Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials?

Abstract

Therapeutic hypothermia is a means of neuroprotection well established in the management of acute ischemic brain injuries such as anoxic encephalopathy after cardiac arrest and perinatal asphyxia. As such, it is the only neuroprotective strategy for which there is robust evidence for efficacy. 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.

Figure 1

Effect of target temperature on the efficacy of hypothermia in improving infarct volume in animal models of stroke. Vertical error bars represent 95% confidence intervals at each point, and the gray bar represents the 95% confidence interval for the overall estimate of efficacy. Adapted from van der Worp et al (2007).

Figure 2

Effect of duration of cooling on the efficacy of hypothermia in improving infarct volume in animal models of stroke. Vertical error bars represent 95% confidence intervals at each point, and the gray bar represents the 95% confidence interval for the overall estimate of efficacy. Adapted from van der Worp et al (2007).

Figure 3

Effect of delay to initiation of treatment on the efficacy of hypothermia in improving infarct volume in animal models of stroke. Vertical error bars represent 95% confidence intervals at each point, and the gray bar represents the 95% confidence interval for the overall estimate of efficacy. Adapted from van der Worp et al (2007).

Figure 4

Effects of α- and pH-stat on different intracranial compartments. CSF, cerebrospinal fluid.

Figure 5

Effect of temperature on the in vitro lytic activity of tPA. Linear regression gives r²=0.348, suggesting a 4.7% decline in thrombolytic activity per degree of hypothermia. Data were obtained from the studies by Yenari et al (1995), Schwarzenberg et al (1998), Shaw et al (2006), and Shaw et al (2007).