Still cooling after all these years: Meta-analysis of pre-clinical trials of therapeutic hypothermia for acute ischemic stroke

Abstract

Therapeutic hypothermia is the most potent neuroprotectant for experimental cerebral ischemia, illustrated in a 2007 meta-analysis published in this journal. To address recent therapeutic nihilism, we systematically reviewed recent experimental literature. Quality scoring showed considerable improvement in study design. Using several outcome measures in a variety of models and species, therapeutic hypothermia was protective compared with normothermia, with powerful and statistically significant normalized treatment effect sizes, in 60 papers comprising 216 comparisons. In the past 5 years, preclinical studies of ischemic stroke re-emphasize that therapeutic hypothermia is potently effective, justifying further development in larger human clinical trials.

Keywords: Acute stroke; animal models; hypothermia; neuroprotection; reperfusion.

Figure 1.

(a) Effect of therapeutic hypothermia on lesion volume, brain edema, and behavioral scores. The treatment effect sizes were estimated from a random effects model meta-analysis of reported endpoints after computing the normalized mean difference for each outcome. The groups are defined in the “Methods” section. For the endpoints stroke volume, cerebral edema, and behavior scores, the mean normalized mean difference is shown with standard error for each group. There are no statistically significant differences among the groups, although hypothermia is superior to normothermia across all measures and all target temperatures. (b) Forest plot of stroke volume after intracarotid cold saline. We computed the normalized mean difference in stroke volumes comparing normothermia treatment to intra-carotid cold saline infused after focal cerebral ischemia. There were 11 studies with a combined estimated treatment effect size of 50.7% (95% CI: 37.9, 63.5), which is highly statistically significant (p < 0.001). The heterogeneity was highly significant, Q₁₀ = 147, p < 0.001 suggesting that there is significant variation among the publications, but after trim-and-fill analysis, we found an estimated number of missing studies to be 0 (SE = 2.1), suggesting the absence of negative publication bias. On possible source of heterogeneity is the variation in delay time (time from stroke onset to start of cooling) and the duration of cooling. Using meta-regression, however, neither variable significantly influenced the estimated treatment effect size. The data therefore suggests a powerful treatment benefit from intracarotid cold saline despite inter-laboratory variation, notably species, stroke model, and target temperature.