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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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.

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Cooling for newborns with hypoxic ischaemic encephalopathy.

Susan Jacobs, Marie Berg, Rod Hunt … (2013)

Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects. To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects. We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.

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Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach.

Nicolas A. Crossley, Emily Sena, Jos Goehler … (2008)

At least part of the failure in the transition from experimental to clinical studies in stroke has been attributed to the imprecision introduced by problems in the design of experimental stroke studies. Using a metaepidemiologic approach, we addressed the effect of randomization, blinding, and use of comorbid animals on the estimate of how effectively therapeutic interventions reduce infarct size. Electronic and manual searches were performed to identify meta-analyses that described interventions in experimental stroke. For each meta-analysis thus identified, a reanalysis was conducted to estimate the impact of various quality items on the estimate of efficacy, and these estimates were combined in a meta-meta-analysis to obtain a summary measure of the impact of the various design characteristics. Thirteen meta-analyses that described outcomes in 15,635 animals were included. Studies that included unblinded induction of ischemia reported effect sizes 13.1% (95% CI, 26.4% to 0.2%) greater than studies that included blinding, and studies that included healthy animals instead of animals with comorbidities overstated the effect size by 11.5% (95% CI, 21.2% to 1.8%). No significant effect was found for randomization, blinded outcome assessment, or high aggregate CAMARADES quality score. We provide empirical evidence of bias in the design of studies, with studies that included unblinded induction of ischemia or healthy animals overestimating the effectiveness of the intervention. This bias could account for the failure in the transition from bench to bedside of stroke therapies.

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The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial

Dennis Azzopardi, Peter Brocklehurst, David Edwards … (2008)

Background A hypoxic-ischaemic insult occurring around the time of birth may result in an encephalopathic state characterised by the need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. There is an increasing risk of death or neurodevelopmental abnormalities with more severe encephalopathy. Current management consists of maintaining physiological parameters within the normal range and treating seizures with anticonvulsants. Studies in adult and newborn animals have shown that a reduction of body temperature of 3–4°C after cerebral insults is associated with improved histological and behavioural outcome. Pilot studies in infants with encephalopathy of head cooling combined with mild whole body hypothermia and of moderate whole body cooling to 33.5°C have been reported. No complications were noted but the group sizes were too small to evaluate benefit. Methods/Design TOBY is a multi-centre, prospective, randomised study of term infants after perinatal asphyxia comparing those allocated to "intensive care plus total body cooling for 72 hours" with those allocated to "intensive care without cooling". Full-term infants will be randomised within 6 hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2°C or to whole body cooling, with rectal temperature kept at 33–34°C for 72 hours. Term infants showing signs of moderate or severe encephalopathy +/- seizures have their eligibility confirmed by cerebral function monitoring. Outcomes will be assessed at 18 months of age using neurological and neurodevelopmental testing methods. Sample size At least 236 infants would be needed to demonstrate a 30% reduction in the relative risk of mortality or serious disability at 18 months. Recruitment was ahead of target by seven months and approvals were obtained allowing recruitment to continue to the end of the planned recruitment phase. 325 infants were recruited. Primary outcome Combined rate of mortality and severe neurodevelopmental impairment in survivors at 18 months of age. Neurodevelopmental impairment will be defined as any of: • Bayley mental developmental scale score less than 70 • Gross Motor Function Classification System Levels III – V • Bilateral cortical visual impairments Trial Registration Current Controlled Trials ISRCTN89547571

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Author and article information

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Marianne Thoresen: marianne.thoresen@medisin.uio.no

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 2 July 2020

Publication date PMC-release: 2 July 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 10833

Affiliations

[1 ]ISNI 0000 0004 1936 8921, GRID grid.5510.1, Department of Physiology, Institute of Basic Medical Sciences, , University of Oslo, ; Domus Medica, Sognsvannsveien 9, 0372 Oslo, Norway

[2 ]ISNI 0000 0004 1936 8921, GRID grid.5510.1, Department of Pathology, , Oslo University Hospitals and University of Oslo, ; Oslo, Norway

[3 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Neonatal Neuroscience, School of Clinical Sciences, , University of Bristol, ; Bristol, UK

[4 ]ISNI 0000000122986657, GRID grid.34477.33, Present Address: Department of Pediatrics, , University of Washington Medical School, ; Seattle, USA

[5 ]ISNI 0000 0004 0571 7705, GRID grid.29524.38, Present Address: Department of Pediatric Neurology, , University Children’s Hospital, ; Ljubljana, Slovenia

[6 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Present Address: Department of Neonatology and Pediatric Intensive Care, , Children’s Hospital University of Bonn, ; Bonn, Germany

Article

Publisher ID: 67532

DOI: 10.1038/s41598-020-67532-2

PMC ID: 7331720

PubMed ID: 32616806

SO-VID: 1f5f29c0-9f6a-4c32-b80a-e6ec69be5dd1

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 6 December 2019

Date accepted : 3 June 2020

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ScienceOpen disciplines: Uncategorized

Keywords: diseases of the nervous system,encephalopathy,brain injuries,paediatric research,preclinical research

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ScienceOpen disciplines: Uncategorized

Keywords: diseases of the nervous system, encephalopathy, brain injuries, paediatric research, preclinical research

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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Most cited references 42

Cooling for newborns with hypoxic ischaemic encephalopathy.

Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach.

The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: A randomised controlled trial

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