Preclinical Work With Global Ischemia

Exploration of induced hypothermia as a protective strategy for global ischemia injury started with the application of intraischemic hypothermia. Early work demonstrated that intraischemic brain cooling from 33°C to 34°C markedly reduced brain damage following 20 min of forebrain ischemia in rats (3). Similar findings were reproduced in gerbils (17). It was then demonstrated that global ischemic damage could be reduced by selective brain cooling, even following prolonged (30 min) ischemia (18).

Once intraischemic hypothermia was demonstrated to be neuroprotective, experiments that assessed the effectiveness of postischemic induction of hypothermia followed. It was demonstrated that 3 hr of hypothermia (30°C), begun 5 min following a 10-min period of global forebrain ischemia, could reduce ischemic injury by 50% (19). This effect was apparently lost if cooling was delayed by 30 min following the ischemic insult. Subsequent studies demonstrated that the longer the period of postischemic hypothermia was maintained, the more extensive was the degree of the resulting neuroprotection (20-22).

Although studies that utilized intraischemic hypothermia conferred permanent neuroprotection, other studies suggested that postischemic neuroprotection might be transient and that cell death was not prevented, but delayed (23,24). It was later demonstrated that longer periods of ischemia or delays in initiating treatment required prolonged periods of hypothermia in order to demonstrate permanent and effective neuroprotection. In one study, 2 hr of hypothermia at 34°C protected against 8 min of ischemia, but not 12 (25). In another study, 12 hr of hypothermia initiated 1 hr postischemia protected totally against 3 min, and only partially against 5 min, of global ischemia (26). Extending the period of cooling to 24 hr protected completely (26). Subsequently, it was demonstrated that, even if hypothermia was started at as late as 6 hr postischemia, it could be protective as long as it was extended (27). Forty-eight hours of hypothermia started 6 hr after 10 min of global ischemia significantly reduced neuronal loss in a 28-day survival model (27). Not only was this benefit realized in younger animals, but also postischemic hypothermia (32°C for 24 hr) in older animals could be neuroprotective, even when evaluated at 30 days posttreatment (22 ).

Together, these preclinical experimental results suggest that the longer the period of ischemia and the greater the latency between the ischemic insult and the onset of therapy, the longer the period of hypothermia required to obtain permanent and effective neuroprotection.

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