Lack of additional benefit from slow rewarming after therapeutic hypothermia for ischaemic brain injury in near-term fetal sheep.

The optimal rate of rewarming after therapeutic hypothermia is unclear. Slow rewarming may reduce cardiovascular instability and rebound seizures, but there is little controlled evidence to support this. The present study aimed to determine whether slow rewarming can improve neuroprotection after 72 h of hypothermia. Fetal sheep (0.85 gestation) received sham occlusion (n = 8) or 30 min of global cerebral ischaemia followed by normothermia (n = 7), or hypothermia from 3 to 72 h with either fast, spontaneous rewarming within 1 h (n = 8) or slow rewarming at 0.5°C h^-1 over 10 h (n = 8). Hypothermia improved EEG and spectral edge recovery, with no significant difference between fast and slow rewarming. Hypothermia reduced the number of seizures, with no significant difference in seizure activity between fast and slow rewarming. Hypothermia improved neuronal survival in the cortex, CA1, CA3, CA4 and dentate gyrus regions of the hippocampus, with no significant difference between fast and slow rewarming. Hypothermia attenuated microglia counts in the cortex, with no significant difference between fast and slow rewarming. The rate of rewarming after a clinically relevant duration of hypothermia did not affect neurophysiological recovery, neuronal survival or attenuation of microglia after global cerebral ischaemia in term-equivalent fetal sheep. KEY POINTS: The rate of rewarming after 72 h of hypothermia did not affect recovery of EEG or spectral edge. There was no difference in the occurrence of seizures as a result of the rate of rewarming after hypothermia. The rate of rewarming after 72 h of hypothermia did not affect neuronal survival in the cortex or hippocampus.