Review article Therapeutic hypothermia for acute stroke Patrick D. Lyden Ã1 , Derk Krieger 2 , Midori Yenari 3,4 , and W. Dalton Dietrich 5 Abstract Hypothermia is the most potent neuroprotective therapy available. Clinical use of hypothermia is limited by technology and homeostatic mechanisms that maintain core body temperature. Recent advances in intravascular cooling catheters and successful trials of hypothermia for cardiac arrest revivified interest in hypothermia for stroke, resulting in Phase 1 clinical trials and plans for further development. Given the recent spate of neuroprotective therapy failures, we sought to clarify whether clinical trials of therapeutic hypothermia should be mounted in stroke patients. We reviewed the preclinical and early clinical trials of hypother- mia for a variety of indications, the putative mechanisms for neuroprotection with hypothermia, and offer several hypoth- eses that remain to be tested in clinical trials. Therapeutic hypothermia is promising, but further Phase 1 and Phase 2 development efforts are needed to ensure that cooling of stroke patients is safe, before definitive efficacy trials. Introduction Hypothermia is recognized as the most potent putative neuroprotectant based on empirical observations and precli- nical experimental data (Fig. 1). Recent insights into under- standing ischemia and reperfusion mechanisms suggest reasons as to why hypothermia may also be an ideal modality for extending the time window for thrombolytic stroke therapy. Although difficulties in cooling patients limited the testing of this potentially effective therapy, recent develop- ments in technology now allow for clinical trials of therapeutic cooling for acute stroke patients. The purpose of this review is to summarize the rationale for hypothermia, the preclinical experience, and the early clinical trials. We will also discuss the advantage and limitations of surface and intravascular cooling approaches. Finally, we will pose research questions that should be addressed in the coming years. Rationale for hypothermia in acute stroke Interest in hypothermia for brain injury dates to anecdotal cases of children submersed under water at near-freezing temperatures for up to 40 min (1–3). However, despite decades of attempts, therapeutic hypothermia has found little use outside of the operating room (4, 5). Even in neurosurgery and cardiothoracic surgery, where hypothermia is routine, definitive evidence of efficacy is lacking from randomized, rigorously blinded, controlled clinical trials. A limited under- standing of neuroprotection mechanisms limits a wider ap- preciation of hypothermia’s therapeutic potential. Only recently have some of the mechanisms of hypothermia effect on the brain come to light. Hypothermia causes a variety of responses in ischemic brain that might confer neuroprotection, as summarized in recent reviews (6). No data exist to clarify the relative importance of these actions individually, but it may be simplistic to conclude that hypothermia induces several neuroprotective actions, analogous to the combinatorial neuroprotective strategy ad- vocated by many (7, 8). Nevertheless, if hypothermia causes multiple, synergistic effects, there is a greater potential for success in a clinical trial. Hypothermia causes significant alterations in metabolism, glutamate release and reuptake, inflammation, and free radical generation (Table 1). Temperature has a profound effect on brain metabolism during ischemia (9). Intraischemic temperature changes of as little as 11C may influence outcome after focal or global brain ischemia. Initially, hypothermia was thought to protect the brain by reducing cerebral metabolism during conditions of reduced substrate; shift to anaerobic glycolysis and lactate production should be reduced (9–11). Hypothermia decreases Correspondence: Patrick D. Lyden à , UCSD Stroke Center, OPC 3rd Floor, Suite#3, 200 W. Arbor Drive, San Diego, CA 92103, USA. Tel: 619 543 7760; Fax: 619 543 7771; email: plyden@ucsd.edu 1 Neurology and Research Services of the San Diego Veteran’s Adminis- tration Medical Center and the Department of Neurosciences, University of California, San Diego, CA, USA 2 Section of Stroke and Neurological Critical Care, The Cleveland Clinic Foundation, Cleveland, OH, USA 3 Department of Neurology, University of California San Francisco School of Medicine, San Francisco, CA, USA 4 Neurology Department of the San Francisco Veteran’s Administration Medical Center, San Francisco, CA, USA 5 Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, USA & 2005 International Stroke Society International Journal of Stroke Vol 1, February 2006, 9–19 9