The TOBY Xe Study

Neuroprotective effects of hypothermia combined with inhaled xenon following perinatal asphyxia

The findings from the TOBY Xe Study are published in Lancet Neurology, on 19 December 2015.

Moderate hypothermia within 6 hours of birth plus inhaled xenon versus moderate hypothermia alone after birth asphyxia: 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.

View the publication

Recruitment
Total
0092
Target
138

Recruitment to TOBY Xe is now closed and we would like to thank everyone who helped us reach this point. Please note, the trial will continue until all recruits are no longer in hospital and data collection has been completed.

Perinatal asphyxia severe enough to cause neonatal hypoxic-ischaemic encephalopathy (HIE) occurs in approximately 3/1000 births in the UK, and over 1000 moderate to severe cases of HIE are expected every year. The risk of death or severe handicap in survivors of moderate or severe HIE is approximately 25 and 75% respectively. Until recently no specific treatment for perinatal asphyxia was available, but trials of mild hypothermia have recently proved that in principle neuroprotective therapy after delivery is possible. However, the therapeutic benefit of hypothermia is modest and further neuroprotective interventions are urgently needed.

Aims

This is a proof-of-concept study to test the hypothesis that following perinatal asphyxia treatment with a combination of hypothermia and inhaled xenon reduces cerebral biochemical abnormality, preserves cerebral structures, and leads to improved clinical outcomes at hospital discharge.

Inclusion Criteria

Infants will be eligible for enrolment into the trial if each of the following criteria is fulfilled:

  • Infant is 36 to 43 weeks gestation with at least one of the following:
    • Apgar score of <5 at 10 minutes after birth;
    • Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth;
    • Acidosis defined as pH <7.00 and/or base deficit > 15mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood).
  • Moderate to severe encephalopathy consisting of altered state of consciousness (reduced or absent response to stimulation) and hypotonia, and abnormal primitive reflexes (weak or absent suck or Moro response). Clinical severity of HIE will be assessed by an encephalopathy score.
  • At least 30 minutes duration of amplitude integrated EEG (aEEG) recording that shows moderately abnormal or suppressed background aEEG activity or seizures.

Exclusion Criteria

Infants will not be eligible for enrolment into the trial if any of the following criteria are fulfilled:

  • If treatment with hypothermia is delayed beyond 6 hours, or infants are expected to be >12 hours of age at the time of randomisation;
  • Infants with ventilatory oxygen requirement > 60%; or with a need for HFOV, Nitric oxide or ECMO therapy.
  • If the attending clinician considers the infant unsuitable to participate because of other serious congenital abnormalities, or the infant’s condition appears terminal.

Study Population

This will be a randomised controlled trial of infants with perinatal asphyxia admitted to Queen Charlotte and Chelsea Hospital (QCCH) and University College London Hospital (UCLH), and St Thomas Hospital, London UK.

Treatment

Following informed parental consent, infants that continue to require endotracheal tube ventilation following resuscitation will be randomised to treatment with hypothermia only or hypothermia and xenon. All infants in both groups will be treated with hypothermia for 72 hours started within 6 hours of delivery and infants allocated to hypothermia and xenon will also receive 30% xenon (balanced with oxygen and air) for 24 hours through a purpose designed delivery system.

Outcome Measures

Structured neurological examination will be done daily during the 1st week after birth and at discharge. MRS and MRI will be performed once between 5-14 days of age. MRS/MRI data analysis will be by investigators blinded to the allocated intervention.

Co-ordination, Sponsorship and Funding

This is a multi-centre trial co-ordinated by Imperial College and the National Perinatal Epidemiology Unit (NPEU) at the University of Oxford and is sponsored by Imperial College, London. Funding is provided by the Medical Research Council.