Introduction

Accurate identification of pathogens, rather than colonising bacteria, is a prerequisite for targeted antibiotic therapy to ensure optimal patient outcome in wounds, such as diabetic foot ulcers. Wound swabs are the easiest and most commonly used sampling technique but most published guidelines recommend instead removal of a tissue sample from the wound bed, which is a more complex process. The aim of this study was to assess the concordance between culture results from wound swabs and tissue samples in patients with suspected diabetic foot infection.

Methods and analysis

Patients with a diabetic foot ulcer that is thought to be infected are being recruited from 25 sites across England in a cross-sectional study. The coprimary endpoints for the study are agreement between the two sampling techniques for three microbiological parameters: reported presence of likely isolates identified by the UK Health Protection Agency; resistance of isolates to usual antibiotic agents; and, the number of isolates reported per specimen. Secondary endpoints include appropriateness of the empiric antibiotic therapy prescribed and adverse events. Enrolling 400 patients will provide 80% power to detect a difference of 3% in the reported presence of an organism, assuming organism prevalence of 10%, discordance of 5% and a two-sided test at the 5% level of significance. Assumed overall prevalence is based on relatively uncommon organisms such as Pseudomonas. We will define acceptable agreement as κ>0.6.

Ethics and dissemination

Concordance in diabetic foot ulcer infection (CODIFI) will produce robust data to evaluate the two most commonly used sampling techniques employed for patients with a diabetic foot infection. This will help determine whether or not it is important that clinicians take tissue samples rather than swabs in infected ulcers. This study has been approved by the Sheffield NRES Committee (Ref: 11/YH/0078) and all sites have obtained local approvals prior starting recruitment.

Study registration

NRES Ref: 11/YH/0078, UKCRN ID: 10440, ISRCTN: 52608451

Background

Objective: To determine the relative effectiveness of evidence-informed practice using two high compression systems: four-layer (4LB) and short-stretch bandaging (SSB) in community care of venous leg ulcers. Design and Setting: Pragmatic, multi-centre, parallel-group, open-label, randomized controlled trial conducted in 10 centres. Cognitively intact adults (≥18 years) referred for community care (home or clinic) with a venous ulceration measuring ≥0.7cm and present for ≥1 week, with an ankle brachial pressure index (ABPI) ≥0.8, without medication-controlled Diabetes Mellitus or a previous failure to improve with either system, were eligible to participate.

Methods

Consenting individuals were randomly allocated (computer-generated blocked randomization schedule) to receive either 4LB or SSB following an evidence-informed protocol. Primary endpoint: time-to- healing of the reference ulcer. Secondary outcomes: recurrence rates, health-related quality of life (HRQL), pain, and expenditures.

Results

424 individuals were randomized (4LB n = 215; SSB n = 209) and followed until their reference ulcer was healed (or maximum 30 months). An intent-to-treat analysis was conducted on all participants. Median time to ulcer healing in the 4LB group was 62 days [95% confidence interval (CI) 51 to 73], compared with 77 days (95% CI 63 to 91) in the SSB group. The unadjusted Kaplan-Meier curves revealed the difference in the distribution of cumulative healing times was not significantly different between group (log rank χ2 = 0.001, P = 0.98) nor ulcers recurrence (4LB, 10.1%; SSB, 13.3%; p = 0.345). Multivariable Cox Proportional Hazard Modeling also showed no significant between-bandage differences in healing time after controlling for significant covariates (p = 0.77). At 3-months post-baseline there were no differences in pain (no pain: 4LB, 22.7%; SSB, 26.7%; p = 0.335), or HRQL (SF-12 Mental Component Score: 4LB, 55.1; SSB, 55.8; p = 0.615; SF-12 Physical Component Score: 4LB, 39.0; SSB, 39.6; p = 0.675). The most common adverse events experienced by both groups included infection, skin breakdown and ulcer deterioration.

Conclusions

The Canadian Bandaging Trial revealed that in the practice context of trained RNs using an evidence-informed protocol, the choice of bandage system (4LB and SSB) does not materially affect healing times, recurrence rates, HRQL, or pain. From a community practice perspective, this is positive news for patient-centred care allowing individual/family and practitioner choice in selecting compression technologies based on circumstances and context.

Trial registration

clinicaltrials.gov Identifier: NCT00202267

Introduction

Leg ulcers usually occur secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders. Between 1.5 and 3.0/1000 people have active leg ulcers. Prevalence increases with age to about 20/1000 in people aged over 80 years.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of standard treatments, adjuvant treatments, and organisational interventions for venous leg ulcers? What are the effects of interventions to prevent recurrence of venous leg ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 80 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: compression bandages and stockings, cultured allogenic (single or bilayer) skin replacement, debriding agents, dressings (cellulose, collagen, film, foam, hyaluronic acid-derived, semi-occlusive alginate), hydrocolloid (occlusive) dressings in the presence of compression, intermittent pneumatic compression, intravenous prostaglandin E1, larval therapy, laser treatment (low-level), leg ulcer clinics, multilayer elastic system, multilayer elastomeric (or non-elastomeric) high-compression regimens or bandages, oral treatments (aspirin, flavonoids, pentoxifylline, rutosides, stanozolol, sulodexide, thromboxane alpha2 antagonists, zinc), peri-ulcer injection of granulocyte-macrophage colony-stimulating factor, short-stretch bandages, single-layer non-elastic system, skin grafting, superficial vein surgery, systemic mesoglycan, therapeutic ultrasound, self-help (advice to elevate leg, advice to keep leg active, advice to modify diet, advice to stop smoking, advice to reduce weight), and topical treatments (antimicrobial agents, autologous platelet lysate, calcitonin gene-related peptide plus vasoactive intestinal polypeptide, freeze-dried keratinocyte lysate, mesoglycan, negative-pressure recombinant keratinocyte growth factor, platelet-derived growth factor).

Key Points

Leg ulcers are usually secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders.

Compression bandages and stockings heal more ulcers compared with no compression, but we don't know which bandaging technique is most effective. Compression is used for people with ulcers caused by venous disease who have an adequate arterial supply to the foot, and who don't have diabetes or rheumatoid arthritis.The effectiveness of compression bandages depends on the skill of the person applying them.We don't know whether intermittent pneumatic compression is beneficial compared with compression bandages or stockings.

Occlusive (hydrocolloid) dressings are no more effective than simple low-adherent dressings in people treated with compression, but we don't know whether semi-occlusive dressings are beneficial.

Peri-ulcer injections of granulocyte-macrophage colony-stimulating factor may increase healing, but we don't know whether other locally applied agents, or therapeutic ultrasound are beneficial, as we found few studies.

Oral pentoxifylline increases ulcer healing in people receiving compression, and oral flavonoids, sulodexide, and mesoglycan may also be effective. We don't know whether oral aspirin, rutosides, thromboxane alpha2 antagonists, zinc, debriding agents, intravenous prostaglandin E1, superficial vein surgery, skin grafting, leg ulcer clinics, larval therapy, laser treatment, or advice to elevate legs, increase activity, lose weight, change diet, or give up smoking increase healing of ulcers in people treated with compression.

Compression bandages and stockings reduce recurrence of ulcers compared with no compression, and should ideally be worn for life. Superficial vein surgery may also reduce recurrence, but we don't know whether systemic drug treatment is effective.

Objective To compare the clinical effectiveness of larval therapy with a standard debridement technique (hydrogel) for sloughy or necrotic leg ulcers.

Design Pragmatic, three armed randomised controlled trial.

Setting Community nurse led services, hospital wards, and hospital outpatient leg ulcer clinics in urban and rural settings, United Kingdom.

Participants 267 patients with at least one venous or mixed venous and arterial ulcer with at least 25% coverage of slough or necrotic tissue, and an ankle brachial pressure index of 0.6 or more.

Interventions Loose larvae, bagged larvae, and hydrogel.

Main outcome measures The primary outcome was time to healing of the largest eligible ulcer. Secondary outcomes were time to debridement, health related quality of life (SF-12), bacterial load, presence of meticillin resistant Staphylococcus aureus, adverse events, and ulcer related pain (visual analogue scale, from 0 mm for no pain to 150 mm for worst pain imaginable).

Results Time to healing was not significantly different between the loose or bagged larvae group and the hydrogel group (hazard ratio for healing using larvae v hydrogel 1.13, 95% confidence interval 0.76 to 1.68; P=0.54). Larval therapy significantly reduced the time to debridement (2.31, 1.65 to 3.2; P<0.001). Health related quality of life and change in bacterial load over time were not significantly different between the groups. 6.7% of participants had MRSA at baseline. No difference was found between larval therapy and hydrogel in their ability to eradicate MRSA by the end of the debridement phase (75% (9/12) v 50% (3/6); P=0.34), although this comparison was underpowered. Mean ulcer related pain scores were higher in either larvae group compared with hydrogel (mean difference in pain score: loose larvae v hydrogel 46.74 (95% confidence interval 32.44 to 61.04), P<0.001; bagged larvae v hydrogel 38.58 (23.46 to 53.70), P<0.001).

Conclusions Larval therapy did not improve the rate of healing of sloughy or necrotic leg ulcers or reduce bacterial load compared with hydrogel but did significantly reduce the time to debridement and increase ulcer pain.

Trial registration Current Controlled Trials ISRCTN55114812 and National Research Register N0484123692.

Objective To assess the cost effectiveness of larval therapy compared with hydrogel in the management of leg ulcers.

Design Cost effectiveness and cost utility analyses carried out alongside a pragmatic multicentre, randomised, open trial with equal randomisation.

Population Intention to treat population comprising 267 patients with a venous or mixed venous and arterial ulcers with at least 25% coverage of slough or necrotic tissue.

Interventions Patients were randomly allocated to debridement with bagged larvae, loose larvae, or hydrogel.

Main outcome measure The time horizon was 12 months and costs were estimated from the UK National Health Service perspective. Cost effectiveness outcomes are expressed in terms of incremental costs per ulcer-free day (cost effectiveness analysis) and incremental costs per quality adjusted life years (cost utility analysis).

Results The larvae arms were pooled for the main analysis. Treatment with larval therapy cost, on average, £96.70 (€109.61; $140.57) more per participant per year (95% confidence interval −£491.9 to £685.8) than treatment with hydrogel. Participants treated with larval therapy healed, on average, 2.42 days before those in the hydrogel arm (95% confidence interval −0.95 to 31.91 days) and had a slightly better health related quality of life, as the annual difference in QALYs was 0.011 (95% confidence interval −0.067 to 0.071). However, none of these differences was statistically significant. The incremental cost effectiveness ratio for the base case analysis was estimated at £8826 per QALY gained and £40 per ulcer-free day. Considerable uncertainty surrounds the outcome estimates.

Conclusions Debridement of sloughy or necrotic leg ulcers with larval therapy is likely to produce similar health benefits and have similar costs to treatment with hydrogel.

Trial registration Current Controlled Trials ISRCTN55114812 and National Research Register N0484123692.

Objective To review the evidence of effectiveness of dressings applied to venous leg ulcers.

Design Systematic review and meta-analysis.

Data sources Hand searches of journals and searches of electronic databases, conference proceedings, and bibliographies up to April 2006; contacts with dressing manufacturers for unpublished studies.

Studies reviewed All randomised controlled trials that evaluated dressings applied to venous leg ulcers were eligible for inclusion. Data from eligible studies were extracted and summarised independently by two reviewers using a data extraction sheet. Methodological quality was assessed independently by two reviewers.

Results The search strategy identified 254 studies; 42 of these fulfilled the inclusion criteria. Hydrocolloids were no more effective than simple low adherent dressings used beneath compression (eight trials; relative risk for healing with hydrocolloid 1.02, 95% confidence interval 0.83 to 1.28). For other comparisons, insufficient evidence was available to allow firm conclusions to be drawn. None of the dressing comparisons showed evidence that a particular class of dressing healed more ulcers. Some differences existed between dressings in terms of subjective outcome measures and ulcer healing rates. The results were not affected by the size or quality of trials or the unit of randomisation. Insufficient data were available to allow conclusions to be drawn about the relative cost effectiveness of different dressings.

Conclusions The type of dressing applied beneath compression was not shown to affect ulcer healing. The results of the meta-analysis showed that applying hydrocolloid dressings beneath compression produced no benefit in terms of ulcer healing compared with applying simple low adherent dressings. No conclusive recommendations can be made as to which type of dressing is most cost effective. Decisions on which dressing to apply should be based on the local costs of dressings and the preferences of the practitioner or patient.

Objective To assess the cost effectiveness of alternating pressure mattresses compared with alternating pressure overlays for the prevention of pressure ulcers in patients admitted to hospital.

Design Cost effectiveness analysis carried out alongside the pressure relieving support surfaces (PRESSURE) trial; a multicentre UK based pragmatic randomised controlled trial.

Setting 11 hospitals in six UK NHS trusts.

Participants Intention to treat population comprising 1971 participants.

Main outcome measures Kaplan Meier estimates of restricted mean time to development of pressure ulcers and total costs for treatment in hospital.

Results Alternating pressure mattresses were associated with lower overall costs (£283.6 per patient on average, 95% confidence interval - £377.59 to £976.79) mainly due to reduced length of stay in hospital, and greater benefits (a delay in time to ulceration of 10.64 days on average, - 24.40 to 3.09). The differences in health benefits and total costs for hospital stay between alternating pressure mattresses and alternating pressure overlays were not statistically significant; however, a cost effectiveness acceptability curve indicated that on average alternating pressure mattresses compared with alternating pressure overlays were associated with an 80% probability of being cost saving.

Conclusion Alternating pressure mattresses for the prevention of pressure ulcers are more likely to be cost effective and are more acceptable to patients than alternating pressure overlays.

Objective To compare whether differences exist between alternating pressure overlays and alternating pressure mattresses in the development of new pressure ulcers, healing of existing pressure ulcers, and patient acceptability.

Design Pragmatic, open, multicentre, randomised controlled trial.

Setting 11 hospitals in six NHS trusts.

Participants 1972 people admitted to hospital as acute or elective patients.

Interventions Participants were randomised to an alternating pressure mattress (n = 982) or an alternating pressure overlay (n = 990).

Main outcome measures The proportion of participants developing a new pressure ulcer of grade 2 or worse; time to development of new pressure ulcers; proportions of participants developing a new ulcer within 30 days; healing of existing pressure ulcers; and patient acceptability.

Results Intention to treat analysis found no difference in the proportions of participants developing a new pressure ulcer of grade 2 or worse (10.7% overlay patients, 10.3% mattress patients; difference 0.4%, 95% confidence interval - 2.3% to 3.1%, P = 0.75). More overlay patients requested change owing to dissatisfaction (23.3%) than mattress patients (18.9%, P = 0.02).

Conclusion No difference was found between alternating pressure mattresses and alternating pressure overlays in the proportion of people who develop a pressure ulcer.

Trial registration ISRCTN 78646179

Objective To assess the clinical effectiveness of weekly delivery of low dose, high frequency therapeutic ultrasound in conjunction with standard care for hard to heal venous leg ulcers.

Design Multicentre, pragmatic, two arm randomised controlled trial.

Setting Community and district nurse led services, community leg ulcer clinics, and hospital outpatient leg ulcer clinics in 12 urban and rural settings (11 in the United Kingdom and one in the Republic of Ireland).

Participants 337 patients with at least one venous leg ulcer of >6 months’ duration or >5 cm2 area and an ankle brachial pressure index of ≥0.8.

Interventions Weekly administration of low dose, high frequency ultrasound therapy (0.5 W/cm2, 1 MHz, pulsed pattern of 1:4) for up to 12 weeks plus standard care compared with standard care alone.

Main outcome measures Primary outcome was time to healing of the largest eligible leg ulcer. Secondary outcomes were proportion of patients healed by 12 months, percentage and absolute change in ulcer size, proportion of time participants were ulcer-free, health related quality of life, and adverse events.

Results The two groups showed no significant difference in the time to healing of the reference leg ulcer (log rank test, P=0.61). After adjustment for baseline ulcer area, baseline ulcer duration, use of compression bandaging, and study centre, there was still no evidence of a difference in time to healing (hazard ratio 0.99 (95% confidence interval 0.70 to 1.40), P=0.97). The median time to healing of the reference leg ulcer was inestimable. There was no significant difference between groups in the proportion of participants with all ulcers healed by 12 months (72/168 in ultrasound group v 78/169 in standard care group, P=0.39 for Fisher’s exact test) nor in the change in ulcer size at four weeks by treatment group (model estimate 0.05 (95% CI –0.09 to 0.19)). There was no difference in time to complete healing of all ulcers (log rank test, P=0.61), with median time to healing of 328 days (95% CI 235 to inestimable) with standard care and 365 days (224 days to inestimable) with ultrasound. There was no evidence of a difference in rates of recurrence of healed ulcers (17/31 with ultrasound v 14/31 with standard care, P=0.68 for Fisher’s exact test). There was no difference between the two groups in health related quality of life, both for the physical component score (model estimate 0.69 (–1.79 to 3.08)) and the mental component score (model estimate –0.93 (–3.30 to 1.44)), but there were significantly more adverse events in the ultrasound group (model estimate 0.30 (0.01 to 0.60)). There was a significant relation between time to ulcer healing and baseline ulcer area (hazard ratio 0.64 (0.55 to 0.75)) and baseline ulcer duration (hazard ratio 0.59 (0.50 to 0.71)), with larger and older ulcers taking longer to heal. In addition, those centres with high recruitment rates had the highest healing rates.

Conclusions Low dose, high frequency ultrasound administered weekly for 12 weeks during dressing changes in addition to standard care did not increase ulcer healing rates, affect quality of life, or reduce ulcer recurrence.

Trial registration ISRCTN21175670 and National Research Register N0484162339