Whole Body Hypothermia for the Treatment of Perinatal Asphyxial Encephalopathy

Lead Research Organisation: University of Oxford
Department Name: Unlisted

Abstract

Although major advances have been made in the care of mothers and babies, approximately 2 out of every 1000 newborn infants suffer from a lack of oxygen (asphyxia) around the time of birth that may cause death or injury to the brain. Currently there are no specific treatments that reduce the risk of death or brain injury following asphyxia. However, many possible treatments have been suggested as a result of experimental work. Of these, mild body cooling (hypothermia) has most consistently shown benefit, and preliminary small studies in babies have been promising.

This proposed randomized trial aims to find out whether mild cooling of babies suffering moderate and severe asphyxia prevents babies from dying or developing later disability (which will be measured when the children are 18 moths of age). To do this, babies who are thought to have suffered asphyxia will be assessed within 6 hours of birth and babies with moderate or severe asphyxia will be randomly selected so that in half the rectal temperature is kept at a normal level (37oC) and in the other half the temperature is kept at 33.5-34 oC for 72 hours, after which it will slowly be returned to normal. All other care in the two groups will be according to current clinical practice. In order to demonstrate a 30% reduction in death and disability with cooling treatment, 236 babies will need to be enrolled into the trial. Information will be collected from the babies at the time of the trial entry, during the first 80 hours after trial entry, when they are discharged from the neonatal unit (or die) and when they are aged 18 months.

Technical Summary

This proposal is for a pragmatic, multicentre, randomized trial to investigate whether a reduction of body temperature by 3-4oC in full term infants with perinatal asphyxial encephalopathy is a safe treatment that may improve survival without neurodevelopmental impairments.

Moderate or severe perinatal asphyxial encephalopathy occurs in approximately 2/1000 births and is associated with an increasing risk of death or neurodevelopmental impairments with more severe encephalopathy: approximately 25% of infants who suffer moderate asphyxial encephalopathy will develop cerebral palsy, whilst almost all infants with severe asphyxial encephalopathy die or survive with multiple handicaps. Perinatal asphyxia may account for up to 30% of cases of cerebral palsy and is a very significant health care and financial burden to the NHS.

236 infants with clinical and EEG evidence of asphyxial encephalopathy will be randomized within 6 hours of birth to either a control group with the rectal temperature kept at 37 +/- 0.2oC or to whole body cooling when the rectal temperature will be kept at 33.5 +/- 0.5oC for 72 hours followed by slow rewarming. The primary outcome measure is the combined rate of mortality and severe neurodevelopmental impairments in survivors at 18 months of age. Secondary outcome measures include the occurrence of adverse effects. An intention to treat analysis will be performed and predefined subgroup analysis will be based on the severity of encephalopathy assessed by amplitude integrated EEG.

Publications

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Azzopardi D (2013) Anticonvulsant effect of xenon on neonatal asphyxial seizures. in Archives of disease in childhood. Fetal and neonatal edition

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Azzopardi D (2007) Hypothermia. in Seminars in fetal & neonatal medicine

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Azzopardi DV (2009) Moderate hypothermia to treat perinatal asphyxial encephalopathy. in The New England journal of medicine

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Campbell H (2018) Hypothermia for perinatal asphyxia: trial-based quality of life at 6-7 years. in Archives of disease in childhood

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Edwards AD (2006) Therapeutic hypothermia following perinatal asphyxia. in Archives of disease in childhood. Fetal and neonatal edition

 
Description Endorsement of hypothermia therapy by NICE and BAPM
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Endorsement has increased uptake of therapeutic hypothermia
 
Description NAAT 2011 Reported_Membership Guideline
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact BAPM guidelines for neural rescue therapy in newborn
 
Description NAAT 2011 reported_BMJ or Lancet Citation
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
Impact New therapy which doubles chance of normal survival and reduces total societal health costs
 
Guideline Title IPG347 Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic perinatal brain injury
Description NICE guideline
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Our work on hypothermia has been the subject of a review by NICE to which we contributed expert guidance. On 17-12-09 NICE held a public hearing and the preliminary guidance is that the treatment should become part of normal NHS practice. In March 2010 formal guidance was published stating that hypothermia should become standard of care. The British Association of Perinatal Medicine simultaneously issued guidelines for the general application of the therapy across the UK.
URL http://www.nice.org.uk/ipg347
 
Description National Institute of Health, USA
Geographic Reach North America 
Policy Influence Type Membership of a guideline committee
Impact NIH workshops to formulate guidelines for: (i) therapeutic hypothermia, (ii) perinatal stroke, and (iii) neonatal hypoglycaemia. Influential in US practice and research agenda
 
Title UK TOBY cooling registry 
Description National registry of treatment with cooling hor neonatal encephalopathy 
Type Of Material Improvements to research infrastructure 
Year Produced 2014 
Provided To Others? No  
Impact National register of clinical use of therapeutic hypothermia in neonates 
 
Description Semmelweiss Unversity 
Organisation Semmelweiss University
Country Hungary 
Sector Academic/University 
PI Contribution Helped set up and anlyse substudy
Collaborator Contribution Enabled secondary studies related to main trial
Impact Pubications
 
Description TOBY UK Cooling Regster 
Organisation University of Oxford
Department National Perinatal Epidemiology Unit Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Clinical Lead for national registry of infants treated with cooling in the Uk
Collaborator Contribution Publications and set up of research network
Impact Publications
Start Year 2006
 
Title Toby Trial 
Description This was a clinical trial of therapeutic hypothermia after perinatal asphyxia: ISRCTN89547571 This therapy is now standard care 
Type Therapeutic Intervention - Physical
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2012
Development Status Closed
Clinical Trial? Yes
Impact As a result of this trial therapeutic hypothermia following perinatal asphyxia was endorsed by NICE and is now standard therapy 
URL http://www.npeu.ox.ac.uk/toby