title: Status epilepticus after prolonged umbilical cord occlusion is associated with greater neural injury in [corrected] fetal sheep at term-equivalent.
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.
authors.affiliation: Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Drury
authors.affiliation: Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Joanne O
authors.initials: JO
authors.lastname: Davidson
authors.affiliation: Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Lotte G
authors.initials: LG
authors.lastname: van den Heuij
authors.affiliation: Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Guido
authors.initials: G
authors.lastname: Wassink
authors.affiliation: Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Eleanor R
authors.initials: ER
authors.lastname: Gunn
authors.affiliation: Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand; Howard Florey Institute, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Lindsea C
authors.initials: LC
authors.lastname: Booth
authors.affiliation: Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
authors.affiliation: Fetal Physiology and Neuroscience Group, Department of Physiology, The University of Auckland, Auckland, New Zealand; Starship Children's Hospital, Auckland, New Zealand.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
mesh_terms: D000818:Animals; D005260:Female; D005311:Fetal Hypoxia / Q000503:physiopathology; D006624:Hippocampus / Q000473:pathology; D007022:Hypotension / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D012640:Seizures; D012756:Sheep; D013226:Status Epilepticus / Q000473:pathology*; D014470:Umbilical Cord / Q000473:pathology*