Preclinical evidence of remote ischemic conditioning in ischemic stroke, a metanalysis update

Abstract

Remote ischemic conditioning (RIC) is a promising therapeutic approach for ischemic stroke patients. It has been proven that RIC reduces infarct size and improves functional outcomes. RIC can be applied either before ischemia (pre-conditioning; RIPreC), during ischemia (per-conditioning; RIPerC) or after ischemia (post-conditioning; RIPostC). Our aim was to systematically determine the efficacy of RIC in reducing infarct volumes and define the cellular pathways involved in preclinical animal models of ischemic stroke. A systematic search in three databases yielded 50 peer-review articles. Data were analyzed using random effects models and results expressed as percentage of reduction in infarct size (95% CI). A meta-regression was also performed to evaluate the effects of covariates on the pooled effect-size. 95.3% of analyzed experiments were carried out in rodents. Thirty-nine out of the 64 experiments studied RIPostC (61%), sixteen examined RIPreC (25%) and nine tested RIPerC (14%). In all studies, RIC was shown to reduce infarct volume (- 38.36%; CI - 42.09 to - 34.62%) when compared to controls. There was a significant interaction caused by species. Short cycles in mice significantly reduces infarct volume while in rats the opposite occurs. RIPreC was shown to be the most effective strategy in mice. The present meta-analysis suggests that RIC is more efficient in transient ischemia, using a smaller number of RIC cycles, applying larger length of limb occlusion, and employing barbiturates anesthetics. There is a preclinical evidence for RIC, it is safe and effective. However, the exact cellular pathways and underlying mechanisms are still not fully determined, and its definition will be crucial for the understanding of RIC mechanism of action.

Figure 1

PRISMA flowchart of systematic review search process and meta-analysis on animal models of ischemic stroke and remote ischemic conditioning (RIC).

Figure 2

Forest plot to illustrate the efficacy of remote ischemic conditioning on infarct volume by animal model from 64 analyzed experiments. Forest plot of mean difference (MD) and their 95% CI for individual trials determined from the result of 64 trials comparing the effect of remote ischemic conditioning with control on infarct volume. Studies are grouped by species. The solid vertical line represents a mean difference of 0 or no effect. Points to the left of the line represent a reduction in infarct volume, and points to the right of the line indicate an increase. Each square around the point effect represents the mean effect size for that study and reflects the relative weighting of the study to the overall effect size estimate. The larger the box, the greater the study contribution to the overall estimate. The weight that each study contributed is in the right-hand column. MD mean difference, CI confidence interval.

Figure 3

Impact of studied factors on infarct volume evaluated by meta-analysis comparisons of all included species. (A) The Baujat plot shown which studies contributed to greater heterogeneity and what were the most influential studies on the overall result. (B) Duration meta-regression graph. There was not greater reduction in volume to longer duration of cerebral ischemia (p = 0.465). (C) Number of cycles meta-regression graph. There was less reduction in volume with a greater number of cycles (p < 0.001). (D) Duration of cycles (min) meta-regression graph. There was a greater reduction in volume as the duration of the cycles increases (p = 0.0165). (E) Conditioning start time meta-regression graph. There was no significant volume reduction based on conditioning onset time (p = 0.205).

Figure 4

Summary of the proposed cellular mechanisms involved on remote ischemic conditioning (RIC).