Randomised clinical trial to compare total contact casts,healing sandals and a shear‐reducing removable boot to heal diabetic foot ulcers

The objective of this study was to evaluate the efficacy of three off‐loading techniques to heal diabetic foot wounds: total contact casts (TCCs), healing sandals (HSs) and a removable boot with a shear‐reducing foot bed (SRB). This was a 12‐week, single‐blinded randomised clinical trial with three parallel treatment groups of adults with diabetes and a foot ulcer (n = 73). Ulcer healing was defined as full reepithelialisation with no drainage. Diabetic patients with grade UT1A or UT2A forefoot ulcers on the sole of the foot were enrolled. Patients with malignancy, immune‐compromising diseases, severe peripheral vascular disease (ankle‐brachial index < 0·60 or transcutaneous oxygen < 25 mm/Hg), alcohol or substance abuse within 6 months, untreated osteomyelitis or Charcot arthropathy with residual deformity that would not fit the HS or boot were excluded. In the intent‐to‐treat analysis, significantly higher proportion of patients were healed in the TCC group (69·6%) compared to those treated with the SRB (22·2%, P < 0·05). There was no difference in the rate of healed ulcers in the HS (44·5%) and TCC groups. Ulcers in the TCC group healed faster than those in the HS group (5·4 ± 2·9 versus 8·9 ± 3·5 weeks, P < 0·02). However, there was no difference in the time to healing in the TCC and SRB groups (6·7 ± 4·3 weeks, P = 0·28). Patients who used HS were significantly more active (4022 ± 4652 steps per day, P < 0·05) than those treated with TCCs (1447 ± 1310) or SRB (1404 ± 1234). It is concluded that patients treated with TCCs had the highest proportion of healed wounds and fastest healing time. The novel shear‐reducing walker had the lowest healing and highest rate of attrition during the study.     

A pilot study evaluating non‐contact low‐frequency ultrasound and underlying molecular mechanism on diabetic foot ulcers

Non‐contact low‐frequency ultrasound (NCLF‐US) devices have been increasingly used for the treatment of chronic non‐healing wounds. The appropriate dose for NCLF‐US is still in debate. The aims of this pilot study were to evaluate the relationship between dose and duration of treatment for subjects with non‐healing diabetic foot ulcers (DFUs) and to explore the correlation between wound healing and change of cytokine/proteinase/growth factor profile. This was a prospective randomised clinical study designed to evaluate subjects with non‐healing DFUs for 5 weeks receiving standard of care and/or NCLF‐US treatment. Subjects were randomly assigned to one of the three groups: application of NCLF‐US thrice per week (Group 1), NCLF‐US once per week (Group 2) and the control (Group 3) that received no NCLF‐US. All subjects received standard wound care plus offloading for a total of 4 weeks. Percent area reduction (PAR) of each wound compared with baseline was evaluated weekly. Profiles of cytokines/proteinase/growth factors in wound fluid and biopsied tissue were quantified to explore the correlation between wound healing and cytokines/growth factor expression. Twelve DFU patients, 2 (16·7%) type 1 and 10 (83·3%) type 2 diabetics, with an average age of 58 ± 10 years and a total of 12 foot ulcers were enrolled. Average ulcer duration was 36·44 ± 24·78 weeks and the average ABI was 0·91 ± 0·06. Group 1 showed significant wound area reduction at weeks 3, 4 and 5 compared with baseline, with the greatest PAR, 86% (P < 0·05); Groups 2 and 3 showed 25% PAR and 39% PAR, respectively, but there were no statistically significant differences between Groups 2 and 3 over time. Biochemical and histological analyses indicated a trend towards reduction of pro‐inflammatory cytokines (IL‐6, IL‐8, IL‐1β, TNF‐α and GM‐CSF), matrix metalloproteinase‐9 (MMP‐9), vascular endothelial growth factor (VEGF) and macrophages in response to NCLF‐US consistent with wound reduction, when compared with control group subjects. This proof‐of‐concept pilot study demonstrates that NCLF‐US is effective in treating neuropathic diabetic foot ulcers through, at least in part, inhibiting pro‐inflammatory cytokines in chronic wound and improving tissue regeneration. Therapeutic application of NFLU, thrice (3) per week, renders the best wound area reduction.     

Analysis of risk factors for amputation in patients with diabetic foot ulcers: a cohort study from a tertiary center

Objective: This study aimed to analyze risk factors for amputation (overall, minor and major) in patients with diabetic foot ulcers (DFUs).Methods: 407 patients with DFUs (286 male, 121 female; mean age = 60, age range = 32-92) who were managed in a tertiary care centre from 2009 to 2019 were retrospectively identified and included in the study. DFUs were categorized based on the Meggit-Wagner, PEDIS, S(AD)SAD, and University of Texas (UT) classification systems. To identify amputation risk-related factors, results of patients with DFUs who underwent amputations (minor or major) were compared to those who received other adjunctive treatments using Chi-Square, one-way analysis of variance (ANOVA) and Spearman correlation analysis.Results: The mean C-reactive protein (CRP) and White Blood Cell (WBC) values were significantly higher in patients with major or minor amputation than in those without amputation. The mean Neutrophil (PNL), Platelets (PLT), wound width, creatinine and sedimentation (ESR) values were significantly higher in patients with major amputation compared to other groups of patients. Elevated levels of High-density lipoprotein (HDL), Hemoglobin (HGB) and albumin were determined to be protective factors against the risk of amputation. Spearman correlation analysis revealed a positive-sided, strong-levelled, significant relation between Wagner grades and amputation status of patients.Conclusion: This study has identified specific factors for major and minor amputation risk of patients with DFUs. Especially infection markers such as CRP, WBC, ESR and PNL were higher in the amputation group. Most importantly, Meggit Wagner, one of the four different classification systems used in the DFUs, was determined to be highly associated with patients’ amputation risk.Level of Evidence: Level IV, Prognostic Study     

Evidence of differential microbiomes in healing versus non‐healing diabetic foot ulcers prior to and following foot salvage therapy

Diabetic foot ulcers (DFU) contribute to 80% of lower extremity amputations. Although physicians currently rely on clinical signs along with non‐specific biomarkers of infection, such as erythrocyte sedimentation rate and C‐reactive protein, to diagnose and monitor DFU, there is no specific and sensitive measure available to monitor or prognosticate the success of foot salvage therapy (FST). To address this we performed a prospective, observational microbiome analysis to test the hypotheses that: (i) the initial microbiomes of healed versus non‐healed DFU are distinct; (ii) the microbial load, diversity and presence of pathogenic organism of the DFU change in response to antibiotics treatment; and (iii) the changes in the DFU microbiome during treatment are prognostic of clinical outcome. To test this, microbiome analyses were performed on 23 DFU patients undergoing FST, in which wound samples were collected at zero, four, and eight weeks following wound debridement and antibiotics treatment. Bacterial abundance was determined using quantitative polymerase chain reaction (qPCR). Eleven patients healed their DFU, while FDT failed to heal DFU in the other 12 patients. Microbiome results demonstrated that healing DFUs had a larger abundance Actinomycetales and Staphylococcaceae (p < 0.05), while DFUs that did not heal had a higher abundance of Bacteroidales and Streptococcaceae (p < 0.05). FST marked increases Actinomycetales in DFU, and this increase is significantly greater in patients that healed (p < 0.05). Future studies to confirm the differential microbiomes, and that increasing Actinomycetales is prognostic of successful FST are warranted. Statement of Clinical Significance: Tracking changes in the prevalence of pathogens in diabetic foot ulcers may be a clinical tool for monitoring treatment response to foot salvage therapy and prognosticating the need for further surgical intervention. The initial wound sample microbiome may provide important prognostic information on the eventual clinical outcome of foot salvage therapy. It may serve as an important clinical tool for patient counseling and making surgical decision of pursuing foot salvage versus amputation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1596–1603, 2019.     

Angiosome‐targeted revascularisation in diabetic foot ulcers

Peripheral vascular disease is a common complication of type 2 diabetes and is often more severe and diffuse than in non‐diabetic individuals with a higher risk of major amputations in the lower limbs. Diabetic foot revascularisation using both traditional bypass surgery and endovascular therapy are often burdened by the failure and the inevitable subsequent massive amputation. In this study, we examined the clinical response of diabetic patients with critical limb ischaemia and extended ischaemic wounds, treated with a new angiosome‐based revascularisation technique. In a 3‐year period, nine diabetic patients with imminent amputation threatening and foot ulcers with no feasible arterial revascularisation options were treated by the angiosome‐based surgical technique by means of deep vein arterialisation. The postoperative tcPO2 evaluation showed a mean increase in the cutaneous oxygen tension in all patients treated. The overall survival rates were 88·88%, 88·88% and 77·77% at 12, 24 and 36 months, respectively. Limb salvage was 100% at 1 year and steady at 88·88% thereafter. Surgical deep venous arterialisation might be considered as an extreme alternative to attempt tissue preservation in limbs unfit for conventional arterial revascularisations. This technique would give advantages to the patients in terms of better compliance to the minor amputations and thus avoiding major limb amputations.     

Clinical outcome and determinants of amputation in a large cohort of Iranian patients with diabetic foot ulcers

ObjectiveDetermining the predictive factors of diabetes foot ulcer (DFU) development and lower extremity amputations (LEA) in patients with diabetes mellitus (DM) is of great importance to compose risk stratification models. The aim of this study is to investigate the outcome and predictors of LEA in patients with DFU in large sample of Iranian patients.MethodsThis prospective cohort study was conducted during a 2-year period from 2014 to 2016, in Shiraz, southern Iran. All the patients with type 1 and 2 DM and DFU were included in the cohort and were followed for 2 years at least. They were visited in the clinic on a monthly basis and development of new DFU and LEA were recorded. The two-year free-DFU survival and predictors of the DFU development and LEA were recorded. Multivariate regression models were used to determine the factors.ResultsA total number of 432 patients with mean age of 56.8 ± 13.3 years were included. The two-year DFU-free survival rate was 0.826. The two-year DFU-free survival was associated with male gender (p = 0.005), foot deformity (p = 0.002), history of prior DFU (p < 0.001), cigarette smoking (p = 0.032), nephropathy (p = 0.005), retinopathy (p = 0.007), ischemic heart disease (p = 0.043), and neuropathy (p < 0.001).ConclusionDevelopment of new DFU is associated with higher age, longer duration of disease, and type I diabetes. LEA was associated with increased white blood cell (WBC), Creatinine and ulcer history for major amputation and ulcer history, fasting blood sugar (FBS), infection, revascularization history, and foot deformity, for minor amputation.     

Management of negative pressure wound therapy in the treatment of diabetic foot ulcers

Diabetic foot (DF) is a common complication of diabetes and the first cause of hospital admission in diabetic patients. In recent years several guidelines have been proposed to reinforce the the management of DF with a notable increase in diabetes knowledge and an overall reduction of amputations. Significant improvements have been reached in the treatment of diabetic foot ulcers (DFUs) and nowadays clinicians have several advanced medications to apply for the best local therapy. Among these, negative pressure wound therapy (NPWT) is a useful adjunct in the management of chronic and complex wounds to promote healing and wound bed preparation for surgical procedures such as skin grafts and flap surgery. NPWT has shown remarkable results although its mechanisms of action are not completely understood. In this paper, we offer a complete overview of this medication and its implication in the clinical setting. We have examined literature related to NPWT concerning human, animal and in vitro studies, and we have summarized why, when and how we can use NPWT to treat DFUs. Further we have associated our clinical experience to scientific evidence in the field of diabetic foot to identify a defined strategy that could guide clinician in the use of NPWT approaching to DFUs.     

Role of matrix metalloproteinases in non‐healing venous ulcers

Chronic venous ulceration (CVU) of the lower limbs is a common condition affecting 1% of the adult population in Western countries, which is burdened with a high complication rate and a marked reduction in the quality of life often due to prolonged healing time. Several metalloproteinases (MMPs) such as MMP‐9 together with neutrophil gelatinase‐associated lipocalin (NGAL) appear to be involved in the onset and healing phases of venous ulcer, but it is still unclear how many biochemical components are responsible for prolonged healing time in those ulcers. In this study, we evaluate the role of MMP‐1 and MMP‐8 in long lasting and refractory venous ulcers. In a 2‐year period we enroled 45 patients (28 female and 17 male, median age 65) with CVU. The enroled population was divided into two groups: group I were patients with non‐healing ulcers (ulcers that had failed to heal for more than 2 months despite appropriate treatments) and group II were patients with healing ulcers (ulcers in healing phases). MMP‐1 and MMP‐8 were measured in fluids and tissues of healing and non‐healing ulcers by means of enzyme‐linked immunosorbent assay (ELISA) and Western blot analysis, respectively. In particular the patterns of the collagenases MMP‐1 and MMP‐8 in healing wounds were distinct, with MMP‐8 appearing in significantly greater amounts especially in the non‐healing group. Our findings suggest that MMP‐1, and MMP‐8 are overexpressed in long lasting CVU. Therefore, this dysregulation may represent the main cause of the pathogenesis of non‐healing CVU.     

A cost‐effectiveness analysis of optimal care for diabetic foot ulcers in Australia

In addition to affecting quality of life, diabetic foot ulcers (DFUs) impose an economic burden on both patients and the health system. This study developed a Markov model to analyse the cost‐effectiveness of implementing optimal care in comparison with the continuation of usual care for diabetic patients at high risk of DFUs in the Australian setting. The model results demonstrated overall 5‐year cost savings (AUD 9100·11 for those aged 35–54, $9391·60 for those aged 55–74 and $12 394·97 for those aged 75 or older) and improved health benefits measured in quality‐adjusted life years (QALYs) (0·13 QALYs, 0·13 QALYs and 0·16 QALYs, respectively) for high‐risk patients receiving optimal care for DFUs compared with usual care. Total cost savings for Australia were estimated at AUD 2·7 billion over 5 years. Probabilistic sensitivity analysis showed that optimal care always had a higher probability of costing less and generating more health benefits. This study provides important evidence to inform Australian policy decisions on the efficient use of health resources and supports the implementation of evidence‐based optimal care in Australia. Furthermore, this information is of great importance for comparable developed countries that could reap similar benefits from investing in these well‐known evidence‐based strategies.     

Cilostazol prevents foot ulcers in diabetic patients with peripheral vascular disease

Diabetic patients are at high risk of foot ulcerations that may lead to limb amputations with important socio‐economic impact. Peripheral vascular disease may be frequently associated in diabetes mellitus type II with its main symptom, intermittent claudication. Many studies reported the known efficacy of cilostazol in treating vascular claudication. Metalloproteinase‐9 (MMP‐9) seems to be a biochemical marker implicated in chronic wounds and in particular in diabetic foot ulcers. Cilostazol appears to have a lowering effect on MMP‐9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients. In our study, two groups of diabetic patients with peripheral vascular disease were divided into two groups according to the presence of claudication in order to receive cilostazol. Group A (31 patients without claudication) were not eligible to receive cilostazol whereas Group B (47 patients with claudication) received cilostazol administration for 24 weeks (100 mg orally twice daily). Median follow up was of 16 months. During the follow up, 4·25% of patients of Group B and 35·48% of patients of Group A (P < 0·01) showed onset of foot ulceration. Although further randomised and controlled studies are required cilostazol seems to show beneficial effects for primary prevention of diabetic foot ulcers.     

Diabetes foot ulceration in a Nigerian hospital: in‐hospital mortality in relation to the presenting demographic,clinical and laboratory features

This prospective study assessed in‐hospital mortality from diabetic foot ulcer in relation to the demographic, clinical and laboratory features at presentation. Forty‐two patients admitted with diabetic foot ulcer were followed up from admission till discharge from hospital. Those who survived or died were compared for any differences in demographic, clinical and laboratory parameters at presentation. The mean age and duration of diabetes for the 42 patients were 56.1 ± 1.9 years and 8.3 ± 1.1 years, respectively. The in‐hospital mortality rate amongst the 42 subjects was 40.5%. Ulcer grade 4, leucocytosis and anaemia were more prevalent in those who demised in comparison with survivors.     

Ulcer‐free survival days and ulcer healing in patients with diabetic foot ulcers: A prospective cohort study

Healing rates may not give a complete indication of the effectiveness and management of diabetic foot ulcers because of high recurrence rates. The most important outcome for patients is remaining ulcer‐free; however, this has hardly been investigated. The aim of our study was to prospectively investigate ulcer‐free survival days and ulcer healing in patients with diabetic foot ulcers. This was a prospective cohort study of all referrals to our diabetic foot expertise centre from December 2014 to April 2017. Outcomes were determined after a minimum follow‐up period of 12 months. Primary outcomes were ulcer‐free survival days and 12‐month healing percentages. Predictors for ulcer‐free survival days and healing were investigated in multivariate analyses. A total of 158 patients were included. Median ulcer‐free survival days in the healed group were 233 days (interquartile range [IQR] 121‐312) and 131 days (IQR 0–298) in the overall population. The healing rate at 12‐month follow up was 67% (106/158), and the recurrence rate was 31% (33/106). Independent predictors of ulcer‐free survival days were duration of diabetes, peripheral artery disease (PAD), cardiovascular disease, end‐stage renal disease (ESRD), and infection. Ulcer‐free survival days are related to PAD and cardiovascular disease, and ulcer‐free survival days should be the main outcome when comparing the effectiveness of management and prevention of the diabetic foot ulcers.     

The efficacy of topical royal jelly on healing of diabetic foot ulcers: a double‐blind placebo‐controlled clinical trial

Foot ulcers are major sources of morbidity in individuals with diabetes mellitus. As royal jelly (RJ, a worker honey bee product) contains enzymatic, antibacterial and vasodilative properties, it can potentially help in healing of diabetic foot ulcers (DFUs). This study aimed to evaluate the efficacy of topical RJ on healing of DFUs. Diabetic patients with foot ulcers who were referred to us at Khorshid Hospital, Isfahan, Iran, were managed by offloading, infection control, vascular improvement and debridement (if required). Then, all ulcers were randomly selected to receive either 5% sterile topical RJ or placebo on their total surface area. Patients were followed for 3 months or until complete healing. Twenty‐five patients (6 females and 19 males) and a total of 64 ulcers were included and randomly allocated to case or control group (32 per group). Four ulcers were excluded and 60 ulcers included in the final analysis. Healing parameters including depth, length and width reduction rate, duration of complete healing and incidence of complete healing did not show any significant difference (P = 0·69, 0·95, 0·7, 0·74 and 0·6, respectively) between groups. We did not observe any side effect of topical RJ application. This study could not confirm any significant superiority of 5% topical RJ over placebo for the treatment of DFUs.     

Relationship between maceration and wound healing on diabetic foot ulcers in Indonesia: a prospective study

The aim of this study was to clarify the relationship between maceration and wound healing. A prospective longitudinal design was used in this study. The wound condition determined the type of dressings used and the dressing change frequency. A total of 62 participants with diabetic foot ulcers (70 wounds) were divided into two groups: non‐macerated (n = 52) and macerated wounds (n = 18). Each group was evaluated weekly using the Bates–Jensen Wound Assessment Tool, with follow‐ups until week 4. The Mann–Whitney U test showed that the changes in the wound area in week 1 were faster in the non‐macerated group than the macerated group (P = 0·02). The Pearson correlation analysis showed a moderate correlation between maceration and wound healing from enrolment until week 4 (P = 0·002). After week 4, the Kaplan–Meier analysis showed that the non‐macerated wounds healed significantly faster than the macerated wounds (log‐rank test = 19·378, P = 0·000). The Cox regression analysis confirmed that maceration was a significant and independent predictor of wound healing in this study (adjusted hazard ratio, 0·324; 95% CI, 0·131–0·799; P = 0·014). The results of this study demonstrated that there is a relationship between maceration and wound healing. Changes in the wound area can help predict the healing of wounds with maceration in clinical settings.     

Differences in the daily activity of patients with diabetic foot ulcers compared to controls in their free‐living environments

The aims of our study were to investigate multiple daily activity outcomes in patients with diabetic foot ulcers (DFU) compared to diabetic peripheral neuropathy (DPN) and diabetes (DM) controls in their free‐living environments. We examined daily activity outcomes of 30 patients with DFU, 23 DPN and 20 DM. All patients wore a validated multi‐sensor device for > 5 days (>22 hours per day) to measure their daily activity outcomes: steps, energy expenditure (kJ), average metabolic equivalent tasks (METs), physical activity (>3·0 METs) duration and energy expenditure, lying duration, sleep duration and sleep quality. We found that DFU patients recorded fewer median (interquartile ranges, IQR) daily steps [2154 (1621–4324)] than DPN [3660 (2742–7705)] and DM [5102 (4011–7408)] controls (P < 0·05). In contrast, DFU patients recorded more mean ± SD daily energy expenditure (kJ) (13 006 ± 3559) than DPN (11 085 ± 1876) and DM (11 491 ± 1559) controls (P < 0·05). We found no other differences in daily activity outcomes (P > 0·1). We conclude that DFU patients typically take fewer steps but expend more energy during their normal daily activity than DPN and DM controls. We hypothesise that the increased energy expenditure for DFU patients may be due to wound healing or an inefficient gait strategy. Further investigations into this energy imbalance in DFU patients may improve healing in future.     

糖尿病足的影像学研究进展

糖尿病足(DF)是糖尿病患者长期神经病变和(或)不同程度血管病变导致的严重慢性并发症,是非外伤性截肢的主要原因。影像学检查对糖尿病足的诊断具有重要意义,本文就目前糖尿病足的影像学研究进展进行综述。     

Monitoring of diabetic foot syndrome treatment: some new perspectives

Diabetic foot syndrome (DFS) is one of the major complications of diabetes, and it can lead to foot amputations. It is very important to assure good medical care for diabetic patients not only during their stay at hospital but also at home. Telecare can be one good solution for extending medical care to patients' homes. There are some reports regarding the application of new technologies in this field. The standard current model of telecare of DFS includes experts at hospital who conduct clinical examinations and decision making at a distance, in close cooperation with a visiting nurse and the patient. In the present paper a new paradigm of the DFS's telecare is introduced, which eliminates the visiting nurse. The designed and developed TeleDiaFoS system consists of a traditional database and mobile patient's module (PM) allowing for documentation of the foot images as well as the results of blood glucose and blood pressure measurements taken by the patient himself at home. A 2-year validation of the TeleDiaFoS system on 10 DFS patients (3 months each) proved its usefulness and led to acceptance of this type of technical support by patients and physicians. The designed and developed system and proposed sterilization procedure of the PM have been found to be easy to use by the patient at home.     

Literature review on the management of diabetic foot ulcer

Diabetic foot ulcer (DFU) is the most costly and devastating complication of diabetes mellitus, which affect 15% of diabetic patients during their lifetime. Based on National Institute for Health and Clinical Excellence strategies, early effective management of DFU can reduce the severity of complications such as preventable amputations and possible mortality, and also can improve overall quality of life. The management of DFU should be optimized by using a multidisciplinary team, due to a holistic approach to wound management is required. Based on studies, blood sugar control, wound debridement, advanced dressings and offloading modalities should always be a part of DFU management. Furthermore, surgery to heal chronic ulcer and prevent recurrence should be considered as an essential component of management in some cases. Also, hyperbaric oxygen therapy, electrical stimulation, negative pressure wound therapy, bio-engineered skin and growth factors could be used as adjunct therapies for rapid healing of DFU. So, it’s suggested that with appropriate patient education encourages them to regular foot care in order to prevent DFU and its complications.