Maturation of the Mitochondrial Redox Response to Profound Asphyxia in Fetal Sheep

Fetal susceptibility to hypoxic brain injury increases over the last third of gestation. This study examined the hypothesis that this is associated with impaired mitochondrial adaptation, as measured by more rapid oxidation of cytochrome oxidase (CytOx) during profound asphyxia. Methods: Chronically instrumented fetal sheep at 0.6, 0.7, and 0.85 gestation were subjected to either 30 min (0.6 gestational age (ga), n = 6), 25 min (0.7 ga, n = 27) or 15 min (0.85 ga, n = 17) of complete umbilical cord occlusion. Fetal EEG, cerebral impedance (to measure brain swelling) and near-infrared spectroscopy-derived intra-cerebral oxygenation (ΔHb = HbO(2) – Hb), total hemoglobin (THb) and CytOx redox state were monitored continuously. Occlusion was associated with profound, rapid fall in ΔHb in all groups to a plateau from 6 min, greatest at 0.85 ga compared to 0.6 and 0.7 ga (p<0.05). THb initially increased at all ages, with the greatest rise at 0.85 ga (p<0.05), followed by a progressive fall from 7 min in all groups. CytOx initially increased in all groups with the greatest rise at 0.85 ga (p<0.05), followed by a further, delayed increase in preterm fetuses, but a striking fall in the 0.85 group after 6 min of occlusion. Cerebral impedance (a measure of cytotoxic edema) increased earlier and more rapidly with greater gestation. In conclusion, the more rapid rise in CytOx and cortical impedance during profound asphyxia with greater maturation is consistent with increasing dependence on oxidative metabolism leading to earlier onset of neural energy failure before the onset of systemic hypotension.