Xenon as an adjuvant to therapeutic hypothermia in near term and term newborns with hypoxic ischaemic encephalopathy

Abstract

BACKGROUND Hypoxic-ischaemic encephalopathy (HIE) is a serious birth complication affecting term and late preterm newborns. Although therapeutic hypothermia (cooling) has been shown to be an effective therapy for neonatal HIE, many cooled infants have poor long-term neurodevelopmental outcomes. In animal models of neonatal encephalopathy, inhaled xenon combined with cooling has been shown to offer better neuroprotection than cooling alone. OBJECTIVES To determine the effects of xenon as an adjuvant to therapeutic hypothermia on mortality and neurodevelopmental morbidity, and to ascertain clinically important side effects of xenon plus therapeutic hypothermia in newborn infants with HIE. To assess early predictors of adverse outcomes and potential side effects of xenon. SEARCH METHODS We used the standard strategy of the Cochrane Neonatal Review Group to search the Cochrane Library (2017, Issue 8), MEDLINE (from 1966), Embase (from 1966), and PubMed (from 1966) for randomised controlled and quasi-randomised trials. We also searched conference proceedings and the reference lists of cited articles. We conducted our most recent search in August 2017. SELEC-TION CRITERIA We included all trials allocating term or late preterm encephalopathic newborns to cooling plus xenon or cooling alone, irrespective of timing (starting age and duration) and concentrations used for xenon administration. DATA COLLECTION AND ANALYSIS Two review authors independently assessed results of searches against predetermined criteria for inclusion, assessed risk of bias, and extracted data. We performed meta-analyses using risk ratios (RRs), risk differences (RDs), and number needed to treat for an additional beneficial outcome (NNTB) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MDs) for continuous data. MAIN RESULTS A single randomised controlled trial enrolling 92 participants was eligible for this review. Researchers have not reported long-term neurodevelopmental outcomes, including the primary outcome of this review -death or long-term major neurodevelopmental disability in infancy (18 months to three years of age). Cooling plus xenon was not associated with reduced mortality at latest follow-up, based upon low quality evidence. Investigators noted no substantial differences between groups for other secondary outcomes of this review, such as biomarkers of brain damage assessed with magnetic resonance imaging and occurrence of seizures during primary hospitalisation. Available data do not show an increased adverse event rate in the cooling plus xenon group compared with the cooling alone group. AUTHORS' CONCLUSIONS Current evidence from one small randomised controlled pilot trial is inadequate to show whether cooling plus xenon is safe or effective in near-term and term newborns with HIE. Further trials reporting long-term neurodevelopmental outcomes are needed.

Therapies for neonatal encephalopathy: Targeting the latent, secondary and tertiary phases of evolving brain injury

“…Data from the second trial, "Cool Xenon 3", using 50% of inhaled xenon, is not yet available. A Cochrane review concluded that data is inadequate to show whether HT plus Xenon is safe or effective in NE [111]. Xenon's major disadvantage is that it is difficult to use in clinical practice due to its scarcity (0.0087 ppm in the air) and high costs, along with the need for closed-circuit delivery (including cuffed tubes) and recycling systems.…”

The Function of the NMDA Receptor in Hypoxic-Ischemic Encephalopathy

“…The noble gas xenon is shown to have neuroprotective effects in hypoxic-ischemic models through inhibiting NMDA receptors by competing for the binding of glycine in many in vitro and in vivo animal models (Hobbs et al, 2008;Zhuang et al, 2010;Faulkner et al, 2011;Zhao et al, 2013;Juul and Ferriero, 2014;Alam et al, 2017;Rüegger et al, 2018;Koziakova et al, 2019).…”

Aktuelles in der Neonatologie

“…Einer klinischen multizentrischen Studie mit 92 Patienten ist allerdings zu entnehmen, dass Xenon bei Neugeborenen keine eindeutig messbaren klinischen Verbesserungen erbrachte[66]. Daher sind weitergehende klinische Studien erforderlich, um die therapeutische Wertigkeit des Xenons beurteilen zu können[67].Die fetale Lungenentwicklung durchläuft im letzten Trimenon die kritische Phase des sakkulären und alveolären Stadiums. Die zu frühe Geburt bedingt, dass diese Phase der Lungenentwicklung unter extrauterinen Bedingungen ablaufen muss.…”