Anesthetic Neuroprotection in Experimental Stroke in Rodents: A Systematic Review and Meta-analysis

Abstract

Background: Patients undergoing endovascular therapy for acute ischemic stroke may require general anesthesia to undergo the procedure. At present, there is little clinical evidence to guide the choice of anesthetic in this acute setting. The clinical implications of experimental studies demonstrating anesthetic neuroprotection are poorly understood. Here, the authors evaluated the impact of anesthetic treatment on neurologic outcome in experimental stroke.

Methods: Controlled studies of anesthetics in stroke using the filament occlusion model were identified in electronic databases up to December 15, 2015. The primary outcome measures, infarct volume, and neurologic deficit score were used to calculate the normalized mean difference for each comparison. Meta-analysis of normalized mean difference values provided estimates of neuroprotection and contributions of predefined factors: study quality, the timing of treatment, and the duration of ischemia.

Results: In 80 retrieved publications anesthetic treatment reduced neurologic injury by 28% (95% CI, 24 to 32%; P < 0.0001). Internal validity was high: publication bias enhanced the effect size by 4% or less, effect size increased with study quality (P = 0.0004), and approximately 70% of studies were adequately powered. Apart from study quality, no predefined factor influenced neuroprotection. Neuroprotection failed in animals with comorbidities. Neuroprotection by anesthetics was associated with prosurvival mechanisms.

Conclusions: Anesthetic neuroprotection is a robust finding in studies using the filament occlusion model of ischemic stroke and should be assumed to influence outcomes in studies using this model. Neuroprotection failed in female animals and animals with comorbidities, suggesting that the results in young male animals may not reflect human stroke.

Figure 1

Results of the Search Strategy (There were 93 comparisons between treated and control animals nested in the 80 included publications)

Figure 2

A. Neuroprotective effects of all included comparisons (k=93) showing individual normalized mean differences and 95% C.I. The summary effect was 28% (24 to 32%) reduction in neurological injury. B. Neuroprotective effects were greater in high quality studies (meta-regression coefficient = 5, (C.I. 2 to 7, 1-sided P value =0.0003). Bars represent the summary effect ± 95% C.I. C. Egger’s regression intercept was 0.8 (C.I. 0.4 to 2.0%, P=0.2030), indicating a failure to detect bias. Long-and short-dash curves represent the 95% confidence and prediction intervals respectively.

Figure 3

Funnel plots of results grouped according to duration of ischemia (permanent vs transient) and timing of treatment before or during/after the onset of ischemia. Vertical lines represent the summary effects; dashed lines denote the 95% confidence intervals.

Figure 4

Venn diagram of molecular proteins associated with neuroprotection in isoflurane (italics) and sevoflurane (underlined) in the filament model of focal cerebral ischemia in rats and mice. Abbreviations as for Table 4.