Anthony I. Shepherd

The effect of dietary nitrate supplementation on the oxygen cost of cycling, walking performance and resting blood pressure in individuals with chronic obstructive pulmonary disease: A double blind placebo controlled, randomised control trial

BACKGROUND Chronic obstructive pulmonary disease (COPD) results in exercise intolerance. Dietary nitrate supplementation has been shown to lower blood pressure (BP), reduce the oxygen cost of exercise, and enhance exercise tolerance in healthy volunteers. This study assessed the effects of dietary nitrate on the oxygen cost of cycling, walking performance and BP in individuals with mild-moderate COPD. METHODS Thirteen patients with mild-moderate COPD were recruited. Participants consumed 70 ml of either nitrate-rich (6.77 mmol nitrate; beetroot juice) or nitrate-depleted beetroot juice (0.002 mmol nitrate; placebo) twice a day for 2.5 days, with the final supplement ~3 hours before testing. BP was measured before completing two bouts of moderate-intensity cycling, where pulmonary gas exchange was measured throughout. The six-minute walk test (6 MWT) was completed 30 minutes subsequent to the second cycling bout. RESULTS Plasma nitrate concentration was significantly elevated following beetroot juice vs. placebo (placebo; 48 ± 86 vs. beetroot juice; 215 ± 84 µM, P = 0.002). No significant differences were observed between placebo vs. beetroot juice for oxygen cost of exercise (933 ± 323 vs. 939 ± 302 ml: min(-1); P = 0.88), distance covered in the 6 MWT (456 ± 86 vs. 449 ± 79 m; P = 0.37), systolic BP (123 ± 14 vs. 123 ± 14 mmHg; P = 0.91), or diastolic BP (77 ± 9 vs. 79 ± 9 mmHg; P = 0.27). CONCLUSION Despite a large rise in plasma nitrate concentration, two days of nitrate supplementation did not reduce the oxygen cost of moderate intensity cycling, increase distance covered in the 6 MWT, or lower BP.

Effects of dietary nitrate supplementation on the oxygen cost of exercise and walking performance in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled crossover trial

Dietary nitrate supplementation has been shown to reduce the oxygen (O2) cost of exercise and enhance exercise tolerance in healthy individuals. This study assessed whether similar effects could be observed in individuals with type 2 diabetes (T2DM). In a randomized, double-blind, placebo-controlled crossover study, 48 participants with T2DM supplemented their diet for 4 days with either nitrate-rich beetroot juice (70ml/day, 6.43mmol nitrate/day) or nitrate-depleted beetroot juice as placebo (70ml/day, 0.07mmol nitrate/day). After each intervention period, resting plasma nitrate and nitrite concentrations were measured subsequent to participants completing moderate-paced walking. Pulmonary gas exchange was measured to assess the O2 cost of walking. After a rest period, participants performed the 6-min walk test (6MWT). Relative to placebo, beetroot juice resulted in a significant increase in plasma nitrate (placebo, 57±66 vs beetroot, 319±110µM; P < 0.001) and plasma nitrite concentration (placebo, 680±256 vs beetroot, 1065±607nM; P < 0.001). There were no differences between placebo juice and beetroot juice for the O2 cost of walking (946±221 vs 939±223ml/min, respectively; P = 0.59) and distance covered in the 6MWT (550±83 vs 554±90m, respectively; P = 0.17). Nitrate supplementation did not affect the O2 cost of moderate-paced walking or improve performance in the 6MWT. These findings indicate that dietary nitrate supplementation does not modulate the response to exercise in individuals with T2DM.

Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial

Nitric oxide alters gastric blood flow, improves vascular function, and mediates glucose uptake within the intestines and skeletal muscle. Dietary nitrate, acting as a source of nitric oxide, appears to be a potential low-cost therapy that may help maintain glucose homeostasis. In a randomized, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardized breakfast, supplemented with either nitrate-rich beetroot juice (11.91 mmol nitrate) or nitrate-depleted beetroot juice as placebo (0.01 mmol nitrate). MRI was used to assess apparent diffusion coefficient (ADC), portal vein flux, and velocity. Plasma glucose, incretin, and C-peptide concentrations and blood pressure were assessed. Outcome variables were measured at baseline and hourly for 3 h. Compared with a placebo, beetroot juice resulted in a significant elevation in plasma nitrate and plasma nitrite concentration. No differences were seen for the young or older adult cohorts between placebo and beetroot juice for ADC, or portal vein flux. There was an interaction effect in the young adults between visits for portal vein velocity. Nitrate supplementation did not reduce plasma glucose, active GLP-1, total GLP-1, or plasma C-peptide concentrations for the young or older adult cohorts. Despite a significant elevation in plasma nitrite concentration following an acute dose of (11.91 mmol) nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults.

Community-based Rehabilitation Training after stroke: protocol of a pilot randomised controlled trial (ReTrain)

Introduction The Rehabilitation Training (ReTrain) intervention aims to improve functional mobility, adherence to poststroke exercise guidelines and quality of life for people after stroke. A definitive randomised controlled trial (RCT) is required to assess the clinical and cost-effectiveness of ReTrain, which is based on Action for Rehabilitation from Neurological Injury (ARNI). The purpose of this pilot study is to assess the feasibility of such a definitive trial and inform its design. Methods and analysis A 2-group, assessor-blinded, randomised controlled external pilot trial with parallel mixed-methods process evaluation and economic evaluation. 48 participants discharged from clinical rehabilitation despite residual physical disability will be individually randomised 1:1 to ReTrain (25 sessions) or control (exercise advice booklet). Outcome assessment at baseline, 6 and 9 months include Rivermead Mobility Index; Timed Up and Go Test; modified Patient-Specific Functional Scale; 7-day accelerometry; Stroke Self-efficacy Questionnaire, exercise diary, Fatigue Assessment Scale, exercise beliefs and self-efficacy questionnaires, SF-12, EQ-5D-5L, Stroke Quality of Life, Carer Burden Index and Service Receipt Inventory. Feasibility, acceptability and process outcomes include recruitment and retention rates; with measurement burden and trial experiences being explored in qualitative interviews (20 participants, 3 intervention providers). Analyses include descriptive statistics, with 95% CI where appropriate; qualitative themes; intervention fidelity from videos and session checklists; rehearsal of health economic analysis. Ethics and dissemination National Health Service (NHS) National Research Ethics Service approval granted in April 2015; recruitment started in June. Preliminary studies suggested low risk of serious adverse events; however (minor) falls, transitory muscle soreness and high levels of postexercise fatigue are expected. Outputs include pilot data to inform whether to proceed to a definitive RCT and support a funding application; finalised Trainer and Intervention Delivery manuals for multicentre replication of ReTrain; presentations at conferences, public involvement events; internationally recognised peer-reviewed journal publications, open access sources and media releases. Trial registration number NCT02429180; Pre-results.

Community-based rehabilitation training after stroke: results of a pilot randomised controlled trial (ReTrain) investigating acceptability and feasibility

Objectives To assess acceptability and feasibility of trial processes and the Rehabilitation Training (ReTrain) intervention including an assessment of intervention fidelity. Design A two-group, assessor-blinded, randomised controlled trial with parallel mixed methods process and economic evaluations. Setting Community settings across two sites in Devon. Participants Eligible participants were: 18 years old or over, with a diagnosis of stroke and with self-reported mobility issues, no contraindications to physical activity, discharged from National Health Service or any other formal rehabilitation programme at least 1 month before, willing to be randomised to either control or ReTrain and attend the training venue, possessing cognitive capacity and communication ability sufficient to participate. Participants were individually randomised (1:1) via a computer-generated randomisation sequence minimised for time since stroke and level of functional disability. Only outcome assessors independent of the research team were blinded to group allocation. Interventions ReTrain comprised (1) an introductory one-to-one session; (2) ten, twice-weekly group classes with up to two trainers and eight clients; (3) a closing one-to-one session, followed by three drop-in sessions over the subsequent 3 months. Participants received a bespoke home-based training programme. All participants received treatment as usual. The control group received an exercise after stroke advice booklet. Outcome measures Candidate primary outcomes included functional mobility and physical activity. Results Forty-five participants were randomised (ReTrain=23; Control=22); data were available from 40 participants at 6 months of follow-up (ReTrain=21; Control=19) and 41 at 9 months of follow-up (ReTrain=21; Control=20). We demonstrated ability to recruit and retain participants. Participants were not burdened by the requirements of the study. We were able to calculate sample estimates for candidate primary outcomes and test procedures for process and health economic evaluations. Conclusions All objectives were fulfilled and indicated that a definitive trial of ReTrain is feasible and acceptable. Trial registration number NCT02429180; Results.

Physical activity, sleep, and fatigue in community dwelling Stroke Survivors

Stroke can lead to physiological and psychological impairments and impact individuals’ physical activity (PA), fatigue and sleep patterns. We analysed wrist-worn accelerometry data and the Fatigue Assessment Scale from 41 stroke survivors following a physical rehabilitation programme, to examine relationships between PA levels, fatigue and sleep. Validated acceleration thresholds were used to quantify time spent in each PA intensity/sleep category. Stroke survivors performed less moderate to vigorous PA (MVPA) in 10 minute bouts than the National Stroke guidelines recommend. Regression analysis revealed associations at baseline between light PA and fatigue (p = 0.02) and MVPA and sleep efficiency (p = 0.04). Light PA was positively associated with fatigue at 6 months (p = 0.03), whilst sleep efficiency and fatigue were associated at 9 months (p = 0.02). No other effects were shown at baseline, 6 or 9 months. The magnitude of these associations were small and are unlikely to be clinically meaningful. Larger trials need to examine the efficacy and utility of accelerometry to assess PA and sleep in stroke survivors.

CARDIOPULMONARY EXERCISE TESTING WITH SUPRAMAXIMAL VERIFICATION PRODUCES A SAFE AND VALID ASSESSMENT OF V̇O2max IN PEOPLE WITH CYSTIC FIBROSIS

The validity and safety of using supramaximal verification (Smax) to confirm a maximal effort during cardiopulmonary exercise testing (CPET) in people with cystic fibrosis (CF) and/or those with severe disease has been questioned. Therefore, this study aimed to investigate these concerns in children, adolescents, and adults with mild-to-severe CF lung disease. Retrospective analysis of 17 pediatric and 28 adult participants with CF [age range: 9.2-62.9 y; forced expiratory volume in 1 s: 66.7% (range: 29.9%-102.3%); 30 men] who completed a routine ramp-incremental cycling test to determine peak oxygen uptake (V̇o2peak) was studied. Maximal oxygen uptake (V̇o2max) was subsequently confirmed by Smax at 110% of peak power output. All participants satisfied the criteria to verify a maximal effort during CPET. However, Smax-V̇o2peak exceeded ramp-V̇o2peak in 3/14 (21.4%) of pediatric and 6/28 (21.4%) adult exercise tests. A valid measurement of V̇o2max was attained in 85.7% of pediatric and 96.4% of adult exercise tests, as Smax-V̇o2peak did not exceed ramp-V̇o2peak by >9%. Adults ( n = 9) experienced a ≥5% reduction in arterial O2 saturation during CPET, 4 during both the ramp and Smax, 3 during only the ramp, and 2 during only Smax. Smax did not significantly worsen perceived breathing effort, chest tightness, throat narrowing, or exertion compared with ramp-incremental testing. Given the clinical importance of aerobic fitness in people with CF, incorporating Smax is recommended to provide a safe and valid measure of V̇o2max in children, adolescents, and adults who span the spectrum of CF disease severity. NEW & NOTEWORTHY Incorporating supramaximal verification into cardiopulmonary exercise testing protocols did not increase the frequency of adverse events or perceived discomfort versus a single-phase incremental exercise test in people with mild-to-severe cystic fibrosis. Furthermore, a valid measure of maximal oxygen uptake (V̇o2max) was obtained from 85.7% of pediatric and 96.4% of adult exercise tests, whereas peak oxygen uptake underestimated aerobic fitness in comparison with V̇o2max in 21.4% of cases (by up to 24.4%).INTRODUCTION The validity and safety of using supramaximal verification (Smax) to confirm a maximal effort during cardiopulmonary exercise testing (CPET) in people with cystic fibrosis (CF) and/or those with severe disease has been questioned. Therefore, this study aimed to investigate these concerns in children, adolescents and adults with mild-to-severe CF lung disease. METHODS Retrospective analysis of 17 pediatric and 28 adult participants with CF (age range: 9.2-62.9 y; forced expiratory volume in 1 s: 66.7% [range: 29.9-102.3%]; 30 males) who completed a routine ramp incremental cycling test to determine peak oxygen uptake (V̇O2peak). Maximal oxygen uptake (V̇O2max) was subsequently confirmed by Smax at 110% of peak power output. RESULTS All participants satisfied the criteria to verify a maximal effort during CPET. However, Smax-V̇O2peak exceeded ramp-V̇O2peak in 3/14 (21.4%) of pediatric and 6/28 (21.4%) adult exercise tests. A valid measurement of V̇O2max was attained in 85.7% of pediatric and 96.4% of adult exercise tests, as Smax-V̇O2peak did not exceed ramp-V̇O2peak by > 9%. Nine adults experienced a {greater than or equal to} 5% reduction in arterial O2 saturation during CPET; 4 during both the ramp and Smax, 3 during only the ramp and 2 during Smax only. Smax did not significantly worsen perceived breathing effort, chest tightness, throat narrowing or exertion compared with ramp incremental testing. CONCLUSIONS Given the clinical importance of aerobic fitness in people with CF, incorporating Smax is recommended to provide a safe and valid measure of V̇O2max in children, adolescents and adults who span the spectrum of CF disease severity.

The acceptability and experience of a functional training programme (ReTrain) in community dwelling stroke survivors in South West England: a qualitative study

Rehabilitation Training (ReTrain) is a group-based approach to functional training post stroke. ReTrain has recently been evaluated through a pilot randomised controlled trial. Objective This article reports on the acceptability of the intervention as described by trial participants. Design A qualitative approach was undertaken. Of the 45 participants recruited into the trial, 23 were randomised to receive ReTrain. Following a sampling strategy, 10 participants undertook 1:1 semistructured audio-recorded interviews. Transcripts were analysed following a modified Framework Approach. Results Six themes were developed including exploration of: the physical and psychological impacts of training,the perceived mechanisms of change, the interaction of the group and approach of the trainer. A further theme considered the reported longer term impact of participation. Overall, the results indicated the acceptability of the intervention, but also key areas for potential modification in the definitive trial. These include a need to consider potential impact on both physical and psychological function, careful consideration of dosing and fatigue and the interpersonal factors that facilitate appropriate level of delivery, the trainer to participant ratio, and enhancing features that support continuation of activity postintervention. Conclusion Overall, this study supports the acceptability of ReTrain and the development of a definitive trial evaluation of this intervention to full. Trial registration number NCT02429180.