Moderate hypothermia is consistently neuroprotective after hypoxic-ischemic insults and is the subject of ongoing clinical trials. In pilot studies, we observed rebound seizure activity in one infant during rewarming from a 72-h period of hypothermia. We therefore quantified the development of EEG-defined seizures during rewarming in an experimental paradigm of delayed cooling for cerebral ischemia. Moderate cerebral hypothermia (n=9) or sham cooling (n=13) was initiated 5.5 h after reperfusion from a 30-min period of bilateral carotid occlusion in near-term fetal sheep and continued for 72 h after the insult. During spontaneous rewarming, fetal extradural temperature rose from 32.5 +/- 0.6 degrees C to control levels (39.4 +/- 0.1 degrees C) in 47 +/- 6 min. Carotid blood flow and mean arterial blood pressure increased transiently during rewarming. The cooling group showed a significant increase in electrical seizure events 2, 3, and 5 h after rewarming, maximal at 2 h (2.9 +/- 1.2 versus 0.5 +/- 0.5 events/h; p <0.05). From 6 h after rewarming, there was no significant difference between the groups. Individual seizures were typically short (28.8 +/- 5.8 s versus 29.0 +/- 6.8 s in sham cooled; NS), and of modest amplitude (35.9 +/- 2.8 versus 38.8 +/- 3.4 microV; NS). Neuronal loss in the parasagittal cortex was significantly reduced in the cooled group (51 +/- 9% versus 91 +/- 5%; p <0.002) and was not correlated with rebound epileptiform activity. In conclusion, rapid rewarming after a prolonged interval of therapeutic hypothermia can be associated with a transient increase in epileptiform events but does not seem to have significant adverse implications for neural outcome.