Therapeutic hypothermia: from lab to NICU.
The possibility of a therapeutic role for cerebral hypothermia during or after resuscitation from perinatal asphyxia has been a long-standing focus of research. However, early studies had limited and contradictory results. It is now known that severe hypoxia-ischemia may not cause immediate cell death, but may precipitate a complex biochemical cascade leading to the delayed development of neuronal loss. These phases include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism from 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. This conceptual framework allows a better understanding of the experimental parameters that determine effective hypothermic neuroprotection, including the timing of initiation of cooling, its duration and the depth of cooling attained. Moderate cerebral hypothermia initiated in the latent phase, between one and as late as 6 h after reperfusion, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been consistently associated with potent, long-lasting neuroprotection in both adult and perinatal species. The results of the first large multicentre randomized trial of head cooling for neonatal encephalopathy and previous phase I and II studies now strongly suggest that prolonged cerebral hypothermia is both generally safe - at least in an intensive care setting - and can improve intact survival up to 18 months of age. Both long-term followup studies and further large studies of whole body cooling are in progress.