Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy: An Updated Systematic Review and Meta-analysis Tagin MA, Woolcott CG, Vincer MJ, Whyte RK, Stinson DA. Hypothermia for neonatal hypoxic ischemic encephalopathy: an updated systematic review and meta-analysis. Arch Pediatr Adolesc Med. Published online February 6, doi: /archpediatrics Copyright restrictions may apply

Background –Peripartum asphyxia remains an important cause of long-term sensorineural impairments and disabilities. –Data from the past 2 decades: therapeutic hypothermia mitigates cerebral injury and improves neurological outcome. –Clinicians have been hesitant to implement hypothermia as a standard of care because of mixed findings in previously published reviews. Study Objective –To update the assessment of therapeutic hypothermia with data from the latest randomized trials, in the form of systematic review and meta- analysis. Copyright restrictions may apply Introduction

Study Design –Systematic review (update of 2007 Cochrane review), using previously established search terms. Study Eligibility –Randomized controlled trials only, comparing hypothermia with normothermia, with data on death or disability at age 18 months or later. –No language restrictions. –Methodological quality assessed using the risk of bias assessment tool recommended by the Cochrane Neonatal Review Group. Outcomes/Analyses –Composite of death or long-term major neurodevelopmental disability (including cerebral palsy, developmental delay, intellectual impairment, blindness, sensorineural deafness requiring amplification). Copyright restrictions may apply Methods

Limitations –Clinical trials in this field are not blinded. –The duration of follow-up is limited to 18 months. Longer-term neurological function and its relationship to function at 18 months remain to be assessed. –Adjuvant therapies for perinatal asphyxia are still warranted given the devastating sequelae of this condition. Copyright restrictions may apply

Results A total of 14 trials were eligible for consideration. –Of these, 7 satisfied rules of quality and lack of bias. –Of these, 6 were additional trials identified since the last Cochrane review; 4 of these satisfied rules of quality and lack of bias. Subjects included in review and meta-analysis: –1214 Newborns with moderate to severe hypoxic ischemic encephalopathy (HIE) were included in this meta-analysis. Newborns with mild HIE were excluded. –Newborns in 4 trials were treated with total body cooling, while in 3 trials selective head cooling was used. Copyright restrictions may apply

Results Copyright restrictions may apply Forest plot of the composite primary outcome of death or major disability in survivors. Diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% CI). M-H indicates Mantel-Haenszel test.

Results Copyright restrictions may apply Forest plot of survival with normal neurological function (“events”). Diamond indicates overall summary estimate for the analysis (width of the diamond represents the 95% CI). M-H indicates Mantel-Haenszel test.

Comment This most recent analysis of therapeutic hypothermia supports its use in newborns with moderate to severe HIE, to reduce the risk of death or major disability at age 18 months. This latest evidence indicates that therapeutic hypothermia can reduce the mortality rate without increasing the disability rate. Early predictors of nonresponders to therapeutic hypothermia are still required to optimize this therapy among children with severe HIE. Copyright restrictions may apply

Comment The realistic therapeutic window for therapeutic cooling is uncertain; in included trials, the latest initiation was no more than 6 hours after birth. The authors recommend initiation of therapeutic hypothermia as soon after birth as possible for newborns with moderate to severe HIE. Copyright restrictions may apply

If you have questions, please contact the corresponding author: –Mohamed A. Tagin, MB, BCh, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada Copyright restrictions may apply Contact Information