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

Detailed description

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.

Interventions

• Device Remote Ischaemic Conditioning
  Cuff inflation to 20mmHg abocve systolic blood pressure for cycles of 5 minutes. Each session will consist of 4 cycles of 5 minte inflation followed by 5 minute deflation. Total session time 40 minutes
• Device Sham Remote Ischaemic Conditioning
  Cuff inlfation to 20mmHg only for cycles of 5 minutes. Each session will consist of 4 cycles of 5 minute inflation followed by 5 minutes of deflation. Total session time of 40 minutes

Primary outcome measures

• Autoregulatory Index [Time frame: Baseline and 6 weeks]

Secondary outcome measures (6)

• Phase DIfference [Time frame: Baseline and 6 weeks]
• Gain [Time frame: Baseline and 6 weeks]
• Clinic Systolic Blood Pressure [Time frame: Baseline and week 6]
• Clinic Diastolic Blood Pressure [Time frame: Baseline to 6 Weeks]
• Clinic Mean Arterial Pressure [Time frame: Baseline to 6 Weeks]
• Blood plasma markers [Time frame: Baseline and 6 weeks]

Eligibility criteria

Inclusion criteria

• Participant is willing and able to give informed consent for participation in the study
• Participant aged 65 - 85
• Participant is able to perform RIC independently at home

Exclusion criteria

• Active cardiovascular or cerebrovascular disease (acute event within the last 12 months)
• Atrial fibrillation or other significant arrhythmias
• Peripheral Vascular Disease
• Haemostatic disorders
• Soft tissue injury or fracture to the upper limb
• Pregnant or breast feeding
• History or current psychiatric illness
• History or current neurological condition (e.g. epilepsy)
• Inability to identify temporal window for transcranial doppler ultrasound at screening visit
• Any condition or presentation under current investigation that is deemed by the study clinician to exclude the participant from the study.
• Having taken part in a research study in the last 3 months involving invasive procedures or an inconvenience allowance

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Basic science

Study locations

United Kingdom · 1 center

• School of Medicine, University of Nottingham, Royal Derby Hospital Centre — Derby

Publications

• Weir P, Maguire R, O'Sullivan SE, England TJ. A meta-analysis of remote ischaemic conditioning in experimental stroke. J Cereb Blood Flow Metab. 2021 Jan;41(1):3-13. doi: 10.1177/0271678X20924077. Epub 2020 Jun 14. PMID 32538284
• Chen HS, Cui Y, Li XQ, Wang XH, Ma YT, Zhao Y, Han J, Deng CQ, Hong M, Bao Y, Zhao LH, Yan TG, Zou RL, Wang H, Li Z, Wan LS, Zhang L, Wang LQ, Guo LY, Li MN, Wang DQ, Zhang Q, Chang DW, Zhang HL, Sun J, Meng C, Zhang ZH, Shen LY, Ma L, Wang GC, Li RH, Zhang L, Bi C, Wang LY, Wang DL; RICAMIS Investigators. Effect of Remote Ischemic Conditioning vs Usual Care on Neurologic Function in Patients With PMID 35972485
• Hou C, Lan J, Lin Y, Song H, Wang Y, Zhao W, Li S, Meng R, Hao J, Ding Y, Chimowitz MI, Fisher M, Hess DC, Liebeskind DS, Hausenloy DJ, Huang J, Li Z, Han X, Yang J, Zhou J, Chen P, Zhu X, Hu P, Pang H, Chen W, Chen H, Li G, Tao D, Yue W, Gao Z, Ji X; RICA investigators. Chronic remote ischaemic conditioning in patients with symptomatic intracranial atherosclerotic stenosis (the RICA trial): a mul PMID 36354026
• Blauenfeldt RA, Hjort N, Valentin JB, Homburg AM, Modrau B, Sandal BF, Gude MF, Hougaard KD, Damgaard D, Poulsen M, Diedrichsen T, Schmitz ML, von Weitzel-Mudersbach P, Christensen AA, Figlewski K, Grove EL, Hreietharsdottir MK, Lassesen HM, Wittrock D, Mikkelsen S, Vaeggemose U, Juelsgaard P, Kirkegaard H, Rostgaard-Knudsen M, Degn N, Vestergaard SB, Damsbo AG, Iversen AB, Mortensen JK, Petersson PMID 37787796
• Bell RM, Basalay M, Botker HE, Beikoghli Kalkhoran S, Carr RD, Cunningham J, Davidson SM, England TJ, Giesz S, Ghosh AK, Golforoush P, Gourine AV, Hausenloy DJ, Heusch G, Ibanez B, Kleinbongard P, Lecour S, Lukhna K, Ntsekhe M, Ovize M, Salama AD, Vilahur G, Walker JM, Yellon DM. Remote ischaemic conditioning: defining critical criteria for success-report from the 11th Hatter Cardiovascular Worksh PMID 35970954
• Hougaard KD, Hjort N, Zeidler D, Sorensen L, Norgaard A, Hansen TM, von Weitzel-Mudersbach P, Simonsen CZ, Damgaard D, Gottrup H, Svendsen K, Rasmussen PV, Ribe LR, Mikkelsen IK, Nagenthiraja K, Cho TH, Redington AN, Botker HE, Ostergaard L, Mouridsen K, Andersen G. Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: a randomized trial. Str PMID 24203849
• Claassen JAHR, Thijssen DHJ, Panerai RB, Faraci FM. Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation. Physiol Rev. 2021 Oct 1;101(4):1487-1559. doi: 10.1152/physrev.00022.2020. Epub 2021 Mar 26. PMID 33769101
• Qu Y, Zhang P, He QY, Sun YY, Wang MQ, Liu J, Zhang PD, Yang Y, Guo ZN. The Impact of Serial Remote Ischemic Conditioning on Dynamic Cerebral Autoregulation and Brain Injury Related Biomarkers. Front Physiol. 2022 Feb 22;13:835173. doi: 10.3389/fphys.2022.835173. eCollection 2022. PMID 35273521

Identifiers

NCT: NCT07179887 · FMHS 192-0625

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗