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A meta-analysis of remote ischaemic conditioning in experimental stroke.

ABSTRACT: Remote ischaemic conditioning (RIC) is achieved by repeated transient ischaemia of a distant organ/limb and is neuroprotective in experimental ischaemic stroke. However, the optimal time and methods of administration are unclear. Systematic review identified relevant preclinical studies; two authors independently extracted data on infarct volume, neurological deficit, RIC method (administration time, site, cycle number, length of limb occlusion (dose)), species and quality. Data were analysed using random effects models; results expressed as standardised mean difference (SMD). In 57 publications incorporating 99 experiments (1406 rats, 101 mice, 14 monkeys), RIC reduced lesion volume in transient (SMD -2.0; 95% CI -2.38, -1.61; p < 0.00001) and permanent (SMD -1.54; 95% CI -2.38, -1.61; p < 0.00001) focal models of ischaemia and improved neurological deficit (SMD -1.63; 95% CI -1.97, -1.29, p < 0.00001). In meta-regression, cycle length and number, dose and limb number did not interact with infarct volume, although country and physiological monitoring during anaesthesia did. In all studies, RIC was ineffective if the dose was <10 or ≥50 min. Median study quality was 7 (range 4-9/10); Egger's test suggested publication bias (p < 0.001). RIC is most effective in experimental stroke using a dose between 10 and 45 min. Further studies using repeated dosing in animals with co-morbidities are warranted.

SUBMITTER: Weir P

PROVIDER: S-EPMC7747156 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A meta-analysis of remote ischaemic conditioning in experimental stroke.

Weir Philippa P Maguire Ryan R O'Sullivan Saoirse E SE England Timothy J TJ

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20200614 1

Remote ischaemic conditioning (RIC) is achieved by repeated transient ischaemia of a distant organ/limb and is neuroprotective in experimental ischaemic stroke. However, the optimal time and methods of administration are unclear. Systematic review identified relevant preclinical studies; two authors independently extracted data on infarct volume, neurological deficit, RIC method (administration time, site, cycle number, length of limb occlusion (dose)), species and quality. Data were analysed us ...[more]

PMID: 32538284

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Project description:Experimental animal studies on the mechanisms of remote ischaemic conditioning (RIC)-induced cardioprotection against ischaemia/reperfusion injury demonstrate involvement of both neuronal and humoral pathways. Autonomic parasympathetic (vagal) pathways confer organ protection through both direct innervation and/or immunomodulation, but evidence in humans is lacking. During acute inflammation, vagal release of acetylcholine suppresses CD11b expression, a critical β2-integrin regulating neutrophil adhesion to the endothelium and transmigration to sites of injury. Here, we tested the hypothesis that RIC recruits vagal activity in humans and has an anti-inflammatory effect by reducing neutrophil CD11b expression. Participants (age:50 ± 19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 3 × 8 min cycles of brachial artery occlusion using a blood pressure cuff (RICblock). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate, heart rate variability (HRV)) before, and 10 min after, the last cycle of RIC. RR-interval increased after RIC (reduced heart rate) by 40 ms (95% confidence intervals (95%CI):13-66; n = 17 subjects; P = 0.003). RR-interval did not change after brachial plexus blockade (mean difference: 20 ms (95%CI:-11 to 50); P = 0.19). The high-frequency component of HRV was reduced after RICblock, but remained unchanged after RIC (P < 0.001), indicating that RIC preserved vagal activity. LPS-induced CD16+CD11b+ expression in whole blood (measured by flow cytometry) was reduced by RIC (3615 median fluorescence units (95%CI:475-6754); P = 0.026), compared with 2331 units (95%CI:-3921 to 8582); P = 0.726) after RICblock. These data suggest that in humans RIC recruits vagal cardiac and anti-inflammatory mechanisms via ischaemia/reperfusion-induced activation of sensory nerve fibres that innervate the organ undergoing RIC.

Project description:AimsThe potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy.Methods and resultsOur primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8-26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1-25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization.ConclusionsRIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.

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A meta-analysis of remote ischaemic conditioning in experimental stroke.

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A meta-analysis of remote ischaemic conditioning in experimental stroke.

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