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Therapeutic hypothermia can partially reduce long-term death and disability in neonates after hypoxic-ischemic encephalopathy. The aim of this study was to determine whether prolonging the duration of cooling from 3 days to 5 days could further improve outcomes of cerebral ischemia in near-term fetal sheep. Fetal sheep (0.85 gestation) received 30 minutes bilateral carotid artery occlusion followed by 3 days of normothermia (n = 8), 3 days of hypothermia (n = 8), or 5 days of hypothermia (n=8) started 3 hours after ischemia. Sham controls received sham ischemia followed by normothermia (n = 8). Cerebral ischemia was associated with profound loss of electroencephalography power and spectral edge, with greater and more rapid recovery in both hypothermia groups (P&lt;0.05). Ischemia was associated with severe loss of neurons in the cortex, hippocampus and thalamus (P &lt; 0.05), with a significant improvement in both hypothermia groups. However, the ischemia-3-day hypothermia group showed greater neuronal survival in the cortex and dentate gyrus compared with ischemia-5-day hypothermia (P &lt; 0.05). Ischemia was associated with induction of iba1-positive microglia, which was attenuated in both hypothermia groups (P &lt; 0.05). Extending the duration of delayed therapeutic hypothermia from 3 to 5 days did not improve outcomes after severe ischemia, and was associated with reduced neuronal survival in some regions.

How Long is Too Long for Cerebral Cooling after Ischemia in Fetal Sheep?