Pre-Existing Hypoxia Is Associated with Greater EEG Suppression and Early Onset of Evolving Seizure Activity during Brief Repeated Asphyxia in Near-Term Fetal Sheep

Guido Wassink,Jenny A Westgate,Alistair J Gunn,Laura Bennet,Joanne O Davidson,Martin Gerbert Frasch

doi:10.1371/journal.pone.0073895

Abstract

Spontaneous antenatal hypoxia is associated with high risk of adverse outcomes, however, there is little information on neural adaptation to labor-like insults. Chronically instrumented near-term sheep fetuses (125 ± 3 days, mean ± SEM) with baseline PaO2 < 17 mmHg (hypoxic group: n = 8) or > 17 mmHg (normoxic group: n = 8) received 1-minute umbilical cord occlusions repeated every 5 minutes for a total of 4 hours, or until mean arterial blood pressure (MAP) fell below 20 mmHg for two successive occlusions. 5/8 fetuses with pre-existing hypoxia were unable to complete the full series of occlusions (vs. 0/8 normoxic fetuses). Pre-existing hypoxia was associated with progressive metabolic acidosis (nadir: pH 7.08 ± 0.04 vs. 7.33 ± 0.02, p<0.01), hypotension during occlusions (nadir: 24.7 ± 1.8 vs. 51.4 ± 3.2 mmHg, p<0.01), lower carotid blood flow during occlusions (23.6 ± 6.1 vs. 63.0 ± 4.8 mL/min, p<0.01), greater suppression of EEG activity during, between, and after occlusions (p<0.01) and slower resolution of cortical impedance, an index of cytotoxic edema. No normoxic fetuses, but 4/8 hypoxic fetuses developed seizures 148 ± 45 minutes after the start of occlusions, with a seizure burden of 26 ± 6 sec during the inter-occlusion period, and 15.1 ± 3.4 min/h in the first 6 hours of recovery. In conclusion, in fetuses with pre-existing hypoxia, repeated brief asphyxia at a rate consistent with early labor is associated with hypotension, cephalic hypoperfusion, greater EEG suppression, inter-occlusion seizures, and more sustained cytotoxic edema, consistent with early onset of neural injury.

Highlights

Chronic antenatal hypoxia due to placental dysfunction or multiple pregnancies is commonly associated with growth retardation and a higher risk of stillbirth [1], and long-term abnormal neurodevelopmental outcome [2]
There was no difference in the 6 hour baseline measurements of carotid blood flow (CaBF), EEG power, or impedance between groups, but mean arterial blood pressure (MAP) was lower in the hypoxic group (41.4 ± 1.5 vs. 46.4 ± 0.8 mmHg, p
Brief repeated umbilical cord occlusions were associated with a minor fall in pH and O2ct, and a moderate rise in base deficit and lactate, whereas pre-existing hypoxia was associated with severe mixed respiratory and metabolic acidosis that progressively worsened throughout the occlusion

Summary

Introduction

Chronic antenatal hypoxia due to placental dysfunction or multiple pregnancies is commonly associated with growth retardation and a higher risk of stillbirth [1], and long-term abnormal neurodevelopmental outcome [2]. We have previously shown that in fetal sheep with pre-existing stable hypoxia even brief umbilical cord occlusions, repeated at a rate consistent with early labor, are associated with severe metabolic acidosis and hypotension [3] These observations clearly indicate that chronic hypoxia is associated with reduced cardiac tolerance to labor-like asphyxia, but the effects on cerebral perfusion and neural adaptation are unclear. De Haan et al reported that suppression of EEG activity was both faster and more profound during 2-minute occlusions repeated every 5 minutes compared to 1-minute occlusions repeated every 2.5 minutes, and associated with greater frequency of epileptiform and spike activity between occlusions [13] These findings strongly suggest that the extent of neural adaptation and aberrant EEG activity during repeated brief asphyxia relates to the development of systemic compromise, and may be linked directly to pre-existing fetal condition

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