OBJECTIVEChronic diabetic foot ulcers are a source of major concern for both patients and health care systems. The aim of this study was to evaluate the effect of hyperbaric oxygen therapy (HBOT) in the management of chronic diabetic foot ulcers.RESEARCH DESIGN AND METHODSThe Hyperbaric Oxygen Therapy in Diabetics with Chronic Foot Ulcers (HODFU) study was a randomized, single-center, double-blinded, placebo-controlled clinical trial. The outcomes for the group receiving HBOT were compared with those of the group receiving treatment with hyperbaric air. Treatments were given in a multi-place hyperbaric chamber for 85-min daily (session duration 95 min), five days a week for eight weeks (40 treatment sessions). The study was performed in an ambulatory setting.RESULTSNinety-four patients with Wagner grade 2, 3, or 4 ulcers, which had been present for >3 months, were studied. In the intention-to-treat analysis, complete healing of the index ulcer was achieved in 37 patients at 1-year of follow-up: 25/48 (52%) in the HBOT group and 12/42 (29%) in the placebo group (P = 0.03). In a sub-analysis of those patients completing >35 HBOT sessions, healing of the index ulcer occurred in 23/38 (61%) in the HBOT group and 10/37 (27%) in the placebo group (P = 0.009). The frequency of adverse events was low.CONCLUSIONSThe HODFU study showed that adjunctive treatment with HBOT facilitates healing of chronic foot ulcers in selected patients with diabetes.

Aims/hypothesis We sought to identify factors related to shortterm outcome of foot ulcers in patients with diabetes treated in a multidisciplinary system until healing was achieved. Methods Consecutively presenting patients with diabetes and worst foot ulcer (Wagner grade 1-5, below ankle) (n=2,511) were prospectively followed and treated according to a standardised protocol until healing was achieved or until death. The number of patients lost to dropout was 31.The characteristics of the remaining 2,480 patients were: 1,465 men, age 68±15 years (range 18-96), type 1 diabetes 18%, type 2 diabetes 82% and insulin-treated 62%. Results The healing rate without major amputation in surviving patients was 90.6% (n=1,867). Sixty-five per cent (n=1,617) were healed primarily, 9% (n=250) after minor amputation and 8% after major amputation; 17% (n=420) died unhealed. Out of 2,060 surviving patients, 1,007 were neuroischaemic (48.8%). In a multiple regression analysis, primary healing was related to co-morbidity, duration of diabetes, extent of peripheral vascular disease and type of ulcer. In neuropathic ulcers, deep foot infection, site of ulcer and co-morbidity were related to amputation. Amputation in neuroischaemic ulcers was related to comorbidity, peripheral vascular disease and type of ulcer. Age, sex, duration of diabetes, neuropathy, deformity and duration of ulcer or site of ulcer did not have an evident influence on probability of amputation. Conclusions/interpretation Patients with diabetic foot ulcer suffer from multi-organ disease. Factors related to outcome are correspondingly complex.

The outcome of management of diabetic foot ulcers remains a challenge, and there remains continuing uncertainty concerning optimal approaches to management. It is for these reasons that in 2008 and 2012, the International Working Group of the Diabetic Foot (IWGDF) working group on wound healing published systematic reviews of the evidence to inform protocols for routine care and to highlight areas, which should be considered for further study. The same working group has now updated this review by considering papers on the interventions to improve the healing of chronic ulcers published between June 2010 and June 2014. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network criteria. Selected studies fell into the following ten categories: sharp debridement and wound bed preparation with larvae or hydrotherapy; wound bed preparation using antiseptics, applications and dressing products; resection of the chronic wound; oxygen and other gases, compression or negative pressure therapy; products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing; application of cells, including platelets and stem cells; bioengineered skin and skin grafts; electrical, electromagnetic, lasers, shockwaves and ultrasound and other systemic therapies, which did not fit in the aforementioned categories. Heterogeneity of studies prevented pooled analysis of results. Of the 2161 papers identified, 30 were selected for grading following full text review. The present report is an update of the earlier IWGDF systematic reviews, and the conclusion is similar: that with the possible exception of negative pressure wound therapy in post-operative wounds, there is little published evidence to justify the use of newer therapies. Analysis of the evidence continues to present difficulties in this field as controlled studies remain few and the majority continue to be of poor methodological quality.

SummaryThe outcome of management of diabetic foot ulcers is poor and there is uncertainty concerning optimal approaches to management. We have undertaken a systematic review to identify interventions for which there is evidence of effectiveness. A search was made for reports of the effectiveness of interventions assessed in terms of healing, ulcer area or amputation in controlled clinical studies published prior to December 2006. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network (SIGN) criteria. Selected studies fell into the following categories: sharp debridement and larvae; antiseptics and dressings; chronic wound resection; hyperbaric oxygen (HBO); reduction of tissue oedema; skin grafts; electrical and magnetic stimulation and ultrasound. Heterogeneity of studies prevented pooled analysis of results. Of the 2251 papers identified, 60 were selected for grading following full text review. Some evidence was found to support hydrogels as desloughing agents and to suggest that a systemic (HBO) therapy may be effective. Topical negative pressure (TNP) may promote healing of post-operative wounds, and resection of neuropathic plantar ulcers may be beneficial. More information was needed to confirm the effectiveness and cost-effectiveness of these and other interventions. No data were found to justify the use of any other topically applied product or dressing, including those with antiseptic properties. Further evidence to substantiate the effect of interventions designed to enhance the healing of chronic ulcers is urgently needed. Until such evidence is available from robust trials, there is limited justification for the use of more expensive treatments and dressings.

SUMMARYThe outcome of management of diabetic foot ulcers is poor, and there is continuing uncertainty concerning optimal approaches to management. It was for these reasons that in 2006 the International Working Group of the Diabetic Foot (IWGDF) working group on wound healing undertook a systematic review of the evidence to inform protocols for routine care and to highlight areas which should be considered for further study. The same working group has now updated this review by considering papers on the interventions to improve the healing of chronic ulcers published between December 2006 and June 2010. Methodological quality of selected studies was independently assessed by two reviewers using Scottish Intercollegiate Guidelines Network criteria. Selected studies fell into the following ten categories: sharp debridement and wound bed preparation with larvae and hydrotherapy; wound bed preparation using antiseptics, applications and dressing products; resection of the chronic wound; hyperbaric oxygen therapy (HBOT); compression or negative pressure therapy; products designed to correct aspects of wound biochemistry and cell biology associated with impaired wound healing; application of cells, including platelets and stem cells; bioengineered skin and skin grafts; electrical, electromagnetic, lasers, shockwaves and ultrasound; other systemic therapies which did not fit in the above categories. Heterogeneity of studies prevented pooled analysis of results. Of the 1322 papers identified, 43 were selected for grading following full text review. The present report is an update of the earlier IWGDF systematic review, but the conclusion is similar: that with the exception of HBOT and, possibly, negative pressure wound therapy, there is little published evidence to justify the use of newer therapies. This echoes the conclusion of a recent Cochrane review and the systematic review undertaken by the National Institute for Health and Clinical Excellence Guidelines Committee in the UK. Analysis of evidence presents considerable difficulties in this field particularly as controlled studies are few and the majority are of poor methodological quality. Copyright © 2012 John Wiley & Sons, Ltd.Keywords diabetes; diabetic foot; ulcer; wound healing; dressing Abbreviations ABPI -ankle : brachial pressure index AKA -above knee amputation ATA -atmosphere absolute (pressure) bFGF -basic fibroblast growth factor BKA -below knee amputation CBA -control before and after (study) DFU -diabetic foot ulcer EGF -epidermal growth factor GCSF -granulocyte-colony stimulating factor HBOT -hyperbaric oxygen therapy

Reapplix ApS.

OBJECTIVETo study trough levels of metformin in serum and its intra-individual variation in patients using a newly developed assay.RESEARCH DESIGN AND METHODSTrough serum levels of metformin were measured once using liquid chromatography–tandem mass spectrometry (LCMSMS) in 137 type 2 diabetic patients with varying renal function (99 men) and followed repeatedly during 2 months in 20 patients (16 men) with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 body surface.RESULTSPatients with eGFR >60, 30–60, and <30 ml/min/1.73 m2 had median trough metformin concentrations of 4.5 μmol/l (range 0.1–20.7, n = 107), 7.71 μmol/l (0.12–15.15, n = 21), and 8.88 μmol/l (5.99–18.60, n = 9), respectively. The median intra-individual overall coefficient of variation was 29.4% (range 9.8–74.2).CONCLUSIONSDetermination of serum metformin with the LCMSMS technique is useful in patients on metformin treatment. Few patients had values >20 μmol/l. Metformin measurement is less suitable for dose titration.

Recommendations1. Clean ulcers regularly with clean water or saline, debride them when possible in order to remove debris from the wound surface and dress them with a sterile, inert dressing in order to control excessive exudate and maintain a warm, moist environment in order to promote healing. (GRADE strength of recommendation: strong; quality of evidence: low) 2. In general, remove slough, necrotic tissue and surrounding callus with sharp debridement in preference to other methods, taking relative contraindications such as severe ischemia into account. (strong; low) 3. Select dressings principally on the basis of exudate control, comfort and cost. (strong; low) 4. Do not use antimicrobial dressings with the goal of improving wound healing or preventing secondary infection. (strong; moderate) 5. Consider the use of systemic hyperbaric oxygen therapy, even though further blinded and randomized trials are required to confirm its costeffectiveness, as well as to identify the population most likely to benefit from its use. (weak; moderate) 6. Topical negative pressure wound therapy may be considered in postoperative wounds even though the effectiveness and cost-effectiveness of the approach remain to be established. (weak; moderate) 7. Do not select agents reported to improve wound healing by altering the biology of the wound, including growth factors, bioengineered skin products and gases, in preference to accepted standards of good quality care. (strong; low) 8. Do not select agents reported to have an impact on wound healing through alteration of the physical environment, including through the use of electricity, magnetism, ultrasound and shockwaves, in preference to accepted standards of good quality care. (strong; low) 9. Do not select systemic treatments reported to improve wound healing, including drugs and herbal therapies, in preference to accepted standards of good quality care. (strong; low)