Background: Asphyxia during labour and/or birth, and subsequent hypoxic ischemic encephalopathy, is a critical cause of life-long neurological deficits and the most common cause of neonatal seizures. The broad aim of this study is to examine the efficacy of current (phenobarbitone) and novel (ganaxolone) anti-seizure compounds for treating newborn seizures, and their effects on neurodevelopment. However firstly we set out to examine the progression of neuronal degeneration after birth asphyxia, and mechanisms that contribute to cell damage at 24, 48 and 72 hours after asphyxia in neonatal lambs.
Methods: With the ewe under general anaesthetic for caesarean-section delivery, we instrument the fetus with femoral artery and vein catheters for monitoring, and then induce severe birth asphyxia by occluding the umbilical cord, while the lamb remains in utero. When mean arterial blood pressure (MAP) decreases to ~18mmHg, lambs are delivered and resuscitated to intensive care. Control lambs are delivered without asphyxia. Amplitude-integrated electroencephalogram (aEEG) wires are secured onto the lamb’s head for seizure analysis (24h and 48h cohorts). Lambs are monitored for 24, 48 or 72h, after which lambs are euthanised and the brain collected for immunohistochemical and molecular analysis.
Results: This study remains ongoing, but to date we have undertaken a total of n=32 lambs; n=1 control and n=1 asphyxia @24h, n=6 control and n=7 asphyxia @48h, and n=6 control and n=11 asphyxia @72h. In these animals, asphyxia was terminated at 9.9±0.4min, when MAP reached ~18mmHg. Asphyxia induced a metabolic acidosis consistent with severe birth asphyxia, with peripheral pH of 6.9 and base-excess −14mmol/l.
Conclusion: This study will provide important insight into the temporal progression of neuronal degeneration following asphyxia at birth. We will then examine how anti-seizure compounds modify seizure activity and neuronal wellbeing.