Blood Pressure, Cerebral Autoregulation, Dynamic Cerebral Autoregulation
Conditions
Keywords
Remote Ischaemic Conditioning, Dynamic Cerebral Autoregulation, Vascular Health, Randomised Controlled Trial
Brief summary
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
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
DEVICESham 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
Sponsors
University of Leicester
University of Nottingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to 85 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Autoregulatory Index | Baseline and 6 weeks | In dynamic cerebral autoregulation analysis, the Autoregulatory Index is a dimensionless index ranging from 0 to 9. 0 represents no autoregulation and 9 represents very strong autoregulation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gain | Baseline and 6 weeks | In dynamic cerebral autoregulation analysis, the Gain quantifies the magnitude of transmission of blood pressure oscillations into cerebral blood flow oscillations. It is reported both as cm/s/mmHg. Lower values represent better autoregulation. |
| Clinic Systolic Blood Pressure | Baseline and week 6 | Resting blood pressure will be calculated using automated sphygmomanometer. The average of 3 recordings will be used. Blood pressure will be rexpressed in units of mmHg. |
| Phase DIfference | Baseline and 6 weeks | In dynamic cerebral autoregulation analysis, the phase difference quantifies the timing shift between oscillations in arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV) at a given frequency. It is reported in degrees with higher values representing stronger autoregulation |
| Clinic Mean Arterial Pressure | Baseline to 6 Weeks | Resting blood pressure will be calculated using automated sphygmomanometer. The average of 3 recordings will be used. Blood pressure will be rexpressed in units of mmHg. |
| Blood plasma markers | Baseline and 6 weeks | Markers of RIC efficacy will be measured by ELISA from blood plasma stored at the time of data collection and analysed at study completion. |
| Clinic Diastolic Blood Pressure | Baseline to 6 Weeks | Resting blood pressure will be calculated using automated sphygmomanometer. The average of 3 recordings will be used. Blood pressure will be rexpressed in units of mmHg. |
Countries
United Kingdom
Contacts
Primary ContactHarry Keevil, MB BChir
Backup ContactTim England, MBChB PhD
Outcome results
None listed