A narrative review on treatment strategies for neonatal hypoxic ischemic encephalopathy

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Abstract

Background and Objective

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of death and disability worldwide. Therapeutic hypothermia (TH) represents a significant achievement in the translation of scientific research to clinical application, but it is currently the only neuroprotective treatment for HIE. This review aims to revisit the use of TH for HIE and its longitudinal impact on patient outcomes to readers new to the field of HIE. We discuss how emerging therapies address the broader pathophysiology of injury progression in the neonatal brain days to years after HIE.

Methods

We included full articles and book chapters published in English on PubMed with references to “hypoxic ischemic encephalopathy”, “birth asphyxia”, “therapeutic hypothermia”, or “neonatal encephalopathy”. We limited our review to outcomes on term infants and to new therapeutics that are in the second phase of clinical trials.

Key Content and Findings

Despite the use of TH for HIE, mortality remains high. Analysis of longitudinal studies reveals a high incidence of ongoing disability even with the implementation of TH. New therapeutics addressing the secondary phase and the less understood tertiary phase of brain injury are in clinical trials as adjunctive treatments to TH to support additional neurological repair and regeneration.

Conclusions

TH successfully improves outcomes after HIE, and it continues to be optimized. Larger studies are needed to understand its use in mild cases of HIE and if certain factors, such as sex, affect long term outcomes. TH primarily acts in the initial phases of injury, while new pharmaceutical therapies target additional injury pathways into the tertiary phases of injury. This may allow for more effective approaches to treatment and improvement of long-term functional outcomes after HIE.

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Most cited references 207

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Sex and gender: modifiers of health, disease, and medicine

Franck Mauvais-Jarvis, Noel C Bairey Merz, Peter Barnes … (2020)

Summary Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.

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Oxygen-derived free radicals in postischemic tissue injury.

J M McCord (1985)

It is now clear that oxygen-derived free radicals play an important part in several models of experimentally induced reperfusion injury. Although there are certainly multiple components to clinical ischemic and reperfusion injury, it appears likely that free-radical production may make a major contribution at certain stages in the progression of the injury. The primary source of superoxide in reperfused reoxygenated tissues appears to be the enzyme xanthine oxidase, released during ischemia by a calcium-triggered proteolytic attack on xanthine dehydrogenase. Reperfused tissues are protected in a variety of laboratory models by scavengers of superoxide radicals or hydroxyl radicals or by allopurinol or other inhibitors of xanthine oxidase. Dysfunction induced by free radicals may thus be a major component of ischemic diseases of the heart, bowel, liver, kidney, and brain.

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Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000.

Li Liu, Hope L Johnson, Simon Cousens … (2012)

Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. Updated total numbers of deaths in children aged 0-27 days and 1-59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1-59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. Of 7·6 million deaths in children younger than 5 years in 2010, 64·0% (4·879 million) were attributable to infectious causes and 40·3% (3·072 million) occurred in neonates. Preterm birth complications (14·1%; 1·078 million, uncertainty range [UR] 0·916-1·325), intrapartum-related complications (9·4%; 0·717 million, 0·610-0·876), and sepsis or meningitis (5·2%; 0·393 million, 0·252-0·552) were the leading causes of neonatal death. In older children, pneumonia (14·1%; 1·071 million, 0·977-1·176), diarrhoea (9·9%; 0·751 million, 0·538-1·031), and malaria (7·4%; 0·564 million, 0·432-0·709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2·7% (0·205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0·451 million [0·339-0·547], 0·363 million [0·283-0·419], and 0·359 million [0·215-0·476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010-15 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. Continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates. The Bill & Melinda Gates Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Transl Pediatr

Journal ID (iso-abbrev): Transl Pediatr

Journal ID (publisher-id): TP

Title: Translational Pediatrics

Publisher: AME Publishing Company

ISSN (Print): 2224-4336

ISSN (Electronic): 2224-4344

Publication date (Electronic): 22 August 2023

Publication date (Print): 30 August 2023

Volume: 12

Issue: 8

Pages: 1552-1571

Affiliations

[1 ]deptDepartment of Neurology , University of Texas McGovern Medical School , Houston, TX, USA;

[2 ]deptDepartment of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience , Baylor College of Medicine , Houston, TX, USA

Author notes

Contributions: (I) Conception and design: All authors; (II) Administrative support: LD McCullough; (III) Provision of study materials or patients: LD McCullough; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Viola Caretti, MD, PhD. Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, 6621 Fannin St, Houston, TX 77030, USA; Department of Neurology, University of Texas McGovern Medical School, Houston, TX 77030, USA. Email: Viola.Caretti@ 123456uth.tmc.edu .

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ORCID: Janelle M. Korf, 0000-0003-0246-6894; Louise D. McCullough, 0000-0002-8050-1686; Viola Caretti, 0000-0002-6702-1426.

Article

Publisher ID: tp-12-08-1552

DOI: 10.21037/tp-23-253

PMC ID: 10485647

PubMed ID: 37692539

SO-VID: 9c9d34c4-6f10-4c41-9c2b-d1888034a4c5

License:

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

History

Date received : 22 April 2023

Date accepted : 08 August 2023

Funding

Funded by: American Heart Association

Award ID: No. 916595

Funded by: the American Heart Association

Award ID: 20MER-AQ15 IT35120410

Funded by: the NINDS

Award ID: R01 NS094543 and R37NS096493

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A narrative review on treatment strategies for neonatal hypoxic ischemic encephalopathy

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Abstract

Background and Objective

Methods

Key Content and Findings

Conclusions

Related collections

Pediatric Pulse: Advancing Neonatal and Child Health

Most cited references 207

Sex and gender: modifiers of health, disease, and medicine

Oxygen-derived free radicals in postischemic tissue injury.

Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000.

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Cited by 3

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