Therapeutic hypothermia and its effects on the preterm fetal sheep

Abstract

There is compelling evidence that 72 h of moderate hypothermia initiated within 2 to 6 h after hypoxia-ischemia can protect against brain injury, disability and death in term newborn infants. Currently, there is no clinical treatment for hypoxic-ischemic encephalopathy for preterm infants. With the worldwide rates of preterm birth steadily increasing, there is much interest in using therapeutic hypothermia to treat preterm hypoxic-ischemic encephalopathy. The goal of this thesis was to investigate the effects and window of opportunity of therapeutic hypothermia on the brain and physiology after asphyxia in preterm fetal sheep. My first study showed that 68.5 h of selective head cooling, initiated 90 min after asphyxia, protected oligodendrocytes in the white matter (WM) and subventricular zone (SVZ) of the preterm fetal sheep brain at 3 days recovery from 25 min of umbilical cord occlusion. Overall proliferation of cells was not reduced by hypothermia in the WM or SVZ. The remainder of the studies focused on the use of 72 h of whole body hypothermia, and assessed effects at 7 days recovery from asphyxia. Two hypothermia protocols were examined, a 30 min onset after asphyxia protocol, and a clinically relevant, 5 h after asphyxia protocol. Whole body hypothermia was associated with mild bradycardia, mild changes in blood pressure and carotid blood flow and transitory suppression of EEG power. All physiological variables resolved to sham values by 96 h after asphyxia. Delayed hypothermia was associated with slower improvement of spectral edge frequency and EEG power than early onset hypothermia. The window of opportunity for SVZ protection was less than 5 h, with significant improvement in numbers of oligodendrocytes after only early onset but not delayed hypothermia. In contrast, there was no significant improvement in number of oligodendrocytes in the white matter tracts, with either early or late cooling. This was associated with reduced proliferation in the white matter, and no induction of microglia and caspase 3, which suggests that lack of replenishment of oligodendrocytes may have contributed to persistent reduction in numbers of oligodendrocytes after therapeutic hypothermia. Overall the studies in this thesis suggest that the window of opportunity for brain protection in the preterm infant is less than 5 hours and that synergistic treatment may be required to protect the WM after hypoxic-ischemic insults.