Focal Cerebral Ischemia: Clinical Studies

Abstract

Acute ischemic stroke is a major leading cause of death and disability throughout the developed world. Although early vascular reperfusion improves the clinical outcome, fewer than 5% of patients with acute ischemic stroke actually receive thrombolytic therapy. The challenge of thrombolytic therapy is that, with time, the ability to recover brain tissue decreases rapidly while vulnerability to reperfusion injury increases. The result of this quandary, a narrow time-window, proved to be the stumbling block in wider dissemination of this treatment. Conceivably, co-administration of a “tissue protectant” could enhance the effectiveness of thrombolysis while expanding the time window and reducing the risks of reperfusion. A promising candidate to serve this purpose is hypothermia. A wealth of animal experiments have demonstrated that hypothermia or simply fever prevention diminishes ischemic damage with transient occlusion followed by reperfusion. In models of permanent occlusion, reduction of infarct size was less impressive (1, 2). In transient ischemia models, hypothermia was most effective when administered during the period of vascular occlusion (intra-ischemic) or immediately after vascular reperfusion (post-ischemic) (3–5). According to these models, hypothermia is efficacious in concert with reperfusion in only a narrow time window. Some investigations suggest that more prolonged periods of hypothermia enhance the benefit of early post-ischemic induction and even may have benefit after permanent occlusion. Consequently, in patients with acute stroke, therapeutic hypothermia will more likely confer benefit in conjunction with early vascular reperfusion and when applied over prolonged periods of time. The use of antipyretic agents has not been shown to effectively reduce core temperature after stroke, although, post-stroke fever can be inhibited. Therapeutic mild (33–36°C) to moderate (28–32°C) hypothermia can be achieved by surface cooling (external cooling) or by using intravenous counter-current heat exchange (endovascular cooling). External cooling is almost invariably associated with imprecise timing and continuation of the hypothermic effect. With endovascular cooling heat is directly removed from, or added to, the thermal core, thus bypassing the heat sink and insulating effects of peripheral tissues. Several early open and controlled studies have shown that endovascular cooling is safe and can effectively manage core temperatures in the mild to moderate hypothermic range. This review of clinical studies will address the advances in the understanding of mechanisms by which hypothermia enhances stroke outcomes and how these insights may help to translate benefits of hypothermia from bench to bedside.