Improving Physical, Physiological, and Psychological Health Outcomes in Patients with Diabetic Foot Ulcers – State of the Art

Diabetic foot disease is a complex and challenging complication of diabetes mellitus, which imposes a significant burden of disease on patients, their carers, and the wider health systems. Recurrence rates are high, and current evidence indicates a high mortality associated with it. While management algorithms have primarily focused on the physical aspects of healing, there is increasing recognition of the critical role played by psychological and biomechanical factors in the development and resolution of diabetic foot disease. Therefore, in this paper, we aim to explore how diabetic foot outcomes can be improved by addressing not only the physical but also the psychological and biomechanical aspects that are integral to the development of this condition and its optimal resolution. We explore new technologies that allow for non-invasive objective assessment of the diabetic foot at risk, and we also explore the role of understanding biomechanics, which is essential to determining risk of foot disease, but also the potential for recurrence. In addition, we discuss the evidence linking depression and cognitive impairment to diabetic foot disease and offer our insight on the research direction required before implementing novel information into front-line clinics

A Synoptic Overview of Neurovascular Interactions in the Foot

Diabetes is a worldwide public health concern as it is associated with various complications. One of the major complications of diabetes is diabetic foot syndrome that results in catastrophic events such as ulceration and amputation. Therefore, the main four strategies of diabetic foot care involve risk prediction, prevention, and early diagnosis and prompt intervention. The drivers of ulceration are multifactorial, and importantly, include microcirculatory changes in the diabetic skin. Cutaneous microcirculation on the foot is greatly influenced by the small fibers which mediate thermal sensation and pain perception in addition to sympathetic activities such as thermoregulation and vasodilation. The interdependence between the neurovascular elements means with the loss of small fiber functions, the corresponding microcirculatory responses may be compromised. Thus, it can be hypothesized that the impairment of the microcirculation may follow the order of the corresponding small fiber nerve dysfunction or vice versa. In this review, select neurovascular investigations that inform the cutaneous microcirculatory and small fiber nerve function in response to pain, cold, and heat and pressure stimuli are reviewed and discussed in this order of sensory loss: the loss of pain, cold, warmth, touch and deep pressure sensation. We also discuss the neurological and vascular characteristics of each of these neurovascular responses. This review highlights the influence of small fibers on cutaneous microcirculation and the need for prospective studies that can determine the course of microcirculatory impairment over time. This, in turn, may help clarify the exact role of microcirculatory changes in the pathway of ulceration. The insights from this review can be pertinent to understand key microcirculatory disturbances and given that the microcirculatory impairment develops at an early stage, relevant interventions can be implemented to possibly reverse or regress the course of the disease. Therefore, knowledge of the neurovascular interactions aids to map the disease progression for early diagnosis and prevention of adverse complications

A Synoptic Overview of Neurovascular Interactions in the Foot

Diabetes is a worldwide public health concern as it is associated with various complications. One of the major complications of diabetes is diabetic foot syndrome that results in catastrophic events such as ulceration and amputation. Therefore, the main four strategies of diabetic foot care involve risk prediction, prevention, and early diagnosis and prompt intervention. The drivers of ulceration are multifactorial, and importantly, include microcirculatory changes in the diabetic skin. Cutaneous microcirculation on the foot is greatly influenced by the small fibers which mediate thermal sensation and pain perception in addition to sympathetic activities such as thermoregulation and vasodilation. The interdependence between the neurovascular elements means with the loss of small fiber functions, the corresponding microcirculatory responses may be compromised. Thus, it can be hypothesized that the impairment of the microcirculation may follow the order of the corresponding small fiber nerve dysfunction or vice versa. In this review, select neurovascular investigations that inform the cutaneous microcirculatory and small fiber nerve function in response to pain, cold, and heat and pressure stimuli are reviewed and discussed in this order of sensory loss: the loss of pain, cold, warmth, touch and deep pressure sensation. We also discuss the neurological and vascular characteristics of each of these neurovascular responses. This review highlights the influence of small fibers on cutaneous microcirculation and the need for prospective studies that can determine the course of microcirculatory impairment over time. This, in turn, may help clarify the exact role of microcirculatory changes in the pathway of ulceration. The insights from this review can be pertinent to understand key microcirculatory disturbances and given that the microcirculatory impairment develops at an early stage, relevant interventions can be implemented to possibly reverse or regress the course of the disease. Therefore, knowledge of the neurovascular interactions aids to map the disease progression for early diagnosis and prevention of adverse complications

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT

Background: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. Objectives: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. Design: A randomised crossover trial with health economic analysis. Setting: Twenty-one secondary care centres in the UK. Participants: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0–10). Interventions: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using overencapsulated capsules and matching placebos. Site pharmacists were unblinded. Outcomes: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory – Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0–10), Patient Global Impression of Change score at week 16 and patients’ preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A withintrial cost–utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. Results: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of –0.1 points (98.3% confidence interval –0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of –0.1 points (98.3% confidence interval –0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval –0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6–16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval –0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin –0.002 (95% confidence interval –0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline –0.006 (95% confidence interval –0.002 to 0.014) qualityadjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin −£113 (95% confidence interval −£381 to £90), ABSTRACT NIHR Journals Library www.journalslibrary.nihr.ac.uk viii amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval −£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval −£13 to £398)]. Limitations: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. Future work: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. Conclusions: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients’ preference in terms of side effects. Trial registration: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in Health Technology Assessment; Vol. 26, No. 39. See the NIHR Journals Library website for further project information

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Laser Doppler Imager Flare (LDIflare) small fibre function

Distal sensorimotor peripheral neuropathy (DSPN), the classical length dependent symmetrical neuropathy of diabetes, can affect up to 50% of those with diabetes leading to significant morbidity, mortality and healthcare costs. There is increasing recognition that small nerve fibres, mediating pain, temperature and autonomic function, are involved early in the course of diabetic neuropathy, preceding large fibre involvement. However, assessment small fibre neuropathy (SFN), continues to be a significant challenge. The currently available options are either invasive, subjective with poor reproducibility, may not directly assess the region of interest or are still in a research phase. Thus, there is an ongoing need for simple, non-invasive and reproducible techniques for the evaluation of SFN. The laser Doppler imager flare (LDIflare) is one such novel, non-invasive technique of assessing small fibre function. It has been shown to be a reliable indicator of small fibre neuropathy, even when other SFN markers are either inconclusive or normal. However, the original methodology, took over an hour to complete, which limited its use as a clinical tool. The LDIflare methodology was therefore modified to overcome this limitation by incorporating an accelerated acclimatisation phase and a shorter duration of skin heating but at a higher final temperature reducing the total procedure time to under 30 minutes. The size of the resultant flares was nearly twice as large compared to the older method while demonstrating similar group differences in those with and without clinical neuropathy. Assessment of the LDIflare in healthy volunteers (n=94) demonstrated significant inverse relationship of LDIflare size to age (r=-0.42, p<0.0001) but not with other anthropometric or metabolic factors except for fasting triglycerides (r=-0.36, p<0.0001). Furthermore, the LDIflare possessed a sensitivity of 77%, specificity of 90%, positive predictive value (PPV) of 82% and negative predictive value of (NPV) 87% for the detection of clinical neuropathy. Recent observations, exploring into the aetiopathogenesis of diabetic neuropathy, have suggested that triggers for neuropathy development in the two main forms of diabetes may be different. Small fibre function (SFF) in individuals with type 1 diabetes with (MV+, n=24) and without (MV-, n=24) renal and retinal microvascular disease, but all without clinical neuropathy was assessed using the LDIflare. The finding of abnormal SFF only in the MV- group suggests that direct microvascular damage is an early aetiopathogenic factor in type 1 diabetes. Furthermore, in another study of normal glucose tolerant individuals not meeting the criteria for metabolic syndrome, SFF was observed to be abnormal with increasing fasting triglyceride concentrations. This is suggestive that hypertriglyceridaemia may play a pathogenic role in the development of neural dysfunction, and may partly explain the presence of neuropathy early in the course of type 2 diabetes, when significant hyperglycaemia is not a factor. The LDIflare in its current modification is a novel, reliable, non-invasive measure and objective method of detecting small fibre neuropathy. It has good reproducibility and offers excellent accuracy for the detection of clinical neuropathy. The age based normative values allow for a clear distinction of abnormal results. While further comparative studies between the LDIflare and modern markers of SFN are desired, the studies included in this submission support the use of the LDIflare technique to investigate abnormalities in the peripheral nervous system, in particular small nerve fibres, in research but also in clinical domains

The rate of decline in small fibre function assessed using axon reflex-mediated neurogenic vasodilatation and the importance of age related centile values to improve the detection of clinical neuropathy.

BACKGROUND: The LDIflare technique (LDIflare) is a simple non-invasive test of small fibre function in dorsal foot skin involving skin heating and measuring the size of the resulting axon reflex-mediated vasodilator (flare) response using a laser Doppler imager (LDI). This study establishes age-related normative reference ranges for the test and determines the rate of decline in small fibre function per decade. Additionally, the potential value of using age related centiles rather than Receiver Operator Curves (ROC) was explored by comparison of the sensitivity and specificity of each analytic technique in identifying clinical neuropathy. METHODS: LDIflare areas were assessed in 94 healthy controls and 66 individuals with diabetes with (DN+, n = 31) and without clinical neuropathy (DN-, n = 35); neuropathy defined as a Neuropathy Disability Score ≥ 3. The age specific 5th centile values were used as the 'cut-offs' for the diagnosis of neuropathy from which sensitivity and specificity were calculated. RESULTS: There was a significant age dependant decrease in LDIflare size (r = -0.42, p<0.0001) with no significant gender differences. The LDIflare size reduced 0.56 cm(2) per decade which gives a percentage reduction of approximately 5.5% per decade. Using the normative 5th centiles as the cut-offs, the technique had a sensitivity of 77%, specificity of 90%, positive predictive value of 82% and negative predictive value of 87%.The ROC analysis gave a threshold of <3.66 cm(2) for the cut-off, resulting in a sensitivity of 75%, specificity of 85%, positive predictive value of 74% and negative predictive value of 86%. CONCLUSIONS: There is an age dependent decrease in small fibre function in the foot of 5.5% per decade. Both analytic techniques demonstrate good sensitivity and specificity for detecting clinical neuropathy but the technique based on age centiles offers better diagnostic accuracy and is therefore proposed as the method of choice

What is the impact of microvascular complications of diabetes on severe COVID-19?

Evidence suggests severe coronavirus disease-19 (COVID-19) infection is characterised by pulmonary and systemic microvasculature dysfunction, specifically, acute endothelial injury, hypercoagulation and increased capillary permeability. Diabetes, which is also characterised by vascular injury in itself, confers an increased risk of adverse COVID-19 outcomes. It has been suggested that pre-existing endothelial dysfunction and microvascular disease in diabetes will exacerbate the vascular insults associated with COVID-19 and thus lead to increased severity of COVID-19 infection. In this article, we evaluate the current evidence exploring the impact of microvascular complications, in the form of diabetic retinopathy and nephropathy, in individuals with COVID-19 and diabetes. Future insights gained from exploring the microvascular injury patterns and clinical outcomes may come to influence care delivery algorithms for either of these conditions