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

Paul P Drury,Guido Wassink,Alistair J Gunn,Laura Bennet,Joanne O Davidson,Lindsea C Booth,Martin Gerbert Frasch

doi:10.1371/journal.pone.0039273

Abstract

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 = HbO2 – 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.

Highlights

The mammalian fetus has a remarkable ability to adapt to and survive far more prolonged periods of asphyxia than adults
In the fetal sheep basal cerebral blood flow and oxygen consumption per 100 g weight increase towards term [9,10], consistent with greater basal neural aerobic dependence that would increase the vulnerability of the brain to asphyxia in late gestation
A similar increase in oxygen consumption and oxygen delivery with increasing gestation is seen in the guinea pig [11], and there is evidence that the preterm brain generates a greater proportion of ATP through non-oxidative metabolism compared to at term [12,13]

Summary

Introduction

The mammalian fetus has a remarkable ability to adapt to and survive far more prolonged periods of asphyxia than adults. Near-term fetal sheep develop selective neural injury after 10 min of complete umbilical cord occlusion [3,4], with much greater injury and reduced survival with longer insults of up to 15 min [5,6]. 0.6 gestation fetal sheep develop little or no injury even after 20 min of occlusion [3,7] and severe, subcortical neural injury requires 30 min of complete occlusion [8]. In the fetal sheep basal cerebral blood flow and oxygen consumption per 100 g weight increase towards term [9,10], consistent with greater basal neural aerobic dependence that would increase the vulnerability of the brain to asphyxia in late gestation. In human infants the ratio of phosphocreatine (PCr) to inorganic orthophosphate increases between 28 and 42 weeks gestation, suggesting increasing basal metabolism [14]

Methods

Results

Conclusion