Abstract P28: Early Antioxidant Treatment Does Not Provide Additive Neuroprotection with Delayed Hypothermia after Asphyxic Cardiac Arrest in Newborn Pigs

Abstract

Clinical efficacy of hypothermia in neonatal hypoxic-ischemic (HI) encephalopathy is limited, in part, by the delay in instituting hypothermia. In a piglet model of HI, half of the neurons in putamen already show ischemic cytopathology by 6 h of recovery. We tested the hypothesis that treatment with the SOD-catalase mimetic EUK-134 at 30 min of recovery provides additive neuronal protection with a clinically relevant delay of 4 h in the onset of whole body hypothermia. Anesthetized piglets were subjected to 40 min of hypoxia (10% inspired O 2 ) followed by 7 min of airway occlusion and resuscitation with epinephrine and chest compressions. Body temperature was maintained at 38.5 °C in normothermic groups and at 34 °C in hypothermic groups from 4 h through 24 h of recovery. All groups were mechanically ventilated and sedated with continuous fentanyl and pancuronium infusion during the 4 –24 h period to reduce the stress of hypothermia and shivering. At 10 days of recovery, viable neurons remaining in putamen in a normothermic control group was reduced to 20±13% (±SD; n=8) of the value in a sham-operated control group (100±19%; n=8). Infusion of EUK-134 (2.5 mg/kg at 30 min recovery + 1.25 mg/kg/h until 4 h recovery) with normothermic recovery resulted in 36±18% (n=8) viable neurons in putamen. Treatment with saline vehicle followed by delayed hypothermia resulted in partial protection (58±25%; n=8). Combining early treatment with EUK-134 and delayed hypothermia did not produce additional protection in putamen (47±29%; n=8). We conclude that early treatment with this antioxidant does not extend the therapeutic window of hypothermia in protecting highly vulnerable neurons of putamen in newborn brain subjected to HI, possibly because a subpopulation of neurons are already undergoing irreversible cell death signaling by the 30 min treatment time with EUK-134.