Point-of-care fluorescence imaging reveals extent of bacterial load in diabetic foot ulcers.

Elevated levels of bacteria, including biofilm, increase the risk of chronic wound infection and inhibit healing. Addressing asymptomatic high bacterial loads is challenged by a lack of clinical terminology and diagnostic tools. This post-hoc multicenter clinical trial analysis of 138 diabetic foot ulcers investigates fluorescence (FL)-imaging role in detecting biofilm-encased and planktonic bacteria in wounds at high loads. The sensitivity and specificity of clinical assessment and FL-imaging were compared across bacterial loads of concern (104 -109 CFU/g). Quantitative tissue culture confirmed the total loads. Bacterial presence was confirmed in 131/138 ulcers. Of these, 93.9% had loads >104 CFU/g. In those wounds, symptoms of infection were largely absent and did not correlate with, or increase proportionately with, bacterial loads at any threshold. FL-imaging increased sensitivity for the detection of bacteria across loads 104 -109 (P < .0001), peaking at 92.6% for >108 CFU/g. Imaging further showed that 84.2% of ulcers contained high loads in the periwound region. New terminology, chronic inhibitory bacterial load (CIBL), describes frequently asymptomatic, high bacterial loads in diabetic ulcers and periwound tissues, which require clinical intervention to prevent sequelae of infection. We anticipate this will spark a paradigm shift in assessment and management, enabling earlier intervention along the bacterial-infection continuum and supporting improved wound outcomes.

People living with diabetes are unaware of their foot risk status or why they are referred to a multidisciplinary foot team.

AIM: People with active diabetic foot disease should be rapidly referred by health professionals along a pathway of care to a multidisciplinary foot team. The aim was to investigate patients' self-reported understanding of their foot risk status and reasons for their referral to a multidisciplinary foot team. METHOD: This seven-month service evaluation included consecutive newly referred patients. Participants completed a questionnaire which asked firstly about their understanding of their foot risk status, secondly about their pathway of care before presentation to the multidisciplinary foot team, and thirdly about their interest in diabetes-related foot education and preferred learning style. RESULTS: There were 202 participants; 65% were male, mean age was 64±15 years (mean±standard deviation (SD)), 86% had type 2 diabetes, and mean HbA1c was 65±23mmol/mol (8.3±3.7%). Only 4% of participants knew their current foot risk status and 52% did not know why their care had been escalated to a multidisciplinary foot clinic. Participants with type 2 diabetes more readily expressed an interest in further foot education compared with participants with type 1 diabetes, (70% versus 29%, p=0.001). CONCLUSIONS: These findings show that people with diabetes and foot disease are less aware of their foot risk status or why they are referred to a multidisciplinary team. Participants indicated a variable interest in further learning about foot complications. These findings indicate possible communication and educational barriers between patients and health professionals which may contribute to delayed presentation or suboptimal engagement.

Multicenter, randomized controlled, observer-blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes-ProNOx1 study.

The aim of this multicenter, prospective, observer-blinded, parallel group, randomized controlled trial was to assess the safety and efficacy of EDX110, a nitric oxide generating medical device, in the treatment of diabetic foot ulcers in a patient group reflecting "real world" clinical practice compared against optimal standard care. Participants were recruited from ten hospital sites in multidisciplinary foot ulcer clinics. The ulcers were full thickness, with an area of 25-2,500 mm2 and either a palpable pedal pulse or ankle brachial pressure index > 0.5. Infected ulcers were included. Treatment lasted 12 weeks, or until healed, with a 12-week follow-up period. Both arms were given optimal debridement, offloading and antimicrobial treatment, the only difference being the fixed used of EDX110 as the wound dressing in the EDX110 group. 135 participants were recruited with 148 ulcers (EDX110-75; Control-73), 30% of which were clinically infected at baseline. EDX110 achieved its primary endpoint by attaining a median Percentage Area Reduction of 88.6% compared to 46.9% for the control group (p = 0.016) at 12 weeks in the intention-to-treat population. There was no significant difference between wound size reduction achieved by EDX110 after 4 weeks and the wound size reduction achieved in the control group after 12 weeks. EDX110 was well tolerated. Thirty serious adverse events were reported (12 in the EDX110 group, of which 4 were related to the ulcer; 18 in the control group, of which 10 were related and 1 possibly related to the ulcer), with significant reduction in serious adverse events related to the ulcer in EDX group. There was no significant difference in adverse events. This study, in a real world clinical foot ulcer population, demonstrates the ability of EDX110 to improve healing, as measured by significantly reducing the ulcer area, compared to current best clinical practice.

Novel use of a Dektak 150 surface profiler unmasks differences in resorption pit profiles between control and Charcot patient osteoclasts.

We hypothesized that newly formed osteoclasts from patients with acute Charcot osteoarthropathy can resorb surfaces of bone more extensively compared with controls. Peripheral blood monocytes, isolated from eight Charcot patients and nine controls, were cultured in vitro on 24-well plates and bovine bone discs in duplicate with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κß ligand (RANKL). Osteoclast formation was assessed by tartrate-resistant acid phosphatase staining (TRAcP) at day 17. Resorption was measured at day 21 after toluidine blue staining by two methods: (1) area of resorption at the surface by image analysis (%) and (2) area of resorption under the surface (µm(2)) measured by a Dektak 150 Surface Profiler. Ten 1,000 µm-long scans were performed per disc. Pits were classified as unidented, bidented, and multidented according to their shape. Although the number of newly formed TRAcP positive multinucleated cells (>3 nuclei) was similar in M-CSF + RANKL-treated cultures between controls and Charcot patients, the latter exhibited increased resorbing activity. The area of resorption on the surface by image analysis was significantly greater in Charcot patients compared with controls (21.1 % [14.5-26.2] vs. 40.8 % [35.4-46.0], median [25-75th percentile], p < 0.01), as was the area of resorption under the surface (2.7 x 10(3) µm(2) [1.6 x 10(3)- 3.9 x 10(3)] vs. 8.3 x 10(3) µm (2) [5.6 x 10(3)- 10.6 x 10(3), [corrected] p < 0.01) after profilometry. In Charcot patients pits were deeper and wider and more frequently presented as multidented pits. This application of the Dektak 150 Surface Profiler revealed novel differences in resorption pit profile from osteoclasts derived from Charcot patients compared with controls. Resorption in Charcot patients was mediated by highly aggressive newly formed osteoclasts from monocytes eroding large and deep areas of bone.

Infrared Thermography Shows That a Temperature Difference of 2.2°C (4°F) or Greater Between Corresponding Sites of Neuropathic Feet Does Not Always Lead to a Diabetic Foot Ulcer.

BACKGROUND: There is emerging interest in the application of foot temperature monitoring as means of diabetic foot ulcer (DFU) prevention. However, the variability in temperature readings of neuropathic feet remains unknown. The aim of this study was to analyze the long-term consistency of foot thermograms of diabetic feet at the risk of DFU. METHODS: A post-hoc analysis of thermal images of 15 participants who remained ulcer-free during a 12-month follow-up were unblinded at the end of the trial. Skin foot temperatures of 12 plantar, 15 dorsal, 3 lateral, and 3 medial regions of interests (ROIs) were derived on monthly thermograms. The temperature differences (∆Ts) of corresponding ROIs of both feet were calculated. RESULTS: Over the 12-month study period, out of the total 2026 plantar data points, 20.3% ROIs were rated as abnormal (absolute ∆T ≥ 2.2°C). There was a significant between-visit variability in the proportion of plantar ROIs with ∆T ≥ 2.2°C (range 7.6%-30.8%, chi-square test, P = .001). The proportion of patients presenting with hotspots (ROIs with ∆T ≥ 2.2°C), abnormal plantar foot temperature (mean ∆T of 12 plantar ROIs ≥ 2.2°C), and abnormal whole foot temperature (mean ∆T of 33 ROIs ≥ 2.2°C) varied between visits and showed no pattern (P > .05 for all comparisons). This variability was not related to the season of assessment. CONCLUSIONS: Despite the high rate of hotspots on monthly thermograms, all feet remained intact. This study underscores a significant between-visit inconsistency in thermal images of neuropathic feet which should be considered when planning DFU-prevention programs for self-testing and behavior modification.

Who was first to diagnose and report neuropathic arthropathy of the foot and ankle: Jean-Martin Charcot or Herbert William Page?

In November 1883, Jean-Martin Charcot and Charles Féré reported on bone and joint disease of the foot in cases of tabes dorsalis, and referred to the condition as 'pied tabétique'--a disabling neuropathic osteoarthropathy that we usually now refer to as the Charcot foot. Charcot had originally described neuropathic osteoarthropathy in more proximal joints in 1868, and in his 1883 paper with Féré stated that involvement of the short bones and small joints of the foot had not yet been described. They emphasised in the paper that one of their cases was the first ever observed, two years earlier, in 1881. It is relevant, however, that it was in this same year that involvement of the foot by tabetic arthropathy was presented to the International Medical Congress in London by an English surgeon, Herbert William Page. We believe that Page was the first to diagnose and to report a case of tabetic neuropathic osteoarthropathy in which the bones of the foot and ankle were involved. He was also the first to propose a link between the tabetic foot and disease of the peripheral nerves, as opposed to the central nervous system.

Grading Fractures on Foot and Ankle X-rays and MRI Scans in the Active Charcot Foot in Diabetes: How Strong Is the Agreement Between Modalities?

OBJECTIVE: To compare X-ray and MRI as diagnostic tests of active Charcot neuro-osteoarthropathy (CNO) in diabetes. RESEARCH DESIGN AND METHODS: X-rays and MRI scans of 48 participants were rated for severity of fracture (0 = no fracture, 1 = fracture, 2 = collapse/fragmentation), and for absence/presence of bone marrow edema (BME) on MRI and absence/presence of bone injury on X-ray. The agreement between modalities was assessed with tests for symmetry, marginal homogeneity, and κ-coefficients. RESULTS: X-ray underscored MRI in grading fractures in the metatarsals (P = 0.05) and tarsals (P < 0.001) and reported as normal 79% of the bones with BME. The agreement between X-ray and MRI for grading severity of fracture was moderate to substantial (κ = 0.53; P < 0.001) and for detecting bone injury, slight to fair (κ = 0.17; P < 0.001). CONCLUSIONS: The significant underperformance of X-ray in the assessment of the hot, swollen foot in diabetes should be considered when confirming or refuting the diagnosis of active CNO.

Peripheral Arterial Disease Located in the Feet of Patients With Diabetes and Foot Ulceration Demands a New Approach to the Assessment of Ischemia.

Peripheral arterial disease (PAD) is common below the knee in diabetes but arteries in the foot are controversially said to be spared of occlusive disease. This is relevant to the convenient site of vascular assessment that is recommended in guidelines. Should assessment be distal at toe/forefoot to detect foot disease or only proximal to detect disease at ankle level? The objective was to determine frequency of PAD at foot and ankle level. This was a cross-sectional observational study, evaluating arterial disease proximally by palpation of pedal pulses and Ankle Brachial Index (ABI), and distally by Toe Brachial Index (TBI), and forefoot transcutaneous oxygen tension (tcpO2), in consecutive patients presenting with foot ulceration. We assessed 301 limbs in 154 patients: 59% of limbs were ulcerated. PAD in the foot was detected in 70% and 74% of limbs by TBI and forefoot tcpO2, respectively, but PAD at ankle level only in 51% and 34% by pulse palpation and ABI, respectively. In limbs with "normal" ABI, PAD was present in the foot in 70% as indicated by low TBI, and in 73% by low tcpO2, with 70% to 64% having associated ulceration, respectively. When compared with arterial waveforms, as a measure of PAD, TBI gave an excellent AUC (area under the curve of the receiver operating characteristic curve) of 0.81 (95% confidence interval: 0.73-0.89), but ABI gave a poor AUC of 0.65 (95% confidence interval: 0.55-0.76). In conclusion, arterial disease is important in the foot and can be detected by TBI, which should be performed even when ABI is normal. Guidelines that recommend TBI only if ABI is artificially raised need updating.

Effect of Recombinant Human Parathyroid Hormone (1-84) on Resolution of Active Charcot Neuro-osteoarthropathy in Diabetes: A Randomized, Double-Blind, Placebo-Controlled Study.

OBJECTIVE: Fractures in Charcot neuro-osteoarthropathy (CN) often fail to heal despite prolonged immobilization with below-knee casting. The aim of the study was to assess the efficacy of recombinant human parathyroid hormone (PTH) in reducing time to resolution of CN and healing of fractures. RESEARCH DESIGN AND METHODS: People with diabetes and acute (active) Charcot foot were randomized (double-blind) to either full-length PTH (1-84) or placebo therapy, both in addition to below-knee casting and calcium and vitamin D3 supplementation. The primary outcome was resolution of CN, defined as a skin foot temperature difference >2°C at two consecutive monthly visits. RESULTS: Median time to resolution was 5 months (95% CI 4, 12) in intervention and 6 months (95% CI 2, 9) in control. On univariate mixed Cox and logistic regression, there was no significant difference in time to resolution between the groups (P = 0.64) or in the likelihood of resolution (P = 0.66). The hazard ratio of resolution was 0.84 (95% CI 0.41, 1.74; P = 0.64), and the odds ratio of resolution by 12 months was 0.80 (95% CI 0.3, 2.13; P = 0.66) (intervention vs. control). On linear regression analysis, there were no significant differences in the effect of treatment on fracture scores quantitated on MRI scans (coefficient 0.13 [95% CI -0.62, 0.88]; P = 0.73) and on foot and ankle X-rays (coefficient 0.30 [95% CI -0.03, 0.63]; P = 0.07). CONCLUSIONS: This double-blind placebo-controlled trial did not reduce time to resolution or enhance fracture healing of CN. There was no added benefit of daily intervention with PTH (1-84) to below-knee casting in achieving earlier resolution of CN.

History of the team approach to amputation prevention: pioneers and milestones.

BACKGROUND: This historical perspective highlights some of the pioneers, milestones, teams, and system changes that have had a major impact on the management of the diabetic foot during the past 100 years. In 1934, American diabetologist Elliott P. Joslin noted that mortality from diabetic coma had fallen from 60% to 5% after the introduction of insulin, yet deaths from diabetic gangrene of the lower extremity had risen significantly. He believed that diabetic gangrene was preventable. His remedy was a team approach that included foot care, diet, exercise, prompt treatment of foot infections, and specialized surgical care. RESULTS: The history of a team approach to management of the diabetic foot chronicles the rise of a new health profession, Podiatric Medicine and Surgery, as well as the emergence of the specialty of Vascular Surgery. The partnership between the diabetologist, vascular surgeon, and podiatrist is a natural one. The complementary skills and knowledge of each can improve limb salvage and functional outcomes. Comprehensive multidisciplinary foot care programs have been shown to increase quality of care and reduce amputation rates by 36% to 86%. The development of distal revascularization techniques to restore pulsatile blood flow to the foot has also been a major advancement. CONCLUSION: Diabetic foot patients are among the most complex and vulnerable of all patient populations. Specialized diabetic foot clinics of the 21st century should be multidisciplinary and equipped to coordinate diagnosis, off-loading, and preventive care; perform revascularization procedures; aggressively treat infections; and manage medical comorbidities.

Diabetic Neuropathic Arthropathy of the Knee: Two Case Reports and a Review of the Literature.

Diabetic neuroarthropathy of the knee or Charcot knee (CK) is a lesser-known complication of diabetes mellitus, with a limited number of case reports and small case series published in the literature. The majority of these reports describe the complexities and challenges that arise in these patients undergoing knee arthroplasty procedures. We present two cases of CK, including a rare case of concurrent bilateral disease, and also a review of the current literature.

Risk factors associated with adverse outcomes in a population-based prospective cohort study of people with their first diabetic foot ulcer.

AIMS/HYPOTHESIS: The aim of this study was to determine which clinic-based measures of diabetes and foot status at baseline were associated with adverse outcomes 18 months later in people with diabetes presenting with their first foot ulcer. SUBJECTS AND METHODS: This was a prospective population-based cohort study of adults with type 1 and type 2 diabetes mellitus presenting with their first foot ulcer (excluding those with severe ischaemia, ankle brachial pressure index <0.5). The main explanatory variables were age, sex, smoking status, ulcer site (dorsal or plantar), size and severity of ulcer, severity of neuropathy, ischaemia, glycosylated haemoglobin, presence of micro- and macrovascular complications, and depression. The main outcomes recorded were death, amputation and recurrence of ulceration, and the time taken for each outcome to occur. RESULTS: Two hundred fifty-three people were recruited. There were 40 deaths (15.8%), 36 amputations (15.5%), and 99 recurrences (43.2%) at 18 months. Our main findings were that being older [hazard ratio (HR) 1.07, 95% CI 1.04-1.11], having lower glycosylated haemoglobin (HR 0.73, 95% CI 0.56-0.96), moderate ischaemia (HR 2.74, 95% CI 1.46-5.14), and depression (HR 2.51, 95% CI 1.33-4.73) were associated with mortality. Ulcer severity was the only explanatory factor significantly associated with amputation (HR 3.18, 95% CI 1.53-6.59). Microvascular complications were the only explanatory factor associated with recurrent ulceration (HR 3.34, 95% CI 1.17-9.56). CONCLUSIONS/INTERPRETATION: Commonly used primary and secondary care clinic-based measures could provide the basis for a risk assessment tool for adverse outcomes following first presentation of diabetic foot ulcers.

Conservative and Pharmacologic Treatments for the Diabetic Charcot Foot.

Charcot neuroarthropathy is a disabling complication of diabetic neuropathy. Prolonged immobilization in a total contact cast (TCC) is among the main treatments. Education of health care professionals in the application of TCC together with well-conducted clinical trials are required to overcome its frequent underuse. There are no established pharmacologic therapies to treat this condition; however, there is an overwhelming need for a new therapeutic approach. Novel targeted drug delivery systems are required to prevent the pathologic bone and joint destruction of the Charcot neuroarthropathy and this may lead to an improved outcome in diabetic patients with this condition.

Nutritional Supplementation for Diabetic Foot Ulcers: The Big Challenge.

Diabetic foot ulcers remain difficult to heal and nutritional supplementation may be an important complementary therapeutic measure. However, we need to clarify many issues before such supplementation is more widely used. Indeed, improvements are needed in the following areas: evaluation of nutritional inadequacy, completion of randomized controlled trials, understanding of patient and ulcer characteristics that favor response to nutritional supplementation, optimal duration of supplementation therapy, and evaluation of patient adherence. The challenge is now to acquire more knowledge in the aforementioned areas.

Inhibition of TNF-α Reverses the Pathological Resorption Pit Profile of Osteoclasts from Patients with Acute Charcot Osteoarthropathy.

We hypothesised that tumour necrosis factor-α (TNF-α) may enhance receptor activator of nuclear factor-κß ligand- (RANKL-) mediated osteoclastogenesis in acute Charcot osteoarthropathy. Peripheral blood monocytes were isolated from 10 acute Charcot patients, 8 diabetic patients, and 9 healthy control subjects and cultured in vitro on plastic and bone discs. Osteoclast formation and resorption were assessed after treatment with (1) macrophage-colony stimulating factor (M-CSF) and RANKL and (2) M-CSF, RANKL, and neutralising antibody to TNF-α (anti-TNF-α). Resorption was measured on the surface of bone discs by image analysis and under the surface using surface profilometry. Although osteoclast formation was similar in M-CSF + RANKL-treated cultures between the groups (p > 0.05), there was a significant increase in the area of resorption on the surface (p < 0.01) and under the surface (p < 0.01) in Charcot patients compared with diabetic patients and control subjects. The addition of anti-TNF-α resulted in a significant reduction in the area of resorption on the surface (p < 0.05) and under the surface (p < 0.05) only in Charcot patients as well as a normalisation of the aberrant erosion profile. We conclude that TNF-α modulates RANKL-mediated osteoclastic resorption in vitro in patients with acute Charcot osteoarthropathy.

Modern Orthopedic Inpatient Care of the Orthopedic Patient With Diabetic Foot Disease.

In this article, we describe emergency and elective pathways within our orthopedic multidisciplinary inpatient care of patients with diabetic foot problems. We performed a retrospective cohort review of 19 complex patients requiring orthopedic surgical treatment of infected ulceration or Charcot feet or deformity at our institution. A total of 30 admissions (19 emergency, 11 elective) were included. The pathways were coordinated by a multidisciplinary team and comprised initial assessment and investigation and a series of key events, which consisted of emergency and elective surgery together with the introduction, and change of intravenous antibiotics when indicated. Patients had rigorous microbiological assessment, in the form of deep ulcer swabs, operative tissue specimens, joint aspirates, and blood cultures according to their clinical presentation as well as close clinical and biochemical surveillance, which expedited the prompt institution of key events. Outcomes were assessed using amputation rates and patient satisfaction. In the emergency group, there were 5.6 ± 3.0 (mean ± SD) key events per admission, including 4.2 ± 2.1 antibiotic changes. In the elective group, there were 4.8 ± 1.4 key events per inpatient episode, with 3.7 ± 1.3 antibiotic changes. Overall, there were 3 minor amputations, and no major amputations. The podiatric and surgical tissue specimens showed a wide array of Gram-positive, Gram-negative, aerobic and anaerobic isolates and 15% of blood cultures showed bacteremia. When 9 podiatric specimens were compared with 9 contemporaneous surgical samples, there was concordance in 2 out of 9 pairs. We have described the successful modern care of the orthopedic diabetic foot patient, which involves close clinical, microbiological, and biochemical surveillance by the multidisciplinary team directing patients through emergency and elective pathways. This has enabled successful surgical intervention involving debridement, pressure relief, and stabilization, with low rates of amputation.

The diabetic foot: the importance of coordinated care.

Because of the severe morbidity and mortality associated with diabetes, diabetic foot care is an essential component of a peripheral vascular service. The goal of this article is to describe the vascular diabetic foot care pathway and how the coordinated foot care service for diabetic patients is delivered at King's College Hospital, London.