Inhaled Gases for Neuroprotection of Neonates: A Review

Abstract

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.

Inhaled H2 or CO2 Do Not Augment the Neuroprotective Effect of Therapeutic Hypothermia in a Severe Neonatal Hypoxic-Ischemic Encephalopathy Piglet Model

“…Molecular H 2 has become an intensively studied cytoprotective/neuroprotective medical gas in the last decade; for recent reviews of the widespread beneficial effects of H 2 , please refer to [ 39 , 40 , 41 , 42 ]. Concerning HIE, many rodent studies using the Rice–Vannucci model of hypoxic-ischemic stress established the neuroprotective effect of H 2 [ 14 , 43 , 44 , 45 , 46 ].…”

Low Variability of Blood Pressure Predicts Abnormal Electroencephalogram in Infants with Hypoxic Ischemic Encephalopathy

“…This information would be of great value to clinicians who hope to identify a subpopulation of HIE infants at relatively greater risk for adverse outcomes and who might benefit from additional interventions such as inhaled noble gases or erythropoietin (which demonstrate marginal cost to benefit ratios for general use, but may be of greater value when targeted to a risk-stratified population. 34,35 ) The current gold standard for physiologic-based prediction is the conventional EEG. As described by Murray et al, 13 several different EEG characteristics including background amplitude, the presence of seizures, and the absence of cyclicity were predictive of adverse neurodevelopmental outcome at 2 years of age for infants who underwent hypothermia.…”

“…This information would be of great value to clinicians who hope to identify a subpopulation of HIE infants at relatively greater risk for adverse outcomes and who might benefit from additional interventions such as inhaled noble gases or erythropoietin (which demonstrate marginal cost to benefit ratios for general use, but may be of greater value when targeted to a risk-stratified population. 34,35 )…”

Hydrogen-induced Neuroprotection in Neonatal Hypoxic-ischemic Encephalopathy

“…Application of therapeutic gases appears to be a straightforward method to achieve neuroprotection as babies born with severe asphyxia usually require assisted ventilation. Medical gas research has identified a number of gases showing neuroprotective effects, including administration of xenon, argon, helium, hydrogen, carbon monoxide, and the management of carbon dioxide and oxygen [8]. The major objective of the present review was to critically examine and discuss the results of the preclinical studies on the neuroprotective effects and the mechanisms of neuroprotection by molecular hydrogen-treatment in HIE animal models, as these were not exhausted in a previous study [8].…”

“…Moderate whole body hypothermia offers significant neuroprotection and has been shown to reduce mortality and improve both short-term and long-term neurodevelopmental outcomes [4][5][6]. However, therapeutic hypothermia is unable to save every affected infant, a systematic meta-analysis of 11 cooling trials concluded that the number needed to treat to benefit is 7 (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), meaning that on average 7 HIE patients with severe encephalopathy must be cooled to avoid 1 death or major disability [7]. Therefore, adjunct neuroprotective measures are warranted to complement the neuroprotective effect of hypothermia.…”