Identification, mechanisms and treatment of perinatal brain injury

Abstract

This thesis explores potential mechanisms of brain injury in preterm and term fetuses. I first demonstrated that prolonged umbilical cord occlusion (UCO) in un-anaesthetised near-term fetal sheep was associated with moderate to severe sub-cortical neuronal injury but with relative sparing of the cortex. Fetuses that had status epilepticus had significantly greater injury than fetuses with discrete seizures alone. There was high mortality due to post-asphyxial hypotension, and i.v. infusion of dopamine, a commonly used inotrope, was ineffective at preventing hypotension or improving survival. The ontogeny of the cerebral mitochondrial response to in-utero oxygen deprivation is unclear. Compared with preterm fetal sheep, I demonstrated that near-term fetal sheep initially showed a more rapid increase of oxidised cytochrome oxidase during UCO followed by delayed loss, suggesting loss of mitochondrial membrane integrity that may contribute to the maturational increase in neuronal vulnerability to hypoxia-ischaemia. Therapeutic hypothermia is incompletely neuroprotective in term neonates, and not available in preterm neonates. I showed that both low-dose melatonin and a novel inhibitor of nNOS were partially neuroprotective when administered prophylactically before UCO in preterm fetal sheep. Neuroprotection with melatonin was partly confounded by basal ganglia protection by the ethanol used as a diluent. Finally, I demonstrated the ability of near-infrared spectroscopy to identify a paradoxical increase in intracerebral oxygenation with reduced oxygen extraction following deep hypothermic circulatory arrest during cardiac surgery in term neonates with congenital heart disease, although this was not associated with new white matter injury.