Gerry Rayman

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+, nu200a=u200a31) and without clinical neuropathy (DN-, nu200a=u200a35); 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 (ru200a=u200a−0.42, p<0.0001) with no significant gender differences. The LDIflare size reduced 0.56 cm2 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 cm2 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.

Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicentre, double-blind, randomised, controlled trial

BACKGROUNDnDiabetic 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.nnnMETHODSnWe 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 cm2 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 cm2 and 5-30 cm2), 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.nnnFINDINGSnBetween 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.nnnINTERPRETATIONnA 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.nnnFUNDINGnLaboratoires Urgo Medical.

LDIflare small fiber function in normal glucose tolerant subjects with and without hypertriglyceridemia

Introduction: We explored determinants of small fiber function (SFF) in normoglycemic individuals to determine influence of metabolic parameters, including triglyceride (TG) levels. Methods: Dorsal foot SFF was assessed by the LDIflare method in 79 individuals without clinical neuropathy, including 43 controls (HC, <1.7 mmol/L), 17 with mild hypertriglyceridemia (MiTG, 1.7–2.25), and 19 with significant hypertriglyceridemia (HiTG, >2.25 mmol/L). Results: LDIflare was significantly smaller in HiTG compared with HC (4.4u2009±u20091.4 vs. 9.3u2009±u20092.9 cm2; Pu2009<u20090.0001) and compared with the MiTG (4.4u2009±u20091.4 vs. 7.0u2009±u20092.1; Pu2009<u20090.0001). Over all, an inverse correlation existed between LDIflare and age (−0.42; Pu2009<u20090.0001), weight (ru2009=u2009−0.37; Pu2009=u20090.004), body mass index (BMI) (−0.51; Pu2009<u20090.0001), Log10 triglycerides (ru2009=u2009−0.66; Pu2009<u20090.0001), total cholesterol (ru2009=u2009−0.26; Pu2009=u20090.02), and TC/HDL ratio (ru2009=u2009−0.40; Pu2009=u20090.002). In multivariate regression analysis, Log10 triglycerides (Pu2009<u20090.0001) and age (Pu2009=u20090.003) were the only independent predictors. Conclusions: There is an inverse correlation between small fiber function and triglycerides in normoglycemic individuals and abnormal SFF in normoglycemic hypertriglyceridemia. Larger prospective studies are required to confirm these findings and to determine whether reduced SFF heralds later clinical neuropathy. Muscle Nerve 52: 113–119, 2015

Virtual Glucose Management in the Hospital Setting

Worldwide, the proportion of persons with diabetes is rapidly increasing, as is the proportion of inpatients with the disease. In England and Wales, the National Diabetes Inpatient Audit found an increase from 15% of occupied hospital beds in 2011 to 17% in 2016 (1); this figure is predicted to reach 20% by 2020, a rate that has already been exceeded in parts of the United States (2). It is essential that inpatient services are geared up to address these increasing demands because poor glycemic control is associated with increased length of stay, morbidity, and mortality in inpatients, and good glycemic control is associated with better patient outcomes (36). Achieving good control in the hospital setting is challenging for many reasons, including interruption of the patients daily routine; changes in the size and timing of meals; reduction in carbohydrate intake from emesis or interruption of enteral feeding; periods of fasting for procedures; the effect of stress associated with illness; and alteration in insulin sensitivity due to use of new medications, such as steroids. Because more than 90% of patients with diabetes are admitted for reasons unrelated to the disease and may be cared for by staff without specific diabetes expertise, in-hospital glycemic management can be less than ideal. Staff training is important, but rapid staff turnoveran increasing problem in many hospitalsmakes it difficult to maintain institutional knowledge of diabetes care and adherence to specified systems of care. Further, diabetes management has become more complex because new classes of diabetes medications, new combinations of existing medications, and biosimilar insulins with new names may be unfamiliar to nonspecialists. Given these difficulties, the National Diabetes Inpatient Audit in England and Wales found that 38% of inpatients had a diabetes medication management error, 48% had an insulin error, and such errors were more common in those who had severe hypoglycemia (1). Twenty percent of patients had 1 or more hypoglycemic episodes in the previous 7 days, and 1.7% had a severe hypoglycemic episode requiring injectable rescue treatment. For all inpatients treated with insulin, a good glucose day, defined as a day with no glucose values of 4 mmol/L or less (72 mg/dL) and no more than 2 values greater than 11 mmol/L (>198 mg/dL), was achieved on less than half of the days of their inpatient stay, and only on one third of the days in people with type 1 diabetes. These are disturbing figures, and although such nationwide data are not available for other countries, anecdotal reports suggest a similar picture elsewhere. On the positive side, these national audits have been associated with modest improvements in many aspects of care, including reductions in medication errors and hypoglycemic events. It is therefore of great interest that Rushakoff and colleagues report impressive improvements in glycemic control with their use of a novel approach, in which their electronic health record was used to generate a daily report of out-of-range glucose values for review by 1 of 3 diabetes specialists, who then remotely reviewed the glucose/insulin charts and remotely made recommendations on medication changes via an electronic note on the treatment chart (7). In the second year after implementation of this virtual glucose management service (vGMS), there was an associated 39% reduction in hyperglycemic patient-days and a 36% reduction in the proportion of hypoglycemic (<3.9 mmol/L [<70 mg/dL]) readings. Others have reported moderate improvements in inpatient glycemia using centrally downloaded results from ward glucose meters to provide alerts of out-of-range results to the inpatient diabetes team (8, 9). The current study is unique not only in the magnitude of change but also because the improvements were delivered by a system that is totally virtual, without the need for a hands-on inpatient diabetes service. Although the study is exciting, it should be reviewed in the context of inpatient diabetes care practiced elsewhere. Unlike in the United States, uptake of electronic health records and electronic prescribing is limited in many countries. For example, in England and Wales, just 17% of hospital trusts have both of these, and fewer than half have fully implemented remote blood glucose monitoring (1). Nevertheless, results such as these should help promote more widespread adoption of such systems. Presumably, the study used a basalbolus regimen to manage hyperglycemia, which is the recommended practice in the United States. In these circumstances, the vGMS would be less labor-intensive and would result in considerable cost savings. However, practice differs in the United Kingdom and other countries, where fewer patients are prescribed a basalbolus regimen after hospitalization. Patients with type 2 diabetes not previously treated with insulin continue to receive their usual diabetes medication unless it is contraindicated; insulin treatment is not necessarily started in patients with newly discovered hyperglycemia; and if insulin is required, a basalbolus regimen is not necessarily used. Of note, a recent publication found that a combination of basal insulin and an oral dipeptidyl peptidase-4 inhibitor was as effective as the basalbolus regimen in patients with type 2 diabetes, with reduced staff burden (10). It is important to note that the 3 providers who gave advice had 10 to 30 years of inpatient diabetes experience among them. Even greater improvements may have been possible if this level of experience were available at bedside. The benefits of bedside visits can be significant. Speaking to patients and staff can help create a more complete picture of the patients diabetes care, often revealing important human factors that would not be discoverable by a vGMS. These include the presence of lipohypertrophy, inappropriate snacking between meals, mistiming of meals, inability to finish meals due to loss of appetite or emesis, errors in carbohydrate counting, faulty delivery devices, and poor injection technique by nurses or self-injecting patients. Ward visits can also result in opportunistic on-the-spot patient and staff education relevant to the problem. An important downside of the vGMS is the absence of patient and specialist interaction. In the United Kingdom, there is increasing emphasis on patient empowerment and their involvement in care planning. Remote orders without patient involvement would not be readily accepted. Finally, the patient journey does not end on discharge. Before discharge, there is often the need to reassess therapy in discussion with the patient and relatives and to coordinate follow-up, which may require continued contact with the specialist team to prevent readmission in patients with poor control. Rushakoff and colleagues work is commendable. However, a combination of a vGMS with selected bedside care by diabetes specialists may lead to even better control. If such care resulted in shorter stays or fewer readmissions, it could even be cost-saving.

The LDIFLARE and CCM Methods Demonstrate Early Nerve Fiber Abnormalities in Untreated Hypothyroidism: A Prospective Study

ContextnRecent studies using skin biopsy suggest presence of small-fiber neuropathy in subclinical hypothyroidism. This study uses two noninvasive methods-the laser Doppler imager flare technique (LDIFLARE) and corneal confocal microscopy (CCM)-to assess small-fiber function (SFF) and small-fiber structure (SFS), respectively, in newly diagnosed hypothyroidism (HT) before and after adequate treatment.nnnDesign and SettingnSingle-center, prospective, intervention-based cohort study.nnnPatients and ParticipantsnTwenty patients with newly diagnosed HT (15 with primary HT and 5 with post-radioiodine HT) along with 20 age-matched healthy controls (HCs).nnnInterventionsnPatients with HT and HCs were assessed neurologically at diagnosis and baseline, respectively. The HT group was reassessed after optimal replacement (defined as TSH level of 0.27 to 4.20 mIU/L) with levothyroxine (LT4) and HCs were reviewed after 1 year.nnnMain Outcome MeasuresnNeurologic assessment for small fibers was performed by using LDIFLARE for SFF and CCM for SFS; large fibers were studied by sural nerve conduction velocity (SNCV) and sural nerve amplitude (SNAP).nnnResultsnAt baseline, both LDIFLARE (mean ± SD) (6.74 ± 1.20 vs 8.90 ± 1.75 cm2; P = 0.0002) and CCM nerve fiber density (CNFD) (expressed as number of fibers per mm2: 50.77 ± 6.54 vs 58.32 ± 6.54; P = 0.002) were significantly reduced in the HT group compared with HCs whereas neither SNCV nor SNAP was different (P ≥ 0.05). After optimal LT4 treatment, both LDIFLARE (7.72 ± 1.12 vs 6.74 ± 1.20 cm2; P ≤ 0.0001) and CNFD (54.43 ± 5.70 vs 50.77 ± 6.54 no./mm2; P = 0.02) improved significantly but remained significantly reduced compared to HCs (P = 0.008 and P = 0.01, respectively) despite normalization of TSH.nnnConclusionsnThis study demonstrates that dysfunction of small fibers precedes large neural fiber abnormalities in early HT. This can be reversed by replacement therapy to achieve a biochemically euthyroid state, but small-fiber neural outcomes continued to remain low compared with values in HCs.

Small fibre dysfunction in hypothyroidism - a prospective study using methods of small fibre function and structure

• The Laser doppler imager flare (LDIFLARE) technique (Figure 1a & 1b) is a simple noninvasive technique, involving skin heating and measuring the size of the axon-reflex mediated flare using laser Doppler imagery – has been shown to be a sensitive marker of C-fibre dysfunction in early diabetes and impaired glucose tolerance patients. It has excellent correlation with intra-epidermal nerve fibre density