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New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

Research output: Contribution to journalArticlepeer-review

Suresh Victor, Eridan Rocha-Ferreira, Ahad Rahim, Henrik Hagberg, David Edwards

Original languageEnglish
JournalEuropean Journal of Paediatrics
Early online date24 Nov 2021
DOIs
Accepted/In press12 Nov 2021
E-pub ahead of print24 Nov 2021

Bibliographical note

Publisher Copyright: © 2021, The Author(s).

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  • HIE_review_manuscript_clean

    HIE_review_manuscript_clean.docx, 901 KB, application/vnd.openxmlformats-officedocument.wordprocessingml.document

    Uploaded date:12 Nov 2021

    Version:Accepted author manuscript

    Licence:CC BY

King's Authors

Abstract

Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44–53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments.What is Known:• Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy.• Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae.What is New:• Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia.• There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.

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