 versus 22.3±1.7 days in the G-CSF and standard groups respectively.

One trial randomised 40 people with diabetes, with foot infections featuring extensive cellulitis, to intravenous G-CSF (filgrastim) or placebo for 7 days (Gough et al 1997). All patients received antibiotic therapy until resolution. A further 17 patients were excluded at the screening stage due to critical leg ischaemia, immediate surgery, renal impairment or psychiatric illness. Median time to hospital discharge, resolution of cellulitis, withdrawal of intravenous antibiotics and negative swab culture were all statistically significantly reduced. At day 7, cellulitis had resolved in 55% of patients on G-CSF and 20% on placebo (p=0.05), and healing had occurred in 21% of patients on G-CSF and 0% on placebo (p=0.09).

This initial result indicates that G-CSF treatment should receive more extensive evaluation. Filgrastim is expensive: using the median reported dose, 7 days of treatment costs approximately £540 per patient. However apparently significant reductions in other resources mean that the cost-effectiveness of G-CSF intervention for foot infection should be formally explored.

Cost effectiveness

Edmonds et al (1999) describes a cost-minimisation study conducted retrospectively around an RCT of the use of filgrastim vs placebo for diabetic patients with extensive foot cellulitis. The clinical study was reported in Gough et al. (1997).

The trial was conducted in the UK but consisted of just 40 patients (20 in each arm). Given such small numbers, it is unlikely that the RCT was sufficiently powered to detect differences and a cost minimisation study may not be appropriate. Furthermore, the source of cost differences in the absence of any difference in clinical outcome requires clarification. The paper states that patients received a combination of four antibiotics in addition to either filgrastim or placebo until cellulitis and ulcer discharge was resolved. More expensive drugs would be used when penicillin hypersensitivity or drug resistance was reported.

Direct medical resource use consumed during hospital stay were calculated by reference to clinical report files and patient hospital records on a subset of 28 patients. Unit costs were calculated using “B-plan software” where possible, which is claimed to be a system which helps to calculate unit costs. Costs are presented in 1996 £’s and covered length of hospital stay, laboratory tests, diagnostic procedures, drugs and surgical interventions.

The median length of hospital stay was 10 days (filgrastim) vs. 17.5 days (placebo) (p=0.02), time to resolution of cellulitis was 7 days (filgrastim) and 12 days (placebo), (p=0.03), time to stopping intravenous antibiotics was 8.5 days (filgrastim) and 14.5 days (placebo), (p=0.02), the proportion of patients where cellulitis had resolved at day 7 was 55% (11) (filgrastim) and 20% (4) (placebo), (p<0.05), the proportion of patients in whom angiography was necessary was 20% (4) (filgrastim) and 35% (7) (placebo), (p=0.6), the proportion of patients in whom surgery was required was 0% (filgrastim) and 20% (4) (placebo), (p=0.34).

Costs were modelled over different treatment stages. During the “well” stage no difference was observed. Large differences were observed between the “no intervention” stage with a mean cost of £9536 (filgrastim) vs. £28,968 (placebo) but this is explained buy a single outlier that was hospitalised for 100 days. In general, results show that filgrastim is cost saving and this saving is greater in patients with no tissue necrosis (n=20).

Electrical stimulation

Electric current has been shown to facilitate wound healing in animal models and improve blood flow to the foot in vascular studies in diabetes patients. Peters et al (2001) conducted a randomised controlled trial to evaluate the effectiveness of electrical stimulation as a facilitator of healing of diabetic foot ulcers. Patients with diabetes and foot ulcers were randomly allocated to receive a current delivered to a Dacron-mesh silver nylon stocking (n=21) or no current but using the same electric stimulation units (n=20). The treatment comprised a dose of 50V with 80 twin peak monophasic pulses per second delivered for 10 minutes followed by 10 minutes of 8 pulses per second of current. Following electric stimulation the device went onto standby for 40 minutes, and then nightly for an 8 hour period each night, for twelve weeks or until the ulcer healed, whichever happened first. All patients also received traditional wound care of debridement, collagen wound gel, and pressure reduction at the site of ulceration. Ulcers healed in 13 (65%) of the patients who received electrical stimulation but only in 7 (35%) of the placebo group (p=0.058). When stratified by compliance (use of the device for 20 hours of more per week), in compliant patients in the treatment group 71% (10/14) healed compared with 50% (3/6) non-compliant treatment patients, 39% (5/13) complaint placebo patients and 29% (2/7) noncompliant placebo patients (p=0.037). There were no significant differences in rate of healing and average time to healing between the treatment and placebo groups. Dropouts were similar in number in the two study groups. High voltage pulsed galvanic electric stimulation may enhance wound healing when used for more than 20 hours per week but further larger studies are needed to confirm the findings of this pilot study.

Sulodexide

Note: this is not listed in BNF, included for completeness of review only.

Various medications have been considered as potential promoters of foot ulcer healing. Koblik et al (2001) conducted a pilot study to assess the impact of sulodexide, an antithrombotic drug used successfully for peripheral occlusive arterial disease, on foot ulcer healing rates. Eighteen patients with persisting diabetic foot syndrome and monolateral foot ulcers were randomised on a 2:1 ratio to treatment with insulin plus sulodexide (1 vial – 600LRV daily for 15 days, then 1 cap –250LSU for 2 months) or a similar insulin plus placebo treatment. Diet control was similar in both groups and all had a 5 day run-in phase for insulin dose adjustment.. There were no statistically significant differences in ulcer healing rates between the two groups. In the sulodexide group, 92% of foot ulcers healed in a mean time of 46.4±5.2 days compared with the placebo group, with 83% healing in 63±8.5 days (p=0.09).

Other treatments for foot ulcers references (with evidence grades where appropriate)

Cultured human dermis

Hyperbaric oxygen

Ketanserin

Growth factors

Granulocyte-colony stimulating factor

Electrical stimulation

Sulodexide

Education for patients with foot ulcers

Recommendation

For patients with foot ulcers or previous amputation, health care professionals could consider offering graphic visualisations of the sequelae of disease and providing clear, repeated reminders about foot care. (B)

Evidence statement

In patients with foot ulcers or previous amputation, 1 trial indicates that education including frank presentation of the consequences of disease and a simple patient instruction checklist reduces morbidity. (Ib)

Evidence

One American randomised trial of an educational intervention was retrieved involving 203 people with diabetes with either uninfected ulcers or previous amputation (Malone et al, 1989). In addition to usual care, the intervention group received 1 (1 hour) education session on foot care which included a slide-show of infected feet and amputated limbs, and a patient instruction checklist. Follow-up was longer in the intervention than control group (mean follow-up 13.2 and 9.2 months respectively).

The study showed a significant reduction in the combined endpoint of limbs free of infection, ulcer or amputation favouring education (education 90%, control 72%). Although there were no significant differences in infection or mortality during follow-up, there was a significant excess of ulceration (education 5%, control 15%) and amputation (education 4%, control 12%) in the control group. Statistical calculations assume ‘independence’ of limbs which may not be valid.

Undoubtedly the educational component contains a ‘scare-tactic’ component and it is unclear whether this approach is generalisable. None the less the reduction in morbidity at approximately 1 year is impressive and the method merits evaluation in the British context.

Education for patients with foot ulcers references (with evidence grades where appropriate)

Copyright © 2003, School of Health and Related Research (ScHARR), University of Sheffield.
Bookshelf ID: NBK51713

Views

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...