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Aim To investigate the effectiveness of fast-track pathway (FTP) in the management of diabetic foot ulceration (DFU) after 2 years of implementation. Methods The study group was composed of patients who referred to a specialized DF centre due to DFUs. Those were divided in two groups: early referral (ER) and late referral (LR) patients. According to FTP, ER were considered patients who referred after 2 weeks in the case of uncomplicated non-healing ulcers (superficial, not infected, not ischemic), within 4 days in the case of complicated ulcers (ischemic, deep, mild infection) and within 24 h in the case of severely complicated ulcers (abscess, wet gangrene, fever). Healing, healing time, minor and major amputation, hospitalization, and survival were evaluated. The follow-up was 6 months. Results Two hundred patients were recruited. The mean age was 70 ± 13 years, 62.5% were male, 91% were affected by type 2 diabetes with a mean duration of 18 ± 11 years. Within the group, 79.5% had ER while 20.5% had LR. ER patients showed increased rates of healing (89.9 vs. 41.5%, p = 0.001), reduced healing time (10 vs. 16 weeks, p = 0.0002), lower rates of minor (17.6 vs. 75.6%, p p p = 0.001), and mortality (4.4 vs. 19.5%, p = 0.02) in comparison to LR. At multivariate analysis, ER was an independent predictor of healing, while LR was an independent predictor for minor and major amputation and hospitalization. Conclusion After the FTP implementation, less cases of LR were reported in comparison to ER. ER was an independent predictor of positive outcomes such as healing, healing time, limb salvage, hospitalization, and survival.

Clinical evidences have shown good results using dermal/epidermal substitutes (DESs) to treat diabetic foot ulcers. Recent studies suggest that, in addition to their scaffold action, DESs may favor wound healing by influencing wound bed inflammatory cells. This study aims to investigate whether DES may influence the inflammatory infiltrate and macrophages polarization toward a reparative phenotype. Fifteen diabetic patients with chronic foot ulcers have been randomly enrolled: 5 treated only by standard of care, served as control group (CG), and 10 treated with DES composed of type 1 bovin collagen (Nevelia, SYMATESE) considered as test group (TG). A biopsy was taken at baseline (T0) and after 30 days (T1). From bioptic paraffin specimen histological, immunohistochemical, and immunofluorescence analysis was performed. Immunohistochemistry reactions evaluated the number of M1 macrophage (CD38+) and M2 macrophage (CD163+). TG patients displayed general macrophage activation and their greater polarization toward M2 subpopulation 30 days after DES implant, compared with CG. From T0 to T1 there was a significant decrease of CD38+ (230 ± 42 and 135 ± 48 mm2, respectively; P < .001) and significant increase of CD163+ (102 ± 21 positive cells/mm2 and 366 ± 42 positive cells/mm2, respectively; P < .001). Confocal microscopy confirmed an increase of M2 cells as expressed by the reduced CD68+/CD163+ ratio. After 6 months of observation 6 patients (60%) of the TG completely healed, while only 1 patient (20%) healed in the CG ( P < .01). The tested DES makes possible to treat diabetic foot ulcers inducing tissue reparative processes through macrophage activation and M2 reparative polarization.

Diabetic foot syndrome (DFS) is a complex disease. The best outcomes are reported with the multi-disciplinary team (MDT) approach, where each member works collaboratively according to his/her expertise. However, which health provider should act as the team leader (TL) has not been determined. The TL should be familiar with the management of diabetes, related complications and comorbidities. He/she should be able to diagnose and manage foot infections, including prompt surgical treatment of local lesions, such as abscesses or phlegmons, in an emergent way in the first meeting with the patient. According to the Organization for Economic Co-operation and Development (OECD) reports, Italy is one of countries with a low amputation rate in diabetic patients. Many factors might have contributed to this result, including 1)the special attention directed to diabetes by the public health system, which has defined diabetes as a "protected disease", and accordingly, offers diabetic patients, at no charge, the best specialist care, including specific devices, and 2)the presence of a network of diabetic foot (DF) clinics managed by diabetologists with medical and surgical expertise. The health care providers all share a "patient centred model" of care, for which they use their internal medicine background and skills in podiatric surgery to manage acute or chronic needs in a timely manner. Therefore, according to Italian experiences, which are fully reported in this document, we believe that only a skilled diabetologist/endocrinologist should act as a TL. Courses and university master's degree programmes focused on DF should guarantee specific training for physicians to become a TL.

The study aims to evaluate the effectiveness of foot revascularization in persons with diabetic foot ulcers (DFUs) and below-the-ankle (BTA) arterial disease. Consecutive patients referred for a new active ischaemic DFU requiring lower limb revascularization were considered. Among those, only patients with a BTA arterial disease were included. Revascularization procedures were retrospectively analysed: in the case of successful foot revascularization (recanalization of pedal artery, or plantar arteries or both) or not, patients were respectively divided in two groups, successful foot perfusion (SFP) and failed foot perfusion (FFP). Healing, minor and major amputation at 12 months of follow-up were evaluated and compared. Eighty patients (80) were included. The mean age was 70.5 ± 10.9 years, 55 (68.7%) were male, 72 (90%) were affected by type 2 diabetes with a mean duration of 22.7 ± 11.3 years. Overall 45 (56.2%) patients healed, 47 (58.7%) had minor amputation and 13 (16.2%) major amputation. Outcomes for SFP and FFP were respectively: healing (89.3 vs. 9.1%, p &lt, 0.0001), minor amputation (44.7 vs. 78.8%, p = 0.0001), major amputation (2.1 vs. 36.3%, p &lt, 0.0001). Failed foot revascularization resulted an independent predictor of non-healing, minor amputation, and major amputation. Foot revascularization is mandatory to achieve healing and avoid major amputation in persons with ischaemic DFU and BTA arterial disease.

Objective: To describe the angiographic characteristics of peripheral arterial disease (PAD) in persons with diabetic foot ulcers (DFUs) on dialysis treatment. Method: The study is a retrospective analysis of patients with DFUs and PAD who had been referred to our diabetic foot clinic. All patients had been managed by a pre-set limb salvage protocol including revascularisation of the affected limb. Arterial lesions (stenosis between 50–99% and occlusions) were retrospectively evaluated through angiogram analysis. According to the presence or not of dialysis, patients were divided into two patient groups: renal-diabetic foot (RDF) and diabetic foot (DF). Distribution of PAD and immediate revascularisation outcome (technical revascularisation outcome) for RDF and DF were separately reported and compared. Results: The sample included 239 patients: mean age was 71.8 years; 72.4% were male; 87.4% had type 2 diabetes; mean diabetes duration was 21.4 years; and the mean HbA1c was 63±22mmol/mol. The RDF group compared with the DF group reported higher numbers of vessels affected (n=5±1.6 versus 3.9±1.5, respectively, pConclusion: In this study, RDF patients showed a widespread distribution of arterial lesions with a higher involvement of foot arteries in comparison with DF patients. BTA arterial disease was found to be an independent predictor of revascularisation failure.

Background: International comparisons of diabetes-related lower extremity amputation rates are still hampered by different criteria used for data collection and analysis. We aimed to evaluate trends and variation of major/minor amputations, using agreed definitions adopted by the Organization for Economic Cooperation and Development in 2015. Methods: Direct age–sex standardized rates were calculated per 100,000 subjects per year between 2000 and 2013, using major/minor amputations with diabetes diagnosis as numerators and the total population or number of people with diabetes as denominators. Longitudinal trends were investigated using generalized estimating equations. Results: Twenty-one countries reported major amputations referred to the general population, showing a mean reduction from 10.8 to 7.5 per 100,000 (− 30.6%). Eleven countries also reported major amputations among people with diabetes, showing a mean reduction from 182.9 to 128.3 per 100,000 (− 29.8%). Minor amputations remained stable over the study period. Longitudinal trends showed a significant average annual decrease of − 0.19 per 100,000 in the general population (95% CI − 0.36 to − 0.02; p =.03) and − 4.52 per 100,000 among subjects with diabetes (95% CI − 6.09 to − 2.94; p

A systematic review and quality assessment was performed to assess the management of diabetic foot osteomyelitis by medical or surgical treatment. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used. All selected studies were evaluated using the Cochrane Risk of Bias Tool to assess the risk of bias for randomized controlled trials. The literature was revised using PubMed (Medline) and Embase (Elsevier) up to September 2020 to identify clinical trials assessing medical or surgical treatment to manage diabetic foot osteomyelitis. A total of six clinical trials that met our inclusion criteria, with a total of 308 participants. Healing rate, complete closure of the wound, and type of complications were the outcomes evaluated. Risk of bias assessment showed that only two of the six clinical trials included in the systematic review had a low risk of bias. Based on our findings, we believe that the management of diabetic foot osteomyelitis remains challenging. There are few high-quality clinical trials that both stratify clinical presentations and compare these treatments. We conclude that the available evidence is insufficient to identify the best option to cure diabetic foot osteomyelitis.

Il piede diabetico rappresenta una delle complicanze più severe del Diabete Mellito (DM) oltre che la prima causa di amputazione non traumatica degli arti inferiori; si stima, infatti, che ogni anno più di un milione di persone con DM siano sottoposte a trattamento demolitivo come conseguenza di questa condizione. Nonostante l’esistenza di linee guida nazionali ed internazionali sul management del piede diabetico, per alcuni aspetti gestionali le raccomandazioni proposte non raggiungono un forte livello di evidenza. Ciò rappresenta una potenziale fonte di incertezza decisionale, ma anche uno spunto da cui partire per chiarire aspetti legati al management del piede diabetico nella realtà italiana. L’obiettivo del presente documento è, quindi, quello di riadattare le raccomandazioni internazionali sulla gestione del piede diabetico alla luce dell’opinione di esperti italiani.

The study aimed to evaluate clinical and vascular characteristics, as well as outcomes, for diabetic persons with foot ulceration and no-option critical limb ischemia (CLI). The study group included a sample of patients admitted to our diabetic foot unit because of a new diabetic foot ulcer and CLI. All subjects were managed using a limb salvage protocol which includes lower-limb revascularization. According to whether or not the revascularization procedure was a success, patients were respectively divided into two groups: successfully treated CLI patients (ST-CLI) and no-option CLI patients (NO-CLI). Failed revascularization was considered in the case of technical recanalization failure of occluded vessels (inability to overcome the obstruction) and/or absence of arterial flow to the foot. Limb salvage, major amputation, and death after 1 year of follow-up were evaluated and compared between the two groups. Overall, 239 patients were included, 74.9% belonging to ST-CLI and 25.1% to NO-CLI. NO-CLI patients reported more cases of ischemic heart disease (80 vs. 62.1, p = 0.008), heart failure (63.3 vs. 32.4%, p &lt, 0.0001), and end-stage renal disease (ESRD) (60 vs. 25.7%) than ST-CLI patients. In addition, more vessels were affected in the NO-CLI group (5.2 &plusmn, 1.6 vs. 4 &plusmn, 1.5, p &lt, 0.0001), and there was more involvement of tibio-peroneal trunk (50 vs. 30.2%, p = 0.006), anterior tibial (93.3 vs. 82.7, p = 0.03), posterior tibial (93.3 vs. 73.7%, p = 0.0005), peroneal (70 vs. 48%, p = 0.002), and below-the-ankle arteries (73.3 vs. 39.1%, p &lt, 0.0001) than ST-CLI. The 1 year outcomes for the whole population were 69.9% limb salvage, 10.9% major amputation, and 19.2% death. The outcomes for NO-CLI and ST-CLI were, respectively, as follows: limb salvage (13.8 vs. 73.4%, p &lt, 0.0001), amputation (30 vs. 4.5%, p = 0.0001), and mortality (50 vs. 8.9%, p &lt, 0.0001). NO-CLI patients showed a more severe pattern of peripheral arterial disease (PAD) with distal arterial lesions and worse outcomes than ST-CLI.

IntroductionThe aim of the study was to identify the sociodemographic and clinical factors associated with death after the first lower-extremity amputation (LEA), minor and major separately, using data from regional health administrative databases.Research design and methodsWe carried out a population-based cohort study including patients with diabetes residing in the Lazio region and undergoing a primary amputation in the period 2012–2015. Each individual was followed up for at least 2 years. Kaplan-Meier analysis was used to evaluate long-term survival; Cox proportional regression models were applied to identify factors associated with all-cause mortality.ResultsThe cohort included 1053 patients, 72% were male, 63% aged ≥65 years, and 519 (49%) died by the end of follow-up. Mortality rates at 1 and 4 years were, respectively, 33% and 65% for major LEA and 18% and 45% for minor LEA. Significant risk factors for mortality were age ≥65, diabetes-related cardiovascular complications, and chronic renal disease for patients with minor LEA, and age ≥75 years, chronic renal disease and antidepressant drug consumption for subjects with major LEA.ConclusionsThe present study confirms the high mortality rates described in patients with diabetes after non-traumatic LEA. It shows differences between minor and major LEA in terms of mortality rates and related risk factors. The study highlights the role of depression as specific risk factor for death in patients with diabetes after major LEA and suggests including its definition and management in strategies to reduce the high mortality rate observed in this group of patients.

Background and Aims The diabetic foot (DF) was traditionally considered a local foot problem due to diabetes; however many observations support the concept that the DF is actually a part of a more complex diabetes related syndrome which includes several long-term complications and co-morbidities. In recent years, an increase in the incidence of ischemic diabetic foot ulcers (DFUs) amongst dialyzed subjects has been observed, going up from approximately 5-10% fifteen years ago to the current rate of approximately 30-35%. Today it is well recognized that end stage renal disease (ESRD) is an independent risk factor for non-healing ulcers and amputation in diabetic subjects. In clinical practice, the presence of foot problems in ESRD diabetic patients is identified as a specific entity termed “renal-diabetic foot”. The aim of this study is to describe the angiographic characteristics of peripheral arterial disease (PAD) in patients with DFUs receiving chronic dialysis treatment. Method The study group was composed of patients with DFUs and PAD who referred to our diabetic foot unit. All patients have been managed with a pre-set limb salvage protocol including revascularization of the affected limb. Arterial lesions (stenosis between 50-99% and occlusions) were retrospectively evaluated through angiogram analysis. According to the presence of dialytic treatment, patients were divided in two subgroups: renal-diabetic foot (RDF) and diabetic foot (DF). Patterns of PAD and immediate revascularization outcome (technical revascularization outcome) for RDF and DF were separately reported and compared Results The demographic and clinical characteristics were reported in Table 1.RDF reported greater number of affected vessels (n= 5±1.6 vs 3.9±1.5, p Conclusion It was interesting to highlight that the above mentioned findings could be specifically related to the effect of renal disease on the arteries of the lower extremity because the two groups, RDF and DF, did not report any difference in terms of other traditional cardiovascular risk factors (age, smoke, arterial hypertension, dyslipidemia, diabetes duration) which could influence the characteristics of PAD. RDF patients showed a widespread distribution of arterial lesions with a higher involvement of foot arteries in comparison to DF subjects. BTA arterial disease is an independent predictor of revascularization failure.

Diabetic foot infections (DFIs) are severe complications of long-standing diabetes, and they represent a diagnostic challenge, since the differentiation between osteomyelitis (OM), soft tissue infection (STI), and Charcot’s osteoarthropathy is very difficult to achieve. Nevertheless, such differential diagnosis is mandatory in order to plan the most appropriate treatment for the patient. The isolation of the pathogen from bone or soft tissues is still the gold standard for diagnosis; however, it would be desirable to have a non-invasive test that is able to detect, localize, and evaluate the extent of the infection with high accuracy. A multidisciplinary approach is the key for the correct management of diabetic patients dealing with infective complications, but at the moment, no definite diagnostic flow charts still exist. This review aims at providing an overview on multimodality imaging for the diagnosis of DFI and to address evidence-based answers to the clinicians when they appeal to radiologists or nuclear medicine (NM) physicians for studying their patients.

This study aims to evaluate clinical and ulcer characteristics as well the outcomes of patients with diabetic foot ulcers (DFUs). The study group was composed of DFUs patients managed by a limb salvage protocol according to guidance. Clinical and ulcers findings were described, and 1-year outcomes defined as limb salvage, healing, healing time, major amputation and death were compared between neuropathic and ischemic DFUs. One thousand, one hundred and ninety-eight subjects were included, 386 (32.2%) neuropathic and 812 (67.8%) ischemic DFUs. Neuropathic patients were younger (69.5 &plusmn, 11.5 vs. 74.5 &plusmn, 11.5, p &lt, 0.0001) and reported less cases of nephropathy (22.8 vs. 39.6%, p &lt, 0.0001), ischemic heart disease (22.8 vs. 36.9, p = 0.0004), cerebrovascular disease (8.3 vs. 17.2%, p = 0.002), heart failure (10.1 vs. 24.7%, p = 0.0002) and end-stage-renal-disease (ESRD) (5.4 vs. 27%, p = 0.0001) than ischemic patients, they also showed less cases of large (&gt, 5 cm2) (10.3 vs. 22.9%, p = 0.0007), infected (40.4 vs. 55.7%, p = 0.0005) and deep to the bone (22.3 vs. 39.2, p = 0.0002) ulcers, as well less multiple ulcerations (21.8 vs. 32.8%, p = 0.006) than patients with ischemic DFUs. The outcomes for neuropathic and ischemic DFUs were limb salvage (98.4 vs. 82.3%, p &lt, 0.0001), healing (97.3 vs. 79.6%, p &lt, 0.0001), healing time (34.9 vs. 35.6 weeks, p = 0.8), major amputation (0.5 vs. 6.6%, p = 0.0001), death (1.1 vs. 11%, p &lt, 0.0001) respectively. Revascularization failure and ESRD were independent predictors of major amputation, while heart failure and number of co-morbidities (&sup3, 5) were independent predictors of death. Ischemic DFUs patients showed more severe clinical and ulcers features as well worse outcomes than neuropathic DFUs patients.

Purpose: To detail a percutaneous technique for distal plantar venous arterialization in diabetic, end-stage renal disease (ESRD) patients with no-option critical limb ischemia (CLI). Technique: After failure of standard intraluminal recanalization attempts, a subintimal approach through the posterior tibial artery (PTA) is begun using a 0.014-inch, 190- or 300-cm-long guidewire supported by a 2-×20-mm, low-profile balloon catheter positioned a short distance behind the narrow “U-shaped” loop in the guidewire. Typically, heavy calcification in the distal tortuous segment of the PTA prevents reentry to the arterial true lumen; however, an entry in the distal lateral or medial plantar vein from a subintimal channel in the plantar artery can be intentionally pursued as a bailout technique, pointing the tip of the guidewire opposite to the arterial wall calcifications. Venous access is confirmed by contrast injection through the balloon catheter. Once the guidewire is advanced in the distal lateral or medial plantar vein and a plantar arteriovenous fistula (AVF) has been created, the AV anastomosis and the occluded PTA segment are dilated with 0.014-inch balloon catheters. The technique has been attempted in 9 consecutive diabetic, ESRD patients (mean age 69 years; 5 men) with no-option CLI; an AVF was created between the PTA and plantar vein in 7 patients. The mean TcPO2 at 1 month was 30±17 mm Hg (vs 7.3±2.2 at baseline). Six ulcers healed over an average of 21±4 weeks. Three of the 9 patients had below-knee amputations. Conclusion: Although further investigations are required, distal plantar venous arterialization may represent a promising technique to improve recanalization rates and limb salvage in diabetic ESRD patients with extremely calcified PTA occlusions.

Foot infection is a well recognized risk factor for major amputation in diabetic patients. The osteomyelitis is one of the most common expression of diabetic foot infection, being present approximately in present in 10%-15% of moderate and in 50% of severe infectious process. An early and accurate diagnosis is required to ensure a targeted treatment and reduce the risk of major amputation. The aim of this review is to report a complete overview about the management of diabetic foot osteomyelitis. Epidemiology, clinical aspects, diagnosis and treatment are widely described according to scientific reccomendations and our experience.

The purpose of this cross-sectional study is evaluate the effectiveness of a dermal-epidermal substitute (DES) composed of 3-dimensional porous matrix of type 1, purified, stabilized, bovin-origin collagen (Nevelia, SYMATESE, Chaponost, France) without a subsequent skin graft in the treatment ischemic postsurgical diabetic foot ulcers. This study group was composed of a sample of consecutive diabetic patients with critical limb ischemia and postsurgical wounds. All patients received a preset limb salvage protocol including the application of the DES, but none received a skin graft. Patients were closely followed until wound healing or different outcome. The outcome measures were healing, nonhealing, major amputation, and death evaluated at 1 and 2 years of follow-up. Forty-one patients were included. The average postsurgical wound area was 69.6 ± 50 cm2. Twenty-one patients (51%) healed; 10 patients (24%) did not heal after 1 year of follow-up; however, all of them achieved a mean ulcer size reduction >50%; 7 patients (17%) were amputees; 3 patients (7.3%) died. In a later follow-up (2 years), wounds in 8 additional patients healed. Successful revascularization was an independent predictor of healing (hazard ratio = 5.1, 95% confidence interval [CI] = 2.5-14-9; P = .0001), the postsurgical ulcer size (>50 cm2) was an independent predictor of nonhealing (hazard ratio = 6.2, 95% CI = 2.1-38.4; P = .0001) while recurrence of critical limb ischemia was an independent predictor of major amputation (odds ratio = 3.4, 95% CI = 1.1-4.5; P = .002). The DES composed of type 1 bovin-origin collagen is useful in the treatment of large postsurgical diabetic foot ulcers, even when the skin graft is not a suitable therapeutic option.

Diabetic foot is a major public health issue, driven by diabetes complications (neuropathy, peripheral vascular disease, foot deformity, and abnormal leucocyte function), which may lead to leg amputation, thus resulting in severe disability, reduced quality of life, and high health costs. The prevention of diabetes complications and the early detection and proper management of diabetic foot wounds are the milestones to avoid major amputations. Unfortunately, in many areas, the prevention of diabetic foot lesions is inadequate and wounds may proceed toward infection and chronicity, with limb- and life-threatening results. Using the Delphi method, we conducted a survey on diabetic foot among Italian experts, selected across different Italian clinical centers. This method was used to achieve a consensus on current opinion and clinical leanings on the diagnosis and management of diabetic foot ulcers. Specifically, the aim of the survey was to evaluate the current management of the diabetic foot syndrome; highlight the differences in the approach among a group of experts; evaluate the role of wound bed preparation and antisepsis; and discuss any areas of disagreement in which evidences are sparse and the clinical judgment plays a crucial role in the decision-making process.

The purpose of this study is to investigate the outcomes of diabetic individuals with ischemic heel ulcers. The study group was composed of a consecutive sample of persons with diabetic ischemic foot ulcers managed by a preset multidisciplinary limb salvage protocol, including revascularization through endovascular technique. The outcome measures were healing, major amputation (above the ankle), and death at 1-year of follow-up. The outcomes between patients with heel ulcers (HUs) and without (NHUs) were compared. A total of 254 patients were recruited. There were 50/254 (19.7%) HUs and 204/254 (79.3%) NHUs. Overall, 190/254 (74.8%) patients healed. The rate of healing for HUs and NHUs was 30/50 (60%) and 160/204 (78.4%); P = .03, respectively. Major amputation occurred in 24/254 (9.4%) patients. The rates of major amputation for HUs and NHUs were 10/50 (20%) and 14/204 (6.9%; P = .002), respectively; 40/254 (15.7%) patients died, unhealed. The rates of mortality for HUs and NHUs were 10/50 (20%) and 30/204 (14.7%; P = .07), respectively. In HUs patients, absence of infection [95% CI = 3.1 (1.6-5.5); P = .002] and superficial ulcers [95% CI = 4.4 (2.2-9.3); P = .0001] were independent predictors of healing, whereas revascularization failure [95% CI = 8.1 (1.5.0-19.4); P = .0001], involvement of the plantar arch [95% CI = 6.3 (2.0-15.4); P = .0001], and dialysis [95% CI = 2.2 (1.3-4.5); P = .006] were independent predictors of major amputation. A multidisciplinary approach achieves good rate of limb salvage in people with diabetic ischemic heel ulcers.

Diabetic foot infections represent a severe complication of long-standing diabetes. If not adequately recognized, the infection could spread from a foot ulcer to the bone, thus causing osteomyelitis (OM) that exposes the patients to the risk of amputation, bacteraemia/septicaemia and death. One of the most difficult aspects in the evaluation of a diabetic foot is to differentiate between OM, soft tissue infection (STI) and Charcot foot because these three conditions require very different therapeutic approaches. Despite the correct diagnosis could be achieved with the isolation of the pathogen from bone or soft tissues, it would be desirable to have non-invasive test able to diagnose and localize an infection with high accuracy. In this chapter, we examine the pros and cons of NM modalities in the approach at diabetic foot disorders.

Aim. To evaluate the prognostic role of procalcitonin (PCT) in patients with diabetic foot infection (DFI) and critical limb ischemia (CLI). Materials and Methods. The study group was composed of diabetic patients with DFI and CLI. All patients were treated according to a preset limb salvage protocol which includes revascularization, wound debridement, antibiotic therapy, and offloading. Inflammatory markers, including PCT, were evaluated at admission. Only positive values of PCT, greater than 0.5 ng/ml, were considered. Hospital outcomes were categorized as limb salvage (discharge with preserved limb), major amputation (amputation above the ankle), and mortality. Results. Eighty-six patients were included. The mean age was 67.3±11.4 years, 80.7% were male, 95.1% had type 2 diabetes, and the mean diabetes duration was 20.5±11.1 with a mean HbA1c of 67±16 mmol/mol. 66/86 (76.8%) of patients had limb salvage, 7/86 (8.1%) had major amputation, and 13/86 (15.1%) died. Patients with positive PCT baseline values in comparison to those with normal values showed a lower rate of limb salvage (30.4 versus 93.6%, p=0.0001), a higher rate of major amputation (13 versus 6.3%, p=0.3), and a higher rate of hospital mortality (56.5 versus 0%, p<0.0001). At the multivariate analysis of independent predictors found at univariate analysis, positive PCT was an independent predictor of major amputation [OR 3.3 (CI 95% 2.0-5.3), p=0.0001] and mortality [OR 4.1 (CI 95% 2.2-8.3), p<0.0001]. Discussion. Positive PCT at admission increased the risk of major amputation and mortality in hospital patients with DFI and CLI.

Hypoglycemic agents differ in mechanism, efficacy, and profile. However, there is uncertainty on their impact on myocardial perfusion. We thus aimed to investigate whether individuals with type 2 diabetes mellitus treated with different drug classes exhibit different perfusion patterns at myocardial perfusion scintigraphy (MPS).We queried our administrative database for patients with diabetes mellitus without prior or recent myocardial infarction. The primary objective was to compare the severity and extent of ischemia at MPS, distinguishing patients according to management strategy. A total of 7592 patients were included [2336 (31%) on diet, 3611 (48%) on metformin, 749 (10%) on sulfonylureas, 449 (6%) on metformin plus sulfonylureas, 447 (6%) on metformin plus insulin]. Unadjusted analyses and analyses adjusting for baseline features suggested that sulfonylureas alone or in combination were associated with more severe ischemia than nonsulfonylurea regimens (P0.05), whereas combination regimens including metformin were associated with more extensive myocardial ischemia than the other regimens (P0.05 for both). However, no significant difference disfavoring either metformin or sulfonylurea regimens persisted after multivariable adjustment for baseline, stress, and angiographic characteristics (all P0.05).Several significant differences in baseline, stress, and scintigraphic features appear evident in patients with diabetes mellitus receiving different hypoglycemic agents or regimens.

Aim To define the outcomes of persons with diabetes and foot ulcers (DFUs) managed through a specific triage pathway during the COVID-19 crisis. Methods Patients who had an active DFU during the COVID-19 emergency were included. All participants were managed using a specific triage system driven both by ulcer’severity and concomitant co-diseases. Subjects with severely complicated DFUs were urgently referred to hospital regardless of the concomitant comorbidities. Subjects with complicated DFUs received outpatient evaluation (within 48–72 h) and were admitted to hospital if required (revascularization, surgical intervention, intravenous antibiotic therapy); after the first outpatient visit or hospitalization, patients were followed according to the number of comorbidities (in the case of 3 or more comorbidities patients were followed up by telemedicine). Patients with uncomplicated DFUs were managed by telemedicine after outpatient evaluation. Healing, major amputation, death and rate of COVID-19 infection were evaluated. The minimum follow-up was 1 month. Results The study group included 151 patients. The mean age was 69.9 ± 14.2 years, 58.9% were male and 91.4% had type 2 diabetes; 58.7% had severely complicated, 21% complicated and 20.3% uncomplicated DFUs. Among those, 78.8% presented with 3 or more comorbidities. One hundred and six patients had regular clinical follow-ups, while 45 were managed through telemedicine. Forty-one (27.1%) patients healed, 3 (1.9%) had major amputations and 3 (1.9%) died. One patient (0.6%) reported COVID-19 positivity due to infection acquired at home. Conclusion The triage pathway adopted during the COVID-19 pandemic showed adequate management of DFUs and no cases of hospital virus exposure.

To evaluate the impact of below-the-ankle (BTA) arterial disease in people with ischemic diabetic foot ulcers (DFUs).Patients with ischemic DFUs treated by a pre-set limb salvage protocol including peripheral revascularization were included. They were divided in two groups according to the involvement of BTA arteries (BTA+) or not (BTA-). Not healing, minor amputation, major amputation and mortality have been evaluated as primary outcome. Revascularization failure has been evaluated as secondary outcome.The study group was composed of 272 patients, 120 (44.1%) belonging to BTA+ group and 152 (55.9%) to BTA-. After 1 year of follow-up the outcomes for BTA+ and BTA- were respectively: not healing (40.8 vs 17.8%, p 0.0001), minor amputation (80.8 vs 20.4%, p 0.0001), major amputation (18.3 vs 6.6%, p = 0.002), mortality (16.7% vs 10.5%, p = 0.001). The rate of revascularization failure was respectively 38.3 vs 11.2%, p 0.0001. At the multivariate analysis BTA arterial disease resulted an independent predictor of not healing [OR 3.5 (CI 95% 2.3-6.1) p = 0.0001], minor amputation [OR 3.1 (1.5-5.9) p 0.0001] and revascularization failure [OR 3.5 (1.9-6.3) p = 0.0001]. BTA+ patients with successful BTA revascularization showed lower rate of not healing (37.8 vs 89.1%) p 0.0001, minor amputation (74.3 vs 91.3%) p = 0.002 and major amputation (8.1 vs 34.8%) p = 0.0003 in comparison to patients with unsuccessful BTA revascularization.BTA arterial disease severely impairs the outcomes of diabetics with ischemic foot ulcers. BTA revascularization reduces the rate of not healing, minor and major amputation.

Purpose The aim of this study is to evaluate the role of Iloprost as an early predictor of successful revascularization in patients affected by ischemic diabetic foot ulcers (DFUs). Methods Consecutive patients with ischemic DFUs with persistent low TcPO2 ( All patients underwent Iloprost infusion and TcPO2 has been recorded at days 3, 14 and 30. According to the TcPO2 reported at day 3, patients were divided into two groups: group A (patients with TcPO2 ≥30mmHg) and group B (patients with TcPO2 Results Twenty-five patients have been included, 12/25 (48%) in Group A and 13/25 (52%) in Group B. There were no significant differences at the baseline and one day after PTA between the two groups while TcPO2 values recorded in Group A at days 3, 14 and 30 after Iloprost infusion were significant higher in comparison to the Group B (χ = 0.005). The rate of re-PTA were respectively 33,3% (Group A) and 53,8% (Group B) (p = 0.03). Conclusions Iloprost may be an early predictor of successful revascularization in patients affected by critical limb ischemia (CLI) and DFUs.

Objective: To establish the rate of clinical recurrence of critical limb ischemia (CLI) in diabetic patients with ischemic foot ulcers (DFUs) treated by percutaneous transluminal angioplasty (PTA). Approach: The study group was composed of 304 patients with ischemic DFUs treated by PTA. We evaluated the rate of clinical recurrence of CLI requiring a second PTA (repeated PTA [rePTA]), the factors related to CLI relapse, and the outcomes of rePTA patients. The follow-up was 12.5 ± 6.6 months. Results: Seventy-four of 304 patients (24.3%) needed rePTA. The mean time to rePTA was 3.5 ± 0.64 months. rePTA group in comparison with no rePTA group had lower rate of healing (28.5% vs. 71.9% p = 0.0001), higher rate of ulcer recurrence (20% vs. 10.3% p = 0.03), major amputation (24.3% vs. 4.3% p = 0.0005), and death (33.3% vs. 7.9% p = 0.002). Glycated hemoglobin, type A1C (HbA1c; 2.2 [1.9-2.7] p = 0.02) and dialysis (1.5 [1.4-3.6] p = 0.006) were independently associated to clinical recurrence of CLI after PTA. Innovation: To identify the outcomes of patients with clinical recurrence of CLI and the clinical factors involved to reduce the rate of restenosis after endovascular treatment and improve the rate of limb salvage. Conclusions: Clinical recurrence of CLI is associated with a high rate of nonhealing ulcer recurrence, major amputation, and death. Dialysis and impaired glycemic control were independent predictors of CLI relapse after endovascular treatment.

Summary Background Diabetic foot ulcers are serious and challenging wounds associated with high risk of infection and lower-limb amputation. Ulcers are deemed neuroischaemic if peripheral neuropathy and peripheral artery disease are both present. No satisfactory treatment for neuroischaemic ulcers currently exists, and no evidence supports one particular dressing. We aimed to assess the effect of a sucrose octasulfate dressing versus a control dressing on wound closure in patients with neuroischaemic diabetic foot ulcers. Methods We did a randomised, double-blind clinical trial (Explorer) in 43 hospitals with specialised diabetic foot clinics in France, Spain, Italy, Germany, and the UK. Eligible participants were inpatients or outpatients aged 18 years or older with diabetes and a non-infected neuroischaemic diabetic foot ulcer greater than 1 cm 2 and of grade IC or IIC (as defined by the University of Texas Diabetic Wound Classification system). We excluded patients with a severe illness that might lead to them discontinuing the trial and those who had surgical revascularisation in the month before study entry. We randomly assigned participants (1:1) via a computer-generated randomisation procedure (concealed block size two); stratified by study centre and wound area (1–5 cm 2 and 5–30 cm 2 ), to treatment with either a sucrose octasulfate wound dressing or a control dressing (the same dressing without sucrose octasulfate) for 20 weeks. Both groups otherwise received the same standard of care for a 2-week screening period before randomisation and throughout the 20-week trial. Dressings were applied by nursing staff (or by instructed relatives for some outpatients). Frequencies of dressing changes were decided by the investigator on the basis of the clinical condition of the wound. Patients were assessed 2 weeks after randomisation, then monthly until week 20 or occurrence of wound closure. The primary outcome, assessed by intention-to-treat, was proportion of patients with wound closure at week 20. This trial is registered with ClinicalTrials.gov, number NCT01717183. Findings Between March 21, 2013, and March 31, 2016, we randomly assigned 240 individuals to treatment: 126 to the sucrose octasulfate dressing and 114 to the control dressing. After 20 weeks, wound closure occurred in 60 patients (48%) in the sucrose octasulfate dressing group and 34 patients (30%) in the control dressing group (18 percentage points difference, 95% CI 5–30; adjusted odds ratio 2·60, 95% CI 1·43–4·73; p=0·002). In both groups, the most frequent adverse events were infections of the target wound: 33 wound infections in 25 (20%) patients of 126 in the sucrose octasulfate dressing group and 36 in 32 (28%) patients of 114 in the control dressing group. Minor amputations not affecting the wound site were also reported in one (1%) patient in the sucrose octasulfate dressing group and two (2%) patients in the control dressing group. Three (2%) patients assigned to the sucrose octasulfate dressing and four (4%) assigned to the control dressing died, but none of the deaths were related to treatment, procedure, wound progression, or subsequent to amputation. Interpretation A sucrose octasulfate dressing significantly improved wound closure of neuroischaemic diabetic foot ulcers without affecting safety after 20 weeks of treatment along with standard care. These findings support the use of sucrose octasulfate dressing as a local treatment for neuroischaemic diabetic foot ulcers. Funding Laboratoires Urgo Medical.

OBJECTIVE Infection commonly complicates diabetic foot ulcers and is associated with a poor outcome. In a cohort of individuals with an infected diabetic foot ulcer, we aimed to determine independent predictors of lower-extremity amputation and the predictive value for amputation of the International Working Group on the Diabetic Foot (IWGDF) classification system and to develop a risk score for predicting amputation. RESEARCH DESIGN AND METHODS We prospectively studied 575 patients with an infected diabetic foot ulcer presenting to 1 of 14 diabetic foot clinics in 10 European countries. RESULTS Among these patients, 159 (28%) underwent an amputation. Independent risk factors for amputation were as follows: periwound edema, foul smell, (non)purulent exudate, deep ulcer, positive probe-to-bone test, pretibial edema, fever, and elevated C-reactive protein. Increasing IWGDF severity of infection also independently predicted amputation. We developed a risk score for any amputation and for amputations excluding the lesser toes (including the variables sex, pain on palpation, periwound edema, ulcer size, ulcer depth, and peripheral arterial disease) that predicted amputation better than the IWGDF system (area under the ROC curves 0.80, 0.78, and 0.67, respectively). CONCLUSIONS For individuals with an infected diabetic foot ulcer, we identified independent predictors of amputation, validated the prognostic value of the IWGDF classification system, and developed a new risk score for amputation that can be readily used in daily clinical practice. Our risk score may have better prognostic accuracy than the IWGDF system, the only currently available system, but our findings need to be validated in other cohorts.

Main goal of human foot evolution was to allow safe and effective barefoot motion on natural grounds. Footwear came afterwards, to protect the foot from extreme environmental conditions, to improve walking and running performance, and to cope with challenging surfaces also including new artificial substrates. But while on the one side shoes and insoles—i.e., footwear—act beneficially on the foot, on the other side they may limit foot function and render the foot itself more fragile and less prone to adaptation. This may lead the shod foot to unnaturally concentrate peak pressures under small areas at heel, forefoot, and hallux. Such a potentially dangerous condition may likely happen in diabetic patients with long-term complications, such as peripheral neuropathy, which deeply modify foot structure, foot function, and the resulting gait. Without proper protection, such patients are made vulnerable and at risk of foot ulceration. Unsuitable footwear may precipitate this condition and may be responsible for the new appearance or the recurrence of a foot ulcer. Research efforts during the last 50 years helped to better understand the criteria to take into account when prescribing or making proper footwear and/or plantar orthoses to: prevent diabetic foot ulceration (primary prevention); manage healing of an active ulcer; and prevent ulcer recurrences (secondary prevention). However, despite these huge advances in knowledge, recent literature still claims the lack of strong evidence about clinical efficacy of diabetic footwear especially in preventing first ulcer occurrence. Main reasons for that, among which the still poor adherence to treatment, are presented and discussed in the following, together with a literature review of the most recent peer-reviewed studies and position papers, to bring attention on the main causes for the still limited success of footwear intervention in diabetes and on a desirable improvement of diabetic foot care.

Aim To establish the role of heart failure (HF) and dialysis (D) in the prognosis of diabetic patients with critical limb ischemia and foot ulcers (FUs). Methods Consecutive diabetic patients with ischemic FUs who referred to our Diabetic Foot Centre were prospectively included. All patients underwent a preset limb salvage protocol including peripheral revascularization. According to the presence of HF and D, they were divided in four groups: group 1 without HF and without D defined as ischemic foot (IF); group 2 with HF and without D defined as heart ischemic foot (H-IF); group 3 without HF and with D defined as renal ischemic foot (R-IF); group 4 with HF and with dialysis defined as heart-renal foot (HR-IF). Survival with limb salvage, survival with major amputation and death were reported after 1 year of follow-up. Results 136 patient have been included: 66 with IF, 26 with H-IF, 24 with R-IF and 20 with HR-IF. The mean age was 68,9 ± 9,7 years, the diabetes duration 20,7 ± 11,6 years, the mean HbA1c 62,7 ± 22,3 mmol/mol. 103/136 (75,7%) survived with limb salvage, 10/136 (7,4%) survived with major amputation, 23/136 (16,9%) died. The outcomes for group IF patients, H-IF, R-IF and HR-IF were respectively: survival with limb salvage (92,4%, 61,5%, 79,2% and 35%), survival with major amputation (6,1%, 7,7%, 8,3% and 10%), death (1,5%, 30,8%, 12,5% and 55%) χ = 0.0001. Heart failure was an independent predictor of death. Discussion The presence of heart failure and dialysis in diabetic patients with ischemic foot ulcers was associated to high risk of amputation and mortality.

Diabetic foot syndrome (DFS) is considered the most severe and complicated framework of 2 diabetes-related long-term complications, peripheral neuropathy and peripheral arterial disease, and foot ulceration is usually their main clinical expression. Due to the presence of several co-morbidities, diabetic foot patients are often very fragile subjects and foot ulceration is usually only an aspect of a complex clinical condition. Diabetes-related chronic complications affecting other organs, mainly kidneys and heart, can deeply influence not only the patient's general health but also the outcomes of foot ulcers. Ulcer-related outcomes may be deeply influenced by co-morbidities associated with diabetic foot disease. Therefore, DFS not only requires a treatment plan addressing ulcers characteristics but also the assessment method of all co-morbidities that may influence the outcomes. A global approach is mandatory to reduce major amputations and increase survival among diabetic patients. The aim of this review is to describe the co-morbidities that influence the pathophysiology of the DFS and its outcomes.

The aim of our study is to analyze factors, including matrix metalloproteinase (MMP) levels, that could influence the integration of dermal grafts in diabetic foot ulcers. From September 2012 to September 2013, 35 diabetic patients with IIA lesion (Texas Wound Classification) and an extensive foot tissue loss were considered suitable for dermal graft. Before the enrollment we ensured the best local conditions: adequate blood supply, control of infection, and offloading. The MMP level of each lesion was evaluated blindly before the application of dermal substitutes. At 1-month follow-up, we analyzed the correlation between clinical patient characteristics, local wound features including MMP levels, dermal substitute applied, and the outcome expressed in terms of dermal graft integration. We observed dermal graft integration in 28/35 patients (80% of our population). In multivariate analysis high MMP level was the only negative predictor for dermal graft integration ( P < .0007). In addition, we divided the patients into 2 groups according to MMP levels: group 1 with low protease activity (24 patients) and group 2 with elevated protease activity (11 patients). The integration of the dermal graft was 100% in group 1 (n = 24 patients) and 36.4% in group 2 (n = 4patients), P < .0001. According to our data, the evaluation of MMP levels may be useful to choose the right strategy to get the best results in terms of clinical success and cost saving. However, further studies are necessary to confirm these findings.

Diabetic foot ulceration remains one of the most common and most serious consequences of diabetes. Persistently high levels of matrix metalloproteases (MMPs) contribute to wound chronicity. Our aim was to assess the concentrations of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in neuropathic and ischemic diabetic foot ulcers by analyzing biopsy samples. In this study, biopsies were taken from 35 diabetic foot ulcers of type 2 diabetes mellitus patients and distinguished in neuropathic (n = 14) or ischemic (n = 21). Zymography assay was utilized for the analysis of MMP-2 and MMP-9 activity. TACE activity was evaluated by a specific fluorimetric assay. mRNA levels of MMPs as well as TIMPs were detected using quantitative real-time polymerase chain reaction. The activity of MMP9 and A Disintegrin and A MetalloProtease Domain 17/TNF-Alpha Converting Enzyme (ADAM17/TACE) was significantly increased in ischemic compared to neuropathic biopsies. No differences were detected between both groups for the mRNA levels of MMPs as well as of ADAMs. However, TIMP3 mRNA expression was decreased in ischemic samples. The combination of increased activity of MMP9 and ADAM17/TACE with decreased concentrations of TIMP-3 mRNA expression in ischemic diabetic foot ulcers compared to neuropathic samples suggests that the increased proteolytic environment may represent a causative factor in the ulcer progression. New treatment strategies for healing diabetic foot ulcers could be directed toward increasing levels of TIMP3.

Aims: Diabetic complications, and in particular diabetic foot ulcers (DFUs), are associated with low health-related quality of life (HRQoL). We evaluated whether the presence of diabetic complications also influenced the improvement of HRQoL during DFU treatment.Methods: 1088 patients presenting for DFU treatment at the centers participating in the Eurodiale study were followed prospectively up to one year. HRQoL was measured both at presentation and after healing or at end of follow up, using EQ-5D: a standardized instrument consisting of five domains and a summary index. The influence of diabetic comorbidity on the course of HRQoL was evaluated for each of the EQ-5D outcomes in multi-level linear regression analyses, adjusting for baseline characteristics.Results: HRQoL improved in all EQ-5D outcomes over the course of treatment for those DFUs that healed. The few significant differences in the development of HRQoL between patients with and without comorbidity showed a more beneficial development for patients with comorbidity in DFUs that did not heal or healed slowly.Conclusions: Comorbidity does not hamper improvement of HRQoL in DFU treatment. On the contrary, HRQoL improved sometimes more in patients with certain comorbidity with hard-to-heal ulcers. (C) 2017 Elsevier Inc. All rights reserved.

Introduction: Diabetes and Chronic Kidney Disease (CKD) are two strong risk factors for peripheral arterial disease (PAD) and Critical Limb Ischemia (CLI). Further renal insufficiency increases the risk of non healing wounds and major amputation. Primary amputation rates of 22% to 44% have been reported for ischaemic foot lesion in End-Stage Renal Disease (ESRD) patients. In our study we evaluated the outcomes after Percutaneus Transluminal Angioplasty (PTA) in diabetic patient in relation to different CKD classes. Materials and Methods: We studied a group of 456 diabetic patients with PAD complicated by foot lesion who underwent PTA because of a CLI. According to the estimated Glomerular Filtration Rate (eGFR mL/min/1.73 m2) we divided the patients into five CKD groups: group 1 eGFR > 90, group 2 eGFR 90 - 60 (n = 160), group 3 eGFR 60 - 30 (n = 152), group 4 eGFR 30 -15 (n = 34) and group 5 Results: Alive without major amputation, alive with major amputation and death were respectively: for group 1 (77.8%, 11.1%, 11.1%), for group 2 (74.4%, 12.5%, 13.1%), for group 3 (80.3%, 11.2%, 8.5%), for group 4 (82.3%, 8.8%, 8.8%). They were 60%, 18.3%, 21.7% for group 5 significantly different from the other CKD groups (χ2 = 0.0175). Our analysis did not highlight any relationship between eGFR and outcomes and eGFR did not show any significant difference according to the different outcomes, and were respectively 60.2 ± 1.3, 61.8 ± 3.4, 63.8 ± 3.5 (P = ns). Conclusion: The outcomes were similar for groups 1-4 and therefore, according to our data, they seemed not to be influenced by the decline of GFR. Outcomes worse significantly in group 5, but this group included only patients with ESRD in dialysis treatment. Although the outcomes after PTA in group 5 was significantly worse than the other groups, still a 60% limb salvage rate was obtained with PTA also in these very fragile patients. PTA was much less aggressive than by-pass and PTA was the only method used to treat CLI in our patients. This could explain why we recorded similar outcomes in all groups despite the decline of GFR that, generally speaking, mirrors a worsening of the general clinical conditions. Worse outcomes were recorded only in group 5 and in this group dialysis by itself might be responsible of the different outcomes.

Adherence of patients to treatment and appropriateness of prescribed footwear are mandatory for successful prevention of Diabetic foot ulceration. In a Public Healthcare Service, footwear approval is under the responsibility of the clinician. In some cases kinetic measurements are taken inside the shoes to support the clinical decision; however, an overall agreement is still missing with respect to a simple, reliable and effective test protocol based on proper threshold values. Authors’ past experiences, specific needs of the Diabetic outpatient service, and suggestions from valuable literature led to an instrumental test protocol based on reference peak pressure (PP) thresholds and gait line (GL) specific for each level of risk. Permission was obtained for one preliminary validation session at the Authors’ outpatient service, during which 11 patients at high/very high risk of ulceration were examined—9 for testing new footwear, 2 for monitoring 12-month-old footwear. The protocol was well accepted by patients and operators, fast and easy to be used. Based on the instrumental, clinical and visual inspection data; 4 new footwear did not pass the test; 5 passed the test but integration or minor changes were requested; the 2 old footwear were found no more effective. As a first positive feedback, after 4 months of wearing the modified prescriptions none of the patients had developed plantar ulcers or signs of tissue damage. Successive data processing proved that in all patients altered PPs and deviated GLs did correlate with alterations of other kinetic parameters. The protocol, which is proved to be sensitive and valuable for the Diabetic foot care, may have a general validity; the delivered specific PP thresholds and reference data, instead, can be reliably used if the test is performed with a calibrated Pedar Insole System and with the wide Insoles in the range UW-YW (EU size 36 - 45).

To demonstrate the usefulness of rearfoot transcutaneous oximetry to assess the peripheral arterial disease in diabetic patients with heel ulcer. From our database of 550 critical limb ischemia diabetic patients followed after a percutaneous transluminal angioplasty, we have selected patients with below the knee arterial disease. Patients were grouped according to the dorsal transcutaneous oximetry value (Group A

Aim To evaluate the outcomes of diabetic dialysis patients with critical limb ischemia and foot ulcer. Methods The study group included 599 diabetic, 99 dialyzed (Ds) (16.5%) and 500 not dialyzed (NDs) (83%) patients with critical limb ischemia and foot ulcers identified as stage C (ischemia) or D (ischemia plus infection) of Texas Wound Classification. All patients were treated by endovascular revascularization. Outcomes were expressed as healing, major amputation, death and non healing after 12 months. The mean follow-up was 15 ± 13 months. Results The outcomes of the whole population were: 48.9% healing, 11.3% major amputation, 12.7% death, 27.1 non healing. At the multivariate analysis dialysis was a negative predictor of healing and a positive predictor of major amputation. Outcomes for Ds and NDs were respectively: healing (30.3 vs 52.6%), major amputation (14.4 vs 10.8%), death (21.1 vs 11%) and non-healing (34.2 vs 25.6%) ( X = 0.0004). Amputation occurred earlier in Ds than in NDs. According to the multivariate analysis in Ds ischemic heart disease and lower ΔTcPO2 were negative predictors for healing. Successful revascularization was a negative predictor for major amputation. HDL and carotid artery disease were predictive factors of death among NDs. Among Ds high blood pressure values were the only predictor of amputation while no variable resulted predictive of healing or death. Conclusions Our study shows that our limb salvage protocol ensures a good rate of limb salvage in Ds even if they have a higher risk of amputation and death compared to NDs.

81 ISSN 1758-1907 10.2217/DMT.12.6 © 2012 Future Medicine Ltd Diabetes Manage. (2012) 2(2), 81–84 Charcot neuropathic osteoarthropathy (CN), commonly referred to as Charcot foot, is a condition affecting the bones, joints and soft tissues of the foot and ankle, characterized by inflammation in the earliest phase [1]. This pathological process culminates in bone and joint destruction and subsequent foot deformity, which predisposes to ulceration. A number of mechanisms operate simultaneously: peripheral sensory and motor neuropathy, biomechanical factors and autonomic neuropathy are all considered to be potential causes of the development of Charcot foot [2]. However, neuropathic osteoarthropathy in its acute phase (acute Charcot foot) is also characterized by uncontrolled inflammation. It has been suggested that the disorder arises from a sustained and uncontrolled release of proinflammatory cytokines, such as TNF-a and IL-1b, induced by microtrauma; this leads to increased expression of the polypeptide receptor activator of nuclear factor-kB ligand (RANKL) from any of a number of local cell types. RANKL triggers the synthesis of NF-kB, and this in turn stimulates the maturation of osteoclasts from osteoclast precursor cells. Osteoclasts cause progressive bone lysis, leading to further fracture, which in turn potentiates the inflammatory process [3,4]. This has subsequently been shown by an increase in proinflammatory phenotypes of monocytes in those with active Charcot foot when compared with diabetic control subjects [5]. On clinical grounds, Charcot foot is characterized by acute and chronic phases. In acute Charcot neuroarthropathy, the foot is warm, edematous, markedly erythematous, has a temperature difference of >2oC between the affected and nonaffected foot, and can be associated with a history of traumas even if under-reported [6]. There is always some degree of sensory neuropathy, in which reflexes, vibratory sense and proprioception are either diminished or absent. Autonomic neuropathy, which coexists with somatosensory neuropathy, can be clinically appreciated by the presence of anhydrosis with very dry skin. Pain may or may not be present. The chronic phase is characterized by deformity of the foot, with abnormal pressure on the plantar surface due to the collapse of the plantar arch and the development of a rocker-bottom deformity.

The diabetic Charcot foot syndrome is a serious and potentially limb-threatening lower-extremity complication of diabetes. First described in 1883, this enigmatic condition continues to challenge even the most experienced practitioners. Now considered an inflammatory syndrome, the diabetic Charcot foot is characterized by varying degrees of bone and joint disorganization secondary to underlying neuropathy, trauma, and perturbations of bone metabolism. An international task force of experts was convened by the American Diabetes Association and the American Podiatric Medical Association in January 2011 to summarize available evidence on the pathophysiology, natural history, presentations, and treatment recommendations for this entity. (J Am Podiatr Med Assoc 101(5): 437–446, 2011)

Objectives The incidence of minor amputation may vary significantly, and determinants of minor amputation have not been studied systematically. We evaluated minor amputation rate, the determinants of minor amputation and differences in amputation rate between European centres. Methods In the Eurodiale study, a prospective cohort study of 1232 patients (1088 followed until end-point) with a new diabetic foot ulcer were followed on a monthly basis until healing, death, major amputation or up to a maximum of 1 year. Ulcers were treated according to international guidelines. Baseline characteristics independently associated with minor amputation were examined using multiple logistic regression modelling. Based on the results of the multivariable analysis, a disease severity score was calculated for each patient. Results One hundred and ninety-four (18%) patients underwent a minor amputation. Predictors of minor amputation were depth of the ulcer (odds ratio 6.08, confidence interval 4.10-9.03), peripheral arterial disease (odds ratio 1.84, confidence interval 1.30-2.60), infection (odds ratio 1.56, confidence interval 1.05-2.30) and male sex (odds ratio 1.42, confidence interval 0.99-2.04). Minor amputation rate varied between 2.4 and 34% in the centres. Minor amputation rate in centres correlated strongly with disease severity score at the moment of presentation to the foot clinic (r = 0.75). Conclusions Minor amputation is performed frequently in diabetic foot centres throughout Europe and is determined by depth of the ulcer, peripheral arterial disease, infection and male sex. There are important differences in amputation rate between the European centres, which can be explained in part by severity of disease at presentation. This may suggest that early referral to foot clinics can prevent minor amputations.

OBJECTIVEDespite increased information on the importance of an inappropriate inflammatory response in the acute Charcot process, there has been no previous attempt to define the specific pathways that mediate its pathogenesis. Here, the role played by monocytes was analyzed.RESEARCH DESIGN AND METHODSThe immune phenotype of peripheral monocytes was studied by fluorescence-activated cell sorter analysis comparing patients with acute Charcot (n = 10) in both the active and recovered phase, diabetic patients with neuropathy (with or without osteomyelitis), and normal control subjects.RESULTSWhen compared with diabetic control subjects and healthy subjects, monocytes from acute Charcot patients showed a proinflammatory immune phenotype characterized by increased production of proinflammatory cytokines, reduced secretion of anti-inflammatory cytokines, increased expression of surface costimulatory molecules, and increased resistance to serum withdrawal-induced apoptosis. In addition, the pattern of circulating cytokines confirmed activation of proinflammatory cytokines. No modulation of the monocyte phenotype was documented in diabetic control subjects and healthy subjects, thus indicating that the proinflammatory alterations of monocytes are specific and causative of acute Charcot.CONCLUSIONSTogether, these data provide evidence for the role of proinflammatory changes in the immune phenotype of monocytes in the pathogenesis of acute Charcot. These alterations may explain the abnormally intense and prolonged inflammatory response that characterizes this disorder and may represent a potential therapeutic target for specific pharmacological interventions.

Aims/hypothesis Outcome data on individuals with diabetic foot ulcers are scarce, especially in those with peripheral arterial disease (PAD). We therefore examined the clinical characteristics that best predict poor outcome in a large population of diabetic foot ulcer patients and examined whether such predictors differ between patients with and without PAD. Methods Analyses were conducted within the EURODIALE Study, a prospective cohort study of 1,088 diabetic foot ulcer patients across 14 centres in Europe. Multiple logistic regression modelling was used to identify independent predictors of outcome (i.e. non-healing of the foot ulcer). Results After 1 year of follow-up, 23% of the patients had not healed. Independent baseline predictors of non-healing in the whole study population were older age, male sex, heart failure, the inability to stand or walk without help, end-stage renal disease, larger ulcer size, peripheral neuropathy and PAD. When analyses were performed according to PAD status, infection emerged as a specific predictor of non-healing in PAD patients only. Conclusions/interpretation Predictors of healing differ between patients with and without PAD, suggesting that diabetic foot ulcers with or without concomitant PAD should be defined as two separate disease states. The observed negative impact of infection on healing that was confined to patients with PAD needs further investigation.

We have read with interest the article by Hoffstad et al. (1), as lower-extremity amputation (LEA) is a topic in which we have had a long-standing interest (2,3). Thus, we would like to share some of our thoughts about its findings. This article focuses its attention on the large increase in the incidence of death among patients with diabetes who underwent a LEA, as has been previously reported by several authors, including ourselves (1,3). This article further highlights the incomplete relationship between mortality and known diabetic complications, such as cardiovascular disease or renal insufficiency, and suggests that the presence of other unspecified factor(s) may be …

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.

Medical knowledge about wound management has improved as recent studies have investigated the healing process and its biochemical background. Despite this, foot ulcers remain an important clinical problem, often resulting in costly, prolonged treatment. A non-healing ulcer is also a strong risk factor for major amputation. Many factors can interfere with wound healing, including the patient's general health status (i.e., nutritional condition indicated by albumin levels) or drugs such as steroids that can interfere with normal healing. Diabetic complications (i.e., renal insufficiency) may delay healing and account for higher amputation rates observed in diabetic patients under dialysis treatment. Wound environment (e.g., presence of neuropathy, ischaemia, and infection) may significantly influence healing by interfering with the physiological healing cascade and adding local release of factors that may worsen the wound. The timely and well-orchestrated release of factors regulating the healing process, observed in acute wounds, is impaired in non-healing wounds that are blocked in a chronic inflammatory phase without progressing to healing. This chronic phase is characterised by elevated protease activity (EPA) of metalloproteinases (MMPs) and serine proteases (e.g., human neutrophil elastase) that interfere with collagen synthesis, as well as growth factor release and action. EPA (mainly MMP 9, MMP-8 and elastase) and inflammatory factors present in the wound bed (such as IL-1, IL-6, and TNFa) account for the catabolic state of non-healing ulcers. The availability of wound dressings that modulate EPA has added new therapeutic options for treating non-healing ulcers. The literature confirms advantages obtained by reducing protease activity in the wound bed, with better outcomes achieved by using these dressings compared with traditional ones. New technologies also allow a physician to know the status of the wound bed environment, particularly EPA, in a clinical setting. These may be helpful in guiding a clinician's options in treating very difficult-to-heal ulcers.

To validate nerve-axon reflex-related vasodilatation as an objective method to evaluate C-nociceptive fibre function by comparing it with the standard diagnostic criteria.Neuropathy was evaluated in 41 patients with diabetes (26 men and 15 women) without peripheral vascular disease by assessing the Neuropathy Symptom Score, the Neuropathy Disability Score (NDS), the vibration perception threshold (VPT), the heat detection threshold (HDT), nerve conduction parameters and standard cardiovascular tests. The neurovascular response to 1% acetylcholine (Ach) iontophoresis was measured at the forearm and at both feet by laser flowmetry. An age-matched and sex-matched control group of 10 healthy people was also included.Significant correlations were observed between the neurovascular response at the foot and HDT (r(s) = -0.658; p0.0001), NDS (r(s) = -0.665; p0.0001), VPT (r(s) = -0.548; p = 0.0005), tibial nerve conduction velocity (r(s) = 0.631; p = 0.0002), sural nerve amplitude (r(s) = 0.581; p = 0.0002) and autonomic function tests. According to the NDS, in patients with diabetes who had mild, moderate or severe neuropathy, a significantly lower neurovascular response was seen at the foot than in patients without neuropathy and controls. A neurovascular response50% was found to be highly sensitive (90%), with a good specificity (74%), in identifying patients with diabetic neuropathy.Small-fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small-fibre impairment is an early event in the natural history of diabetic neuropathy.

Background. The diabetic foot often undergoes abnormal plantar pressures, changing in walking strategy, ulcerative processes. The present study focuses on the effects that diabetes-induced alterations of Achilles tendon, plantar fascia and first metatarsophalangeal joint—both anatomical and functional—may have on foot loading. Methods. Sixty-one diabetic patients, with or without neuropathy, and 21 healthy volunteers were recruited. Thickness of Achilles tendon and plantar fascia was measured by ultrasound. Flexion–extension of the first metatarso-phalangeal joint was measured passively. Main biomechanic parameters of foot–floor interaction during gait were acquired and related to the above measurements. Findings. Plantar fascia and Achilles tendon were significantly (P < 0.05) thicker in diabetics than in controls; mean values (SD) for controls, diabetics without and with neuropathy were 2.0 mm (0.5), 2.9 mm (1.2) and 3.0 mm (0.8) for plantar fascia, respectively, and 4.0 mm (0.5), 4.6 mm (1.0) and 4.9 mm (1.7) for Achilles tendon, respectively. Flexion–extension of the first metatarso-phalangeal joint was significantly (P < 0.05) smaller in diabetics than in controls; mean values (SD) for controls, diabetics without and with neuropathy were 100.0 (10.0), 54.0 (29.4) and 54.9 (17.2), respectively. The increase in the vertical force under the metatarsals was strongly related (R = 0.83, explained variance = 70.1%) to the changes in the three above parameters. Interpretation. Thickening of plantar fascia and Achilles tendon in diabetics, more evident in the presence of neuropathy, concurs to develop a rigid foot, which poorly absorbs shock during landing (performs the physiological impact force absorption during landing). More generally, an overall alteration of the foot–ankle complex motion likely occurs throughout the whole gait cycle, which partly explains the abnormal loading under the forefoot. 2005 Elsevier Ltd. All rights reserved.

Magnetic resonance (MR) imaging has improved the possibility of evaluating musculoskeletal structures thus gaining an important role in the diagnosis and treatment of foot and ankle pathologies. In this review, the normal and pathological images of the ankle and foot obtained using MR techniques are presented and discussed. The high soft-tissue contrast resolution and the multiplanar sections of MRI allow the imaging of contiguous tissues where small contrast differences exist, such as ligamentous and tendinous injuries or impingement syndromes. The spatial resolution with high sensitivity for bone signal changes offers an early detection of osseous abnormalities such as stress fractures or osteonecrosis. Here it is specified possibilities and limitations of MRI in the diabetic foot: this technique is superior to nuclear medicine and computed tomography (CT), however it is unable to distinguish between neuro arthropathy and infection.

In recent years, life expectancy has increased in many societies consequent to better health conditions. Although the trends of decreasing mortality rates from ischemic heart disease and stroke have continued into the 21st century, both causes continue to be the biggest killers in the Western societies. No change is predicted in the foreseeable future and consequently both these conditions contribute significantly to the burden of disease. 1 Diabetes is considered a cardiovascular disease equivalent and with diabetes patients share the benefits of the improved approach to the treatment of cardiovascular disease. However, because of the longer life span and disease duration, other chronic complications such as peripheral arterial disease (PAD) may well become more evident. In a recent survey, PAD was present in 21% of newly diagnosed type 2 diabetic patients 2 and in about 50% of the patients admitted to a diabetic foot clinic on account of a new foot ulcer. It is interesting to emphasize that half of those patients had concomitant peripheral neuropathy. 3 Neuropathy can mask the classic PAD symptoms as claudication, thereby delaying a diagnosis. On the other hand, the presence of PAD may limit the use of total contact cast that is considered the “gold standard” treatment for neuropathic ulcerations. PAD alone is responsible for the increased risk of lower limb amputation observed in patients with diabetes. 4,5 In type 1 diabetes, the overall 25-year cumulative incidence of lower extremity amputation (LEA) is 10.1%. History of heavy smoking, high HbA1c, presence of hypertension are all factors related to PAD and major determinants associated with LEA. 6 In addition, major complex gender differences exist in diabetes-related LEA: Men are more likely to undergo LEA. 7 The presence of a foot infection increases the risk of LEA. A multidisciplinary approach to diabetic foot problems is mandatory to reduce the frequency of LEA, particularly when PAD is complicated by the presence of infected foot ulcers. 8 Today significantly better outcomes are expected for patients with diabetes affected by critical limb ischemia (CLI) based on improved technical options in peripheral revascularization, new options in antibiotic therapy, and aggressive wound debridement and wound care. Until recently, open peripheral arterial bypass has been the firstline surgical treatment option for PAD. Although open bypass is associated with successful results, the invasive nature of the surgery can limit optimal overall outcome. Endovascular procedure is less invasive; however, it reaches similar limb salvage rates in patients with CLI, 9 with the added benefits of fewer wound complications and a shorter hospital stay. As expected, endovascular therapy is increasingly being considered as a first-line treatment option in carefully selected PAD diabetic patients. With the widespread adoption of endovascular therapy, there has been a profound shift in practice patterns for lower extremity PAD. In the past decade, there has been a consistent increase in the number of patients treated by peripheral transluminal angioplasty because of CLI. 10 Hong et al 10 reported that in the general population the average annual number of endovascular interventions is increased by 78% while there is a concomitant decrease in open bypass by 20%. The same authors found that the trends in amputation were consistent with the increase in endovascular therapy. The number of major amputations (ankle to above-the-knee level) decreased by 21% and the number of minor amputations, defined as involving the toe and forefoot, showed a moderate decrease of 5%. Although better outcomes for CLI have been observed in the general population, the LEA observed in patients with diabetes are reportedly reduced, unchanged, or even increased. A recent survey conducted in England reported that the number and incidence of amputations decreased in the aging nondiabetic population whereas the overall population