Although transient global ischemia models well resemble the human condition of postcardiac arrest global ischemia, the same cannot be said for focal ischemia. Focal ischemic stroke in humans is a markedly heterogeneous condition, with similar syndromes being produced by quite different pathophysiologic mechanisms. Vascular occlusion in humans can occur from embolic, as well as locally thrombotic, processes. The location and caliber of the occluded vessels vary considerably, as does the collateral flow within a particular vascular distribution. In addition to the anatomical variables listed above, the duration of vascular occlusion also varies from transient events without permanent injury to complete occlusions with irreversible infarction of the supplied territory. Animal studies that attempt to model ischemic stroke are, for the most part, models of either transient or complete large-vessel occlusions. The most commonly used model is the middle cerebral artery occlusion (MCAO) model, which uses either an intraluminal suture or direct ligation or clipping of the vessel (28). Although other models have been developed, including clot embolization and focal cerebral sclerosis, most of the work reviewed here used MCAO models (28,29). Most of these models produce strokes that resemble human large-vessel infarctions [middle cerebral artery (MCA) strokes]. Outcome variables include histopathology, neurotransmitter levels, and functional assessments based on physiologic testing. These outcomes have been measured early (hours to days) in some studies and late (days to weeks) in others.
As variable as the models are in inducing ischemic injury, the treatment paradigms are equally variable. Some investigators initiated hypothermia prior to, or immediately following, onset of ischemia (30-37), whereas others delayed the treatment by minutes to hours postischemia (32,34,35,38). The delay in treatment onset varied from minutes up to 6 hr. It is, therefore, not surprising that the degree of neuroprotection demonstrated ranges from none to as much as 65% reduction in infarct volume (32,34,35,38). Although short periods of hypothermia could result in transient neuroprotection, it became apparent that, if hypothermia (30°C) was prolonged for up to 24 hr, it could result in sustained neuroprotection, even at 3 weeks (48% reduction in infarct volume) (30). No evidence from animal studies shows that hypothermia can be delayed beyond 1 hr after ischemia in permanent focal ischemia and still be protective (32).
The potential benefits of immediate and delayed hypothermia have been evaluated in transient focal ischemia models more extensively and with more consistent results than in permanent occlusion models. In most studies, the duration of ischemia varied from 30 min to 6 hr, with most using 2 hr. Outcomes have been analyzed immediately and at long-term endpoints (1 to 2 months postinfarct).
Nearly all of the studies that utilized intraischemic hypothermia demonstrated neuroprotection (30-92% reduction in infarct volume) when applied for durations as little as 1 hr and up to 24 hr (36,37,39-47). Hypothermia has also been found to be neuroprotective when applied postischemia, although not to the extent observed when instituted intraischemically (37,40,41,43,46,48-54). Delays of greater than 6 hr have not been shown to be effective in focal ischemia, compared to global ischemia, in which prolonged periods of hypothermia might still be beneficial. In general, the longer the delay from the onset of ischemia to hypothermia, the longer hypothermia needs to be applied in order to be beneficial (37,41,43,45,46,50-54). Although moderate hypothermia (32°C) was generally neuroprotective in most models, deeper cooling (27°C) was not shown to be more effective than moderate hypothermia (no protection, versus 46% reduction in infarct volume) (41 ).
The current evidence overwhelmingly supports moderate hypothermia (32-34°C) as the temperature of choice for neuroprotection. The duration of cooling chosen then depends on the length of the ischemic period and the time delay to onset of therapy.
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