Remote Ischaemic Conditioning in the Older Person and Effects on Dynamic Cerebral Autoregulation

Overview

Remote Ischaemic Conditioning (RIC) is the process of inducing short periods of ischaemia in a limb with the aim of improving vascular health systemically. Recent findings have demonsatrated efficacy in a variety of clinical settings. However, the ideal protocol of RIC \[dose\] is unknown. Dynamic Cerebral Autoregulation (dCA) has been shown to increase in response to RIC. The goal of this trial is to study whether an increase in RIC protocol intensity results in a larger effect on biomarkers of vascular health such as dCA. Participants shall: Receive RIC daily, RIC thrice weekly or sham RIC thrice weekly for 6 weeks Visit the School of Medicine at baseline and at 6 weeks for measurement of biomarkers of vascular health including blood pressure, indices od dCA and blood plasma samples

Remote Ischaemic Conditioning (RIC) involves the delivery of short periods of ischaemia to a limb (using a blood pressure cuff), with the aim of promoting resilience to ischaemia in distant organs. It has shown promise as in intervention in both the treatment of acute ischaemic stroke and secondary prevention of cerebrovascular events. Various protocols exist ranging from single sessions of RIC delivered around the time of an ischaemic event, known as acute RIC, to repeated sessions delivered over days, weeks or even months, known as chronic RIC. Preclinical work in animal models of stroke demonstrated consistent benefits of RIC. However, translation of these findings to human trials has yielded mixed results. Two large randomised controlled trials conducted in recent years have suggested benefit where RIC is given as a treatment following acute ischaemic stroke or when used in the secondary prevention of stroke in patients with symptomatic intracranial atherosclerosis. However, other clinical trials of RIC have yielded neutral results. For example, the RESIST trial, which used RIC as an intervention following both acute ischaemic and haemorrhagic stroke. It is not known exactly why the promising findings in preclinical studies have not been replicated in human trials. It is likely that protocols of RIC, i.e. the 'dose', which proved effective in animal models of stroke, may not be sufficient when applied to multimorbid human populations who have also received current standard therapy. These therapies, such as antiplatelets, themselves provide cerebrovascular protection and may abrogate some of the benefit of RIC. It may be that more intense protocols of RIC, particularly chronic RIC, are needed to illicit benefit in humans. To answer this question, work should be done to investigate the effect of RIC protocol intensity on vascular health in older adults. Too often in RIC research, there has been a rapid jump from preclinical study to large RCT. These RCTs initially used protocols of RIC based on those used in preclinical studies. With increasing awareness of the potential problems with this approach, RCTs now tend to use more intense protocols of RIC. However, very little work has been done examining the effect of RIC on biomarkers of vascular health to inform the choice of RIC dose, informing future trial design. Dynamic cerebral autoregulation (dCA) is a measure of the regulation of cerebral blood flow in response to changes in systemic blood pressure. It has been shown to be impaired in the immediate post stroke period (≈2 weeks) and severely impaired autoregulation in the hours after stroke has been correlated with worse outcomes. Dynamic Cerebral Autoregulation has also been shown to improve in young adults given 2 weeks of RIC. We propose to conduct a further study in older adults, aged 65-85, investigating the effect of chronic RIC on biomarkers of vascular health including dCA and blood pressure (BP), comparing two difference dosing regimens.