Brain Advance Access published online on May 3, 2007
Brain, doi:10.1093/brain/awm083
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Review Article |
Hypothermia in animal models of acute ischaemic stroke: a systematic review and meta-analysis
1Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre, Utrecht, The Netherlands, 2Department of Clinical Neurosciences, University of Edinburgh, UK and 3National Stroke Research Institute and University of Melbourne Department of Medicine, Melbourne, Australia
Correspondence to:
Dr H. Bart van der Worp, Department of Neurology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands E-mail: h.b.vanderworp{at}umcutrecht.nl
Induced hypothermia is proposed as a treatment for acute ischaemic stroke, but there have been too few clinical trials involving too few patients to draw any conclusions about the therapeutic benefit of cooling. Animal studies of induced hypothermia in focal cerebral ischaemia have tested cooling throughout a wide range of target temperatures, durations and intervals between stroke onset and the initiation of hypothermia. These studies, therefore, provide an opportunity to evaluate the effectiveness of different treatment strategies in animal models to inform the design of future clinical trials. We performed a systematic review and meta-analysis of the evidence for efficacy of hypothermia in animal models of ischaemic stroke, and identified 101 publications reporting the effect of hypothermia on infarct size or functional outcome, including data from a total of 3353 animals. Overall, hypothermia reduced infarct size by 44% [95% confidence interval (CI), 40–47%]. Efficacy was highest with cooling to lower temperatures (
31°C), where treatment was started before or at the onset of ischaemia and in temporary rather than permanent ischaemia models. However, a substantial reduction in infarct volume was also observed with cooling to 35°C (30%; 95% CI, 21–39%), with initiation of treatment between 90 and 180 min (37%; 95% CI, 28–46%) and in permanent ischaemia models (37%; 95% CI, 30–43%). The effects of hypothermia on functional outcome were broadly similar. We conclude that in animal models of focal cerebral ischaemia, hypothermia improves outcome by about one-third under conditions that may be achievable for large numbers of patients with ischaemic stroke. Large randomized clinical trials testing the effect of hypothermia in patients with acute ischaemic stroke are warranted.
Key Words: ischaemic stroke; animal model; hypothermia; systematic review; meta-analysis
Abbreviations: NOCSS, Nordic Cooling Stroke Study; PAIS, Paracetamol (Acetaminophen) In Stroke
Received December 6, 2006. Revised February 23, 2007. Accepted March 19, 2007.
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