Abstract
BackgroundThe TOBY-Xe proof of concept randomised trial found no effect of xenon combined with hypothermia after birth asphyxia on the lactate to N-acetyl aspartate ratio (Lac/NAA) in the thalamus and fractional anisotropy (FA) in white matter tracts measured within 15 days of birth. To confirm that these biomarkers are qualified to predict long-term outcome after neural rescue therapy we assessed surviving participants at 2–3 years of age.MethodsOf the 92 infants in TOBY-Xe, one was omitted from the study, 69 survived and we assessed 62 participants, 32 in the hypothermia and xenon and 30 in the hypothermia only groups. We examined the relation between Lac/NAA and FA and the scores of the Bayley Scales of Infant and Toddler Development III and calculated their predictive accuracy for moderate or severe disability or death.ResultsFifteen of 62 participants (24%) developed moderate/severe disability, and 22/92 (24%) died.The Lac/NAA ratio (difference in medians 0.628, 95% CI -0.392 to 4.684) and FA (difference in means −0.055, 95% CI -0.033 to −0.077) differed significantly between participants with or without moderate or severe disability or death and were significantly related with development scores in both groups. Adverse outcomes were correctly identified in 95.65% of cases by Lac/NAA and 78.79% by FA, with adequate mean calibration of the model.InterpretationThe results confirm the qualification of the cerebral magnetic resonance biomarkers employed in the TOBY-Xe study as predictors of outcome after neuroprotective therapy.FundThe Centre for the Developing Brain, King's College London, UK.
Highlights
Xenon, a monoatomic gas that is approved for inhalational anaesthesia, showed promising neuroprotective effects when combined with moderate hypothermia following asphyxia in studies in animals and in a preliminary clinical study in adults following cardiac arrest [1,2,3,4]
Relationship between early cerebral biomarkers and neurodevelopment: The lactate to N-acetyl aspartate ratio (Lac/NAA) ratio in the thalamus and fractional anisotropy (FA) in the posterior limb of the internal capsule measured within 15 days of birth were significantly related with the composite cognitive, language and motor developmental scores assessed at 2–3 years of age in the whole population and in each treatment group (Fig. 2, Table 3)
Recent studies confirmed the accuracy of MRS and MRI biomarkers for predicting an adverse outcome following birth asphyxia and neonatal encephalopathy, but without testing any therapeutic intervention. (10;11) The present study aimed to confirm prospectively the qualification of the cerebral biomarkers after an adjunct neuroprotective treatment with therapeutic hypothermia
Summary
A monoatomic gas that is approved for inhalational anaesthesia, showed promising neuroprotective effects when combined with moderate hypothermia following asphyxia in studies in animals and in a preliminary clinical study in adults following cardiac arrest [1,2,3,4]. Several single centre studies and one large multicentre prospective study assessed brain injury following neonatal encephalopathy by magnetic resonance spectroscopy and/or tensor imaging In these studies, the thalamic peak area lactate/ N-acetyl aspartate (Lac/ NAA) ratio and the NAA metabolite concentration were reported to be the optimal predictors of neurodevelopmental outcome at 2–3 years but no study has prospectively qualified these biomarkers for rapid assessment of adjunct neural rescue therapy with hypothermia following birth asphyxia. The TOBY-Xe proof of concept randomised trial found no effect of xenon combined with hypothermia after birth asphyxia on the lactate to N-acetyl aspartate ratio (Lac/NAA) in the thalamus and fractional anisotropy (FA) in white matter tracts measured within 15 days of birth To confirm that these biomarkers are qualified to predict long-term outcome after neural rescue therapy we assessed surviving participants at 2–3 years of age. Fund: The Centre for the Developing Brain, King's College London, UK
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