Status epilepticus after prolonged umbilical cord occlusion is associated with greater neural injury in [corrected] fetal sheep at term-equivalent.

Paul P Drury,Lindsea C Booth,Joanne O Davidson,Alistair J Gunn,Laura Bennet,Eleanor R Gunn,Guido Wassink,Lotte G Van Den Heuij,Olivier Baud

doi:10.1371/journal.pone.0096530

Paul P Drury, Lindsea C Booth + Show 7 more

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https://doi.org/10.1371/journal.pone.0096530

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Abstract

The majority of pre-clinical studies of hypoxic-ischemic encephalopathy at term-equivalent have focused on either relatively mild insults, or on functional paradigms of cerebral ischemia or hypoxia-ischemia/hypotension. There is surprisingly little information on the responses to single, severe ‘physiological’ insults. In this study we examined the evolution and pattern of neural injury after prolonged umbilical cord occlusion (UCO). 36 chronically instrumented fetal sheep at 125–129 days gestational age (term = 147 days) were subjected to either UCO until mean arterial pressure was < = 8 mmHg (n = 29), or sham occlusion (n = 7). Surviving fetuses were killed after 72 hours for histopathologic assessment with acid-fuchsin thionine. After UCO, 11 fetuses died with intractable hypotension and 5 ewes entered labor and were euthanized. The remaining 13 fetuses showed marked EEG suppression followed by evolving seizures starting at 5.8 (6.8) hours (median (interquartile range)). 6 of 13 developed status epilepticus, which was associated with a transient secondary increase in cortical impedance (a measure of cytotoxic edema, p<0.05). All fetuses showed moderate to severe neuronal loss in the hippocampus and the basal ganglia but mild cortical cell loss (p<0.05 vs sham occlusion). Status epilepticus was associated with more severe terminal hypotension (p<0.05) and subsequently, greater neuronal loss (p<0.05). In conclusion, profound UCO in term-equivalent fetal sheep was associated with delayed seizures, secondary cytotoxic edema, and subcortical injury, consistent with the predominant pattern after peripartum sentinel events at term. It is unclear whether status epilepticus exacerbated cortical injury or was simply a reflection of a longer duration of asphyxia.

Highlights

Moderate to severe hypoxic-ischemic encephalopathy (HIE) occurs in 1–4 per 1000 live births at term in developed nations [1]
umbilical cord occlusion (UCO) was associated with marked fetal hypoxemia and acidemia (Table 1), increased blood hemoglobin, sustained bradycardia and peripheral vasoconstriction, with initial hypertension followed by profound hypotension and cerebral hypoperfusion, suppression of the EEG and a delayed rise in cortical impedance (Figure 1)
The present study demonstrates that in 0.85 gestation fetal sheep prolonged UCO continued until profound hypotension developed was associated with high mortality, and in survivors there was a pattern of predominantly subcortical neuronal loss, with relative sparing of the cortex

Summary

Introduction

Moderate to severe hypoxic-ischemic encephalopathy (HIE) occurs in 1–4 per 1000 live births at term in developed nations [1]. Predominant cortical injury in a watershed distribution is common, but is more typically associated with prolonged partial hypoxia [2,5]. Most of these cases are associated with acute events around the time of birth [6,7]. The central finding from pre-clinical studies is that cell death can evolve for many hours after surprisingly severe insults, providing a window of opportunity for intervention [8,9]. Most previous studies of UCO in term-equivalent fetal sheep have examined either relatively short insults, which are associated with selective hippocampal injury, without significant seizure activity [14], or repeated or partial UCO [15,16]

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