The effect of resuscitation in 100% oxygen on brain injury in a newborn rat model of severe hypoxic-ischaemic encephalopathy

Smit, Elisa; Liu, Xun; Gill, Hannah; Jary, Sally; Wood, Thomas H.; Thoresen, Marianne

doi:10.1016/j.resuscitation.2015.07.050

Cited by 7 publications

(8 citation statements)

References 39 publications

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“…This suggests that we can use these short-term markers to identify useful temperature comparisons for more in-depth future investigations into mechanism and outcome. As we previously found that the hippocampus is the area that is most sensitive to the neuroprotective effects of HT at P14 10 15 , we also employed hippocampal area loss and CA1 neuronal counts in order to ascertain any further temperature-dependent changes in the hippocampus at this early time point 62 63 . However, in order to truly investigate whether milder cooling provides equivalent neuroprotection, long-term improvements in neurobehavioural outcome should be demonstrated, and this will be a focus of future work.…”

Section: Discussionmentioning

confidence: 99%

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Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia

Wood

Osredkar

Puchades

et al. 2016

Sci Rep

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Therapeutic hypothermia (HT) is standard care for moderate and severe neonatal hypoxic-ischaemic encephalopathy (HIE), the leading cause of permanent brain injury in term newborns. However, the optimal temperature for HT is still unknown, and few preclinical studies have compared multiple HT treatment temperatures. Additionally, HT may not benefit infants with severe encephalopathy. In a neonatal rat model of unilateral hypoxia-ischaemia (HI), the effect of five different HT temperatures was investigated after either moderate or severe injury. At postnatal-day seven, rat pups underwent moderate or severe HI followed by 5 h at normothermia (37 °C), or one of five HT temperatures: 33.5 °C, 32 °C, 30 °C, 26 °C, and 18 °C. One week after treatment, neuropathological analysis of hemispheric and hippocampal area loss, and CA1 hippocampal pyramidal neuron count, was performed. After moderate injury, a significant reduction in hemispheric and hippocampal loss on the injured side, and preservation of CA1 pyramidal neurons, was seen in the 33.5 °C, 32 °C, and 30 °C groups. Cooling below 33.5 °C did not provide additional neuroprotection. Regardless of treatment temperature, HT was not neuroprotective in the severe HI model. Based on these findings, and previous experience translating preclinical studies into clinical application, we propose that milder cooling should be considered for future clinical trials.

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Section: Discussionmentioning

confidence: 99%

“…Hippocampal area loss was analysed in the moderate model, as previously described 62 63 . Sections at the level of the hippocampi were scanned at a higher resolution (2400dpi), and two consecutive sections from each animal were analysed with ImageJ.…”

Section: Methodsmentioning

confidence: 99%

Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia

Wood

Osredkar

Puchades

et al. 2016

Sci Rep

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“…A meta-analysis of 2133 babies13 revealed a reduction in mortality for infants resuscitated in 21% versus 100% oxygen (relative risk (RR) 0.69, 95% CI 0.54 to 0.88) and a trend towards a reduction in HIE. In animal models of neonatal asphyxia, resuscitation with 21% versus 100% oxygen resulted in comparable or improved outcomes of death, neurobehavioural disability and cell death 14. In an asphyxiated lamb model, 100% versus 21% oxygen for resuscitation caused an increase in cerebral blood flow (this is counterintuitive as cerebral vasoconstriction is the typical response with oxygen) 15.…”

Section: Advances In the Management Of Hiementioning

confidence: 99%

“…In animal models of neonatal asphyxia, resuscitation with 21% versus 100% oxygen resulted in comparable or improved outcomes of death, neurobehavioural disability and cell death. 14 In an asphyxiated lamb model, 100% versus 21% oxygen for resuscitation caused an increase in cerebral blood flow (this is counterintuitive as cerebral vasoconstriction is the typical response with oxygen). 15 The hypoxic brain may have lost autoregulatory abilities and be 'pressure passive', increasing the risk of hyperoxia and flow mediated brain injury.…”

Section: Advances In the Management Of Hie Resuscitationmentioning

confidence: 99%

Management and investigation of neonatal encephalopathy: 2017 update

Martinello

Hart

Yap

et al. 2017

Arch Dis Child Fetal Neonatal Ed

141

116

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This review discusses an approach to determining the cause of neonatal encephalopathy, as well as current evidence on resuscitation and subsequent management of hypoxic-ischaemic encephalopathy (HIE). Encephalopathy in neonates can be due to varied aetiologies in addition to hypoxic-ischaemia. A combination of careful history, examination and the judicious use of investigations can help determine the cause. Over the last 7 years, infants with moderate to severe HIE have benefited from the introduction of routine therapeutic hypothermia; the number needed to treat for an additional beneficial outcome is 7 (95% CI 5 to 10). More recent research has focused on optimal resuscitation practices for babies with cardiorespiratory depression, such as delayed cord clamping after establishment of ventilation and resuscitation in air. Around a quarter of infants with asystole at 10 min after birth who are subsequently cooled have normal outcomes, suggesting that individualised decision making on stopping resuscitation is needed, based on access to intensive treatment unit and early cooling. The full benefit of cooling appears to have been exploited in our current treatment protocols of 72 hours at 33.5°C; deeper and longer cooling showed adverse outcome. The challenge over the next 5–10 years will be to assess which adjunct therapies are safe and optimise hypothermic brain protection in phase I and phase II trials. Optimal care may require tailoring treatments according to gender, genetic risk, injury severity and inflammatory status.

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“…The evidence regarding resuscitation with 100% oxygen is conflicting. A recent study done by Smit et al failed to show statistical difference in cortical and hippocampal volume loss or in short-term neurological testing between immature rats resuscitated with either 21 or 100% oxygen following a modified Rice-Vannucci model of hypoxic-ischemic brain injury (50). Newborn piglets resuscitated with 100% O 2 improved restoration of mean arterial blood pressure with no difference in amino acid build up in cerebral striatum (glutamate, taurine, and alanine) when compared to those resuscitated with 21% O 2 (63).…”

Section: Preclinical Studiesmentioning

confidence: 96%

Inhaled Gases for Neuroprotection of Neonates: A Review

et al. 2020

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Importance: Hypoxic-ischemic encephalopathy (HIE) is a significant cause of morbidity and mortality in neonates. The incidence of HIE is 1-8 per 1,000 live births in developed countries. Whole-body hypothermia reduces the risk of disability or death, but 7 infants needed to be treated to prevent death or major neurodevelopmental disability. Inhalational gases may be promising synergistic agents due to their rapid onset and easy titratability.Objective: To review current data on different inhaled gases with neuroprotective properties that may serve as adjunct therapies to hypothermia.Evidence review: Literature review was performed using the PubMed database, google scholar, and ClinicalTrials.Gov. Results focused on articles published from January 1, 2005, through December 31, 2017. Articles published earlier than 2005 were included when appropriate for historical perspective. Our review emphasized preclinical and clinical studies relevant to the use of inhaled agents for neuroprotection.Findings: Based on the relevance to our topic, 111 articles were selected pertaining to the incidence of HIE, pathophysiology of HIE, therapeutic hypothermia, and emerging therapies for hypoxic-ischemic encephalopathy in preclinical and clinical settings. Supplemental tables summarizes highly relevant 49 publications that were included in this review. The selected publications emphasize the emergence of promising inhaled gases that may improve neurologic survival and alleviate neurodevelopmental disability when combined with therapeutic hypothermia in the future.Conclusions: Many inhaled agents have neuroprotective properties and could serve as an adjunct therapy to whole-body hypothermia. Inhaled agents are ideal due to their easy administration, titrability, and rapid onset and offset. oxide; NRF2, nuclear erythroid 2-related factor 2; OGD, oxygen and glucose deprivation; pCREB, phosphorylated cAMP response element binding protein; ROS, reactive oxygen species; Tyr216-GSK-3β, Phospho-glycogen synthase kinase-3β Tyr-216.Frontiers in Pediatrics | www.frontiersin.org Disclosure: Mallinckrodt Pharmaceuticals provided nitric oxide gas for a preclinical study in which all authors are involved.

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The effect of resuscitation in 100% oxygen on brain injury in a newborn rat model of severe hypoxic-ischaemic encephalopathy

Cited by 7 publications

References 39 publications

Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia

Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia

Management and investigation of neonatal encephalopathy: 2017 update

Inhaled Gases for Neuroprotection of Neonates: A Review

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