Determination of significant parameters in remote ischemic postconditioning for ischemic stroke in experimental models: A systematic review and meta-analysis study

Abstract

Objectives: To systematically review studies using remote ischemia postconditioning (RIPostC) for ischemic stroke in experimental models and obtain factors that significantly influence treatment outcomes.

Materials and methods: Peer-reviewed studies were identified and selected based on the eligibility criteria, followed by extraction of data on potentially influential factors related to model preparation, postconditioning, and measure time based on outcome measures including infarct size, neurological scales, and cell tests with autophagy, apoptosis, normal-neuron, and damaged-neuron counting. Then, all data were preprocessed, grouped, and meta-analyzed with the indicator of the standardized mean difference.

Results: Fifty-seven studies with 224 experiments (91 for infarct size, 92 for neurological scales, and 41 for cell-level tests) were included. There was little statistical difference between different model preparations, treated body parts, number of treatments, and sides. And treatment effect was generally a positive correlation with the duration of conditioning time to stroke onset with exceptions at some time points. Based on infarct size, the number of cycles per treatment, duration of occlusion, and release per cycle showed significant differences. Combined with the effect sizes by other measures, the occlusion/release duration of 8-10 min per cycle is better than 5 min, and three cycles per treatment were most frequently used with good effects. Effect also varied when measuring at different times, showing statistical differences in infarct size and most neurological scales. RIPostC is confirmed as an effective therapeutic intervention for ischemic stroke, while the RIPostC-mediated autophagy level being activated or inhibited remained conflicting.

Conclusions: Conditioning time, number of cycles per treatment, duration of occlusion, and release per cycle were found to influence the treatment effects of RIPostC significantly. More studies on the relevant influential factors and autophagy mechanisms are warranted.

Keywords: experimental models; ischemia; meta-analysis; remote ischemic postconditioning; stroke.

FIGURE 1

Flow chart of study and information through the different phases based on PRISMA Statement

FIGURE 2

Summary of factors and outcome measures. The factors include the categories of animal model (green), postconditioning (sky blue), and measure time (yellow). Notably, measure time actually cannot influence the real treatment effect but likely affects the outcome measures, so we included it and recorded the measure time points with the stroke onset as a reference; the factor of conditioning time is only in the subgroup of single‐visit treatment because multi‐visit treatments have multiple times of conditioning, which are difficult to count and of little significance. Outcome measures contain cell‐level tests (orange), neurological scales (dark blue), and infarct size (gray). For the cell‐level tests and neurological scales have different methods with different principles, they would be merged into three groups and two groups based on the criterion that there is no statistical difference within groups but significant differences between groups (distinguished by the shades of color), respectively. d, days; h, hours; No., numbers; min, minutes.

FIGURE 3

Treatment effects for the factor of conditioning time based on different outcome measures. Treatment effects presented by standardized mean difference (SMD in Y‐axis) along with different conditioning times (X‐axis) are represented by lines with error bars (bars: 95% confidence intervals; solid points: number of animals, the larger the point is, the more number is). And the outcome measures include infarct size (upper left, blue; p = 0.32, intragroup test); Group A in neurological scales with Longa 5‐point scale, Belayev 12‐point scale, mNSS 18‐point scale, and Ladder rung walking test, (middle left, orange; p = 0.02); Group B in neurological scales with Garcia 18‐point scale (bottom left, green; p = 0.0008); Group D in cell‐level tests with autophagy level (middle right, red); and Group E in cell‐level tests with apoptosis and normal‐neuron density (bottom right, purple; p = 0.27), all of which almost follow the trend that the treatment effect is better when the time point of conditioning is longer from the onset of stroke. But some of studies were not subject to the trend and drawn out particularly as outliers including Qi et al., (star points); Gao et al., (hexagon points); Qi et al., (“X” points). d, days; h, hours; min, minutes.

FIGURE 4

Treatment effects based on infarct size for factors including number of cycles per treatment, duration of occlusion, and release per cycle. Treatment effects presented by standardized mean difference (SMD in Y‐axis) along with different treatment levels of factors including number of cycles per treatment (left, blue; p < 0.00001, intragroup test), duration of occlusion (p = 0.0007), and release per cycle (right, orange; p = 0.003) are represented by lines with error bars (bars: 95% confidence intervals; solid points: number of animals, the larger the point is, the more number is). As we can see, three cycles per treatment work best among all possible treatment levels in the factor, while effect sizes are generally positive correlation with the duration of occlusion and release per cycle.