Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis

Abstract Therapeutic hypothermia (HT) is standard care for term infants with hypoxic–ischaemic (HI) encephalopathy. However, the efficacy of HT in preclinical models, such as the Vannucci model of unilateral HI in the newborn rat, is often greater than that reported from clinical trials. Here, we re...

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Autores principales:	Thomas R. Wood, Julia K. Gundersen, Mari Falck, Elke Maes, Damjan Osredkar, Else Marit Løberg, Hemmen Sabir, Lars Walløe, Marianne Thoresen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/feb62e6a11344e0da9ff0aee5d584154
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spelling	oai:doaj.org-article:feb62e6a11344e0da9ff0aee5d5841542021-12-02T18:18:32ZVariability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis10.1038/s41598-020-67532-22045-2322https://doaj.org/article/feb62e6a11344e0da9ff0aee5d5841542020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-67532-2https://doaj.org/toc/2045-2322Abstract Therapeutic hypothermia (HT) is standard care for term infants with hypoxic–ischaemic (HI) encephalopathy. However, the efficacy of HT in preclinical models, such as the Vannucci model of unilateral HI in the newborn rat, is often greater than that reported from clinical trials. Here, we report a meta-analysis of data from every experiment in a single laboratory, including pilot data, examining the effect of HT in the Vannucci model. Across 21 experiments using 106 litters, median (95% CI) hemispheric area loss was 50.1% (46.0–51.9%; n = 305) in the normothermia group, and 41.3% (35.1–44.9%; n = 317) in the HT group, with a bimodal injury distribution. Median neuroprotection by HT was 17.6% (6.8–28.3%), including in severe injury, but was highly-variable across experiments. Neuroprotection was significant in females (p < 0.001), with a non-significant benefit in males (p = 0.07). Animals representing the median injury in each group within each litter (n = 277, 44.5%) were also analysed using formal neuropathology, which showed neuroprotection by HT throughout the brain, particularly in females. Our results suggest an inherent variability and sex-dependence of the neuroprotective response to HT, with the majority of studies in the Vannucci model vastly underpowered to detect true treatment effects due to the distribution of injury.Thomas R. WoodJulia K. GundersenMari FalckElke MaesDamjan OsredkarElse Marit LøbergHemmen SabirLars WalløeMarianne ThoresenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thomas R. Wood Julia K. Gundersen Mari Falck Elke Maes Damjan Osredkar Else Marit Løberg Hemmen Sabir Lars Walløe Marianne Thoresen Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis
description	Abstract Therapeutic hypothermia (HT) is standard care for term infants with hypoxic–ischaemic (HI) encephalopathy. However, the efficacy of HT in preclinical models, such as the Vannucci model of unilateral HI in the newborn rat, is often greater than that reported from clinical trials. Here, we report a meta-analysis of data from every experiment in a single laboratory, including pilot data, examining the effect of HT in the Vannucci model. Across 21 experiments using 106 litters, median (95% CI) hemispheric area loss was 50.1% (46.0–51.9%; n = 305) in the normothermia group, and 41.3% (35.1–44.9%; n = 317) in the HT group, with a bimodal injury distribution. Median neuroprotection by HT was 17.6% (6.8–28.3%), including in severe injury, but was highly-variable across experiments. Neuroprotection was significant in females (p < 0.001), with a non-significant benefit in males (p = 0.07). Animals representing the median injury in each group within each litter (n = 277, 44.5%) were also analysed using formal neuropathology, which showed neuroprotection by HT throughout the brain, particularly in females. Our results suggest an inherent variability and sex-dependence of the neuroprotective response to HT, with the majority of studies in the Vannucci model vastly underpowered to detect true treatment effects due to the distribution of injury.
format	article
author	Thomas R. Wood Julia K. Gundersen Mari Falck Elke Maes Damjan Osredkar Else Marit Løberg Hemmen Sabir Lars Walløe Marianne Thoresen
author_facet	Thomas R. Wood Julia K. Gundersen Mari Falck Elke Maes Damjan Osredkar Else Marit Løberg Hemmen Sabir Lars Walløe Marianne Thoresen
author_sort	Thomas R. Wood
title	Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis
title_short	Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis
title_full	Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis
title_fullStr	Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis
title_full_unstemmed	Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis
title_sort	variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/feb62e6a11344e0da9ff0aee5d584154
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Variability and sex-dependence of hypothermic neuroprotection in a rat model of neonatal hypoxic–ischaemic brain injury: a single laboratory meta-analysis

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