Hypothermia: do we understand when it does and does not work?
Alistair Jan Gunn, Laura Bennet
Depts of Physiology and Paediatrics, University of Auckland, Auckland, New Zealand
The possibility of a therapeutic role for hypothermia during or after resuscitation from ischemic events, such as asphyxia at birth, or cardiac arrest in adults has been a long-standing focus of research. However, early studies had limited and contradictory results. It is now known that severe hypoxia-ischemia precipitates a complex biochemical cascade leading to the delayed development of neuronal loss. Associated with the evolution of injury pathophysiologically defined phases have been described clinically and experimentally. These include a latent phase after reperfusion, with initial recovery of cerebral oxidative metabolism but EEG suppression, followed by a secondary phase characterised by accumulation of cytotoxins, seizures, cytotoxic oedema, and failure of cerebral oxidative metabolism from 6 to 15 h post-insult. Although many of the secondary processes can be injurious, the outcome of experimental treatment studies, and their development after the onset of oxidative failure suggest that they are primarily epiphenomena of the 'execution' phase of programmed cell death.
This conceptual framework allows a better understanding of the experimental parameters that have now been shown to determine effective hypothermic neuroprotection, including the timing of initiation of cooling, its duration and the depth of cooling attained. Moderate (32 to < 34 ºC) cerebral hypothermia initiated in the latent phase, between one and in some studies as late as 6 hours after reperfusion, and continued for a sufficient duration (typically 48 hours plus), has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. Cooling can improve neuropathological,1-5 cerebral energetic,6,7 electrophysiological 1,8 and functional outcomes.4,9 Further, indirect evidence for a general effect of hypothermia comes from studies of pharmacological treatment that suggest that apparent neuroprotective drug effects, for example with glutamate antagonists, in several models are mediated completely or in part by secondary mild prolonged cooling, and are abolished by prevention of hypothermia. Although cooling may be protective even if initiated as long as 6 h after reperfusion, short periods (less than 24 h) of cooling do not seem to be effective, there is rapid loss of effect as treatment delay is increased 8 and cooling does not seem to be protective if initiated after the onset of delayed seizures.8,10 Further, hypothermia seems to be less protective with the most severe cerebral injuries.4,7,10
Conversely, it is striking that mild hyperthermia in the early recovery phase is associated with worse outcome. Preventing spontaneous delayed hyperthermia of as little as 1.5°C can reduce injury, or to enable long-lasting neuroprotection from a relatively short period of induced hypothermia for example, or to prevent secondary damage associated with seizures. It is of considerable concern that hyperthermia is common in patients with stroke, and correlates strongly with size of infarction.
Clinically, there are now increasing data from large randomized controlled trials of neonatal encephalopathy,11,12 and cardiac arrest in adults,13,14 that early induction of hypothermia can improve long-term neurological recovery. Despite encouraging phase II evidence, large trials of hypothermia for stroke are still in progress. In contrast, there does not seem to be significant effect of cooling after head injury. This may suggest a different pathogenesis of traumatic injury, however, it is also notable that in the single largest trial cooling was induced an unrealistically late interval after injury. The results of the experimental and clinical studies reviewed here strongly emphasise the importance of starting treatment in the early recovery period after ischemia or asphyxia, and avoiding hyperthermia even well afterwards. These findings also have considerable implications hypothermia used during neurosurgical and cardiac bypass operations. Perhaps we need to consider the possible risks and benefits of continuing treatment during recovery and more immediately preventing delayed pyrexia.
Time of Presentation
Saturday 7 May 2005 - 1030-1200
References
1. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997;99(2):248-56.
