title: Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe): a proof-of-concept, open-label, randomised controlled trial.
abstract: Moderate cooling after birth asphyxia is associated with substantial reductions in death and disability, but additional therapies might provide further benefit. We assessed whether the addition of xenon gas, a promising novel therapy, after the initiation of hypothermia for birth asphyxia would result in further improvement.
  
  
  
  Total Body hypothermia plus Xenon (TOBY-Xe) was a proof-of-concept, randomised, open-label, parallel-group trial done at four intensive-care neonatal units in the UK. Eligible infants were 36-43 weeks of gestational age, had signs of moderate to severe encephalopathy and moderately or severely abnormal background activity for at least 30 min or seizures as shown by amplitude-integrated EEG (aEEG), and had one of the following: Apgar score of 5 or less 10 min after birth, continued need for resuscitation 10 min after birth, or acidosis within 1 h of birth. Participants were allocated in a 1:1 ratio by use of a secure web-based computer-generated randomisation sequence within 12 h of birth to cooling to a rectal temperature of 33·5°C for 72 h (standard treatment) or to cooling in combination with 30% inhaled xenon for 24 h started immediately after randomisation. The primary outcomes were reduction in lactate to N-acetyl aspartate ratio in the thalamus and in preserved fractional anisotropy in the posterior limb of the internal capsule, measured with magnetic resonance spectroscopy and MRI, respectively, within 15 days of birth. The investigator assessing these outcomes was masked to allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00934700, and with ISRCTN, as ISRCTN08886155.
  
  
  
  The study was done from Jan 31, 2012, to Sept 30, 2014. We enrolled 92 infants, 46 of whom were randomly assigned to cooling only and 46 to xenon plus cooling. 37 infants in the cooling only group and 41 in the cooling plus xenon group underwent magnetic resonance assessments and were included in the analysis of the primary outcomes. We noted no significant differences in lactate to N-acetyl aspartate ratio in the thalamus (geometric mean ratio 1·09, 95% CI 0·90 to 1·32) or fractional anisotropy (mean difference -0·01, 95% CI -0·03 to 0·02) in the posterior limb of the internal capsule between the two groups. Nine infants died in the cooling group and 11 in the xenon group. Two adverse events were reported in the xenon group: subcutaneous fat necrosis and transient desaturation during the MRI. No serious adverse events were recorded.
  
  
  
  Administration of xenon within the delayed timeframe used in this trial is feasible and apparently safe, but is unlikely to enhance the neuroprotective effect of cooling after birth asphyxia.
  
  
  
  UK Medical Research Council.
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Bioengineering, King's College London, London, UK. Electronic address: denis.azzopardi@kcl.ac.uk.
authors.forename: Denis
authors.initials: D
authors.lastname: Azzopardi
authors.affiliation: EGA Institute for Women's Health, University College London, London, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
authors.affiliation: UCL Hospitals NHS Foundation Trust, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.affiliation: Faculty of Engineering Science, University College London, London, UK.
authors.forename: Ernest
authors.initials: E
authors.lastname: Cady
authors.affiliation: Department of Medical Physics, Guy's & St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Charles-Edwards
authors.affiliation: Division of Neonatology, Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Aniko
authors.initials: A
authors.lastname: Deierl
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Bioengineering, King's College London, London, UK.
authors.forename: Gianlorenzo
authors.initials: G
authors.lastname: Fagiolo
authors.affiliation: Faculty of Natural Sciences, Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Franks
authors.affiliation: National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: James
authors.initials: J
authors.lastname: Griffiths
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Bioengineering, King's College London, London, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hajnal
authors.affiliation: National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Edmund
authors.initials: E
authors.lastname: Juszczak
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Bioengineering, King's College London, London, UK.
authors.forename: Basil
authors.initials: B
authors.lastname: Kapetanakis
authors.affiliation: National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Linsell
authors.affiliation: Anesthesia and Perioperative Care, University of California San Francisco School of Medicine, San Francisco, CA, USA.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
authors.affiliation: National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Omar
authors.initials: O
authors.lastname: Omar
authors.affiliation: National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
authors.forename: Brenda
authors.initials: B
authors.lastname: Strohm
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Bioengineering, King's College London, London, UK.
authors.forename: Nora
authors.initials: N
authors.lastname: Tusor
authors.affiliation: Centre for the Developing Brain, Division of Imaging Sciences and Bioengineering, King's College London, London, UK.
authors.forename: A David
authors.initials: AD
authors.lastname: Edwards
mesh_terms: D000138:Acidosis / Q000209:etiology; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001034:Apgar Score; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001238:Asphyxia Neonatorum / Q000150:complications / Q000628:therapy*; D003131:Combined Modality Therapy; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D007231:Infant, Newborn; D020772:Internal Capsule / Q000000981:diagnostic imaging*; D019344:Lactic Acid / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D017063:Outcome Assessment, Health Care; D012151:Resuscitation; D016037:Single-Blind Method; D013788:Thalamus / Q000000981:diagnostic imaging*; D014978:Xenon / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D018685:Anesthetics, Inhalation; D001224:Aspartic Acid; D019344:Lactic Acid; D014978:Xenon; C000179:N-acetylaspartate