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

Denis Azzopardi, Nicola J. Robertson, Alan Bainbridge, Ernest Cady, Geoffrey Charles-Edwards, Aniko Deierl, Gianlorenzo Fagiolo, Nicholas P. Franks, James Griffiths, Joseph Hajnal, Edmund Juszczak, Basil Kapetanakis, Louise Linsell, Mervyn Maze, Omar Omar, Brenda Strohm, Nora Tusor, A. David Edwards

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: UK Medical Research Council.

Original languageEnglish
Pages (from-to)145-153
Number of pages9
JournalThe Lancet Neurology
Volume15
Issue number2
DOIs
Publication statusPublished - 1 Feb 2016
Externally publishedYes

Fingerprint

Xenon
Asphyxia
Hypothermia
Randomized Controlled Trials
Parturition
Internal Capsule
Anisotropy
Random Allocation
Thalamus
Lactic Acid
Magnetic Resonance Spectroscopy
Extremities
Fat Necrosis
Intention to Treat Analysis
Apgar Score
Subcutaneous Fat
Neonatal Intensive Care Units
Brain Diseases
Neuroprotective Agents
Acidosis

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

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. / Azzopardi, Denis; Robertson, Nicola J.; Bainbridge, Alan; Cady, Ernest; Charles-Edwards, Geoffrey; Deierl, Aniko; Fagiolo, Gianlorenzo; Franks, Nicholas P.; Griffiths, James; Hajnal, Joseph; Juszczak, Edmund; Kapetanakis, Basil; Linsell, Louise; Maze, Mervyn; Omar, Omar; Strohm, Brenda; Tusor, Nora; Edwards, A. David.

In: The Lancet Neurology, Vol. 15, No. 2, 01.02.2016, p. 145-153.

Research output: Contribution to journalArticle

Azzopardi, D, Robertson, NJ, Bainbridge, A, Cady, E, Charles-Edwards, G, Deierl, A, Fagiolo, G, Franks, NP, Griffiths, J, Hajnal, J, Juszczak, E, Kapetanakis, B, Linsell, L, Maze, M, Omar, O, Strohm, B, Tusor, N & Edwards, AD 2016, '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', The Lancet Neurology, vol. 15, no. 2, pp. 145-153. https://doi.org/10.1016/S1474-4422(15)00347-6
Azzopardi, Denis ; Robertson, Nicola J. ; Bainbridge, Alan ; Cady, Ernest ; Charles-Edwards, Geoffrey ; Deierl, Aniko ; Fagiolo, Gianlorenzo ; Franks, Nicholas P. ; Griffiths, James ; Hajnal, Joseph ; Juszczak, Edmund ; Kapetanakis, Basil ; Linsell, Louise ; Maze, Mervyn ; Omar, Omar ; Strohm, Brenda ; Tusor, Nora ; Edwards, A. David. / 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. In: The Lancet Neurology. 2016 ; Vol. 15, No. 2. pp. 145-153.
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T1 - Moderate hypothermia within 6 h of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia (TOBY-Xe)

T2 - A proof-of-concept, open-label, randomised controlled trial

AU - Azzopardi, Denis

AU - Robertson, Nicola J.

AU - Bainbridge, Alan

AU - Cady, Ernest

AU - Charles-Edwards, Geoffrey

AU - Deierl, Aniko

AU - Fagiolo, Gianlorenzo

AU - Franks, Nicholas P.

AU - Griffiths, James

AU - Hajnal, Joseph

AU - Juszczak, Edmund

AU - Kapetanakis, Basil

AU - Linsell, Louise

AU - Maze, Mervyn

AU - Omar, Omar

AU - Strohm, Brenda

AU - Tusor, Nora

AU - Edwards, A. David

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: UK Medical Research Council.

AB - Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: UK Medical Research Council.

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