Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia

Abstract

Background: 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. Methods: Of 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. Results: Fifteen 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. Interpretation: The results confirm the qualification of the cerebral magnetic resonance biomarkers employed in the TOBY-Xe study as predictors of outcome after neuroprotective therapy. Fund: The Centre for the Developing Brain, King's College London, UK.

Proton Magnetic Resonance Spectroscopy Lactate/N-Acetylaspartate Within 48 h Predicts Cell Death Following Varied Neuroprotective Interventions in a Piglet Model of Hypoxia–Ischemia With and Without Inflammation-Sensitization

“…Nevertheless, in clinical studies of NE, lower DWI-MD is associated with adverse neurodevelopmental outcomes (41,43). FA may have more utility in the prediction of outcome as pseudonormalization does not occur; however, we showed poor correlation with TUNEL-positive cell death, which concurs with results from the TOBY Xe neuroprotection study in babies, where FA added little extra to Lac/NAA in accurately predicting neurodevelopmental outcome (10).…”

“…Using a threshold of 0.39, the sensitivity and specificity of BGT Lac/NAA for 2-year motor outcome was 100% and 97%, cognition 90% and 97% and language 81% and 97%, respectively (8). In the TOBY Xenon early-phase clinical neuroprotection trial, adverse outcomes were correctly identified in 95.65% of cases by basal ganglia and thalamus (BGT) Lac/NAA, whereas prediction of adverse outcome using fractional anisotropy (FA) was 78.79% (10). Using Lac/NAA peak area ratio as a qualified biomarker in the clinical context in a small proof-of-concept neuroprotection trial therefore avoids substantial financial and opportunity costs associated with large randomized controlled trials (RCTs).…”

Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia

“…Amplitude-integrated EEG and 1 H MRS are validated ( Azzopardi et al , 2019 ; Lally et al , 2019 ; Mitra et al , 2019 ) translational biomarkers used in the clinical setting for infants with NE. Here, we showed double therapy with HT+MEL and HT+Epo was associated with more rapid aEEG recovery than H + V. In the clinical setting, aEEG recovery after HI predicts outcomes in infants with NE ( Thoresen et al , 2010 ; Csekő et al , 2013 ; Chandrasekaran et al , 2017 ).…”

Combination treatments with therapeutic hypothermia for hypoxic‐ischemic neuroprotection

“…The effect of Xenon on neurodevelopmental outcome was not directly reported in the original study 41 . However, the MRS results were strongly correlated with neurodevelopmental outcomes at 2 to 3 years of age in the surviving participants 41,42 . An important caveat for this study is that Xenon was only started before 6 hours in seven of 46 infants, and seven were started after 12 hours.…”

“…41 However, the MRS results were strongly correlated with neurodevelopmental outcomes at 2 to 3 years of age in the surviving participants. 41,42 An important caveat for this study is that Xenon was only started before 6 hours in seven of 46 infants, and seven were started after 12 hours. This delay is much longer than tested in animal studies, so it is plausible that this delay was outside of the window of opportunity for the efficacy of Xenon.…”