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Although there is overwhelming evidence from animal studies that cooling also improves outcome after focal cerebral ischemia, this has not been adequately tested in patients with acute ischemic stroke. There are still some uncertainties about crucial factors relating to the delivery of hypothermia, and the resolution of these would allow improvements in the design of phase III studies in these patients and improvements in the prospects for successful translation. In this study, we discuss critical issues relating first to the targets for therapy including the optimal depth and duration of cooling, second to practical issues including the methods of cooling and the management of shivering, and finally, of factors relating to the design of clinical trials. Consideration of these factors should inform the development of strategies to establish beyond doubt the place of hypothermia in the management of acute ischemic stroke.<\/jats:p>","DOI":"10.1038\/jcbfm.2010.44","type":"journal-article","created":{"date-parts":[[2010,4,7]],"date-time":"2010-04-07T05:44:54Z","timestamp":1270619094000},"page":"1079-1093","source":"Crossref","is-referenced-by-count":155,"title":["Therapeutic Hypothermia for Acute Ischemic Stroke: Ready to Start Large Randomized Trials?"],"prefix":"10.1177","volume":"30","author":[{"given":"H Bart","family":"van der Worp","sequence":"first","affiliation":[{"name":"Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm R","family":"Macleod","sequence":"additional","affiliation":[{"name":"Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Kollmar","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital of Erlangen, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the European Stroke Research Network for Hypothermia (EuroHYP)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2010,3,31]]},"reference":[{"key":"bibr1-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa041175"},{"key":"bibr2-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.12.6.723"},{"key":"bibr3-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e31819fffd3"},{"key":"bibr4-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60503-1"},{"key":"bibr5-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1992.77.3.0438"},{"key":"bibr6-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.106.474080"},{"key":"bibr7-jcbfm.2010.44","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1213\/00000539-199907000-00029","volume":"89","author":"Baumgardner JE","year":"1999","journal-title":"Anesth Analg"},{"key":"bibr8-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-9572(02)00276-9"},{"key":"bibr9-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa003289"},{"key":"bibr10-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1747-4949.2006.00044.x"},{"key":"bibr11-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.64.1.90"},{"key":"bibr12-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199505000-00011"},{"key":"bibr13-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2008.04.016"},{"key":"bibr14-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.resuscitation.2007.07.002"},{"key":"bibr15-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000129840.66938.75"},{"key":"bibr16-jcbfm.2010.44","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1213\/00000539-199807000-00036","volume":"87","author":"De Witte JL","year":"1998","journal-title":"Anesth Analg"},{"key":"bibr17-jcbfm.2010.44","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199309000-00009"},{"key":"bibr18-jcbfm.2010.44","doi-asserted-by":"crossref","unstructured":"Den Hertog HM, van der Worp HB, Tseng MC, Dippel DW (2009a) Cooling therapy for acute stroke. 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