Nonadditive Neuroprotection With Early Glutamate Receptor Blockade and Delayed Hypothermia After Asphyxia in Preterm Fetal Sheep

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Abstract
Background and Purpose—: Hypothermia induced after perinatal hypoxia–ischemia is partially protective. This study examined whether early treatment with the noncompetitive N-methyl -d- aspartate receptor antagonist, dizocilpine, can augment neuroprotection with delayed hypothermia after severe asphyxia in preterm fetal sheep at 0.7 weeks gestation (equivalent to 28–32 weeks in humans). Methods—: Fifty minutes after umbilical cord occlusion for 25 minutes, fetuses were randomized to either dizocilpine (2 mg/kg estimated fetal weight intravenously, then 0.07 mg/kg/h for 4 hours) and then after 5.5 hours to whole-body cooling to 3°C below baseline, or sham cooling, until 72 hours, and euthanized 7 days after umbilical cord occlusion. Results—: Delayed hypothermia was associated with improved neuronal survival ( P P =0.004) and caspase-3-positive cells ( P P P <0.05) with no apparent additive effect with delayed hypothermia. Conclusions—: Early N-methyl -d- aspartate blockade and a clinical regime of delayed whole-body hypothermia provide nonadditive neuroprotection in the preterm brain.

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