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Hypothermia for HIE – TOBY Trial Results
Azzopardi DV, Strohm B, Edwards AD, et al. for the TOBY Study Group. Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy. N Engl J Med (Oct 1, 2009); 361:1349-1358. Full Text | PDF
Background Whether hypothermic therapy improves neurodevelopmental outcomes in newborn infants with asphyxial encephalopathy is uncertain.
Methods We performed a randomized trial of infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy. We compared intensive care plus cooling of the body to 33.5°C for 72 hours and intensive care alone. The primary outcome was death or severe disability at 18 months of age. Prespecified secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes.
Results Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived but had severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% confidence interval [CI], 0.68 to 1.07; P=0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk, 1.57; 95% CI, 1.16 to 2.12; P=0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (relative risk, 0.67; 95% CI, 0.47 to 0.96; P=0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P=0.03 for each) and the Gross Motor Function Classification System (P=0.01). Improvements in other neurologic outcomes in the cooled group were not significant. Adverse events were mostly minor and not associated with cooling.
Conclusions Induction of moderate hypothermia for 72 hours in infants who had perinatal asphyxia did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors.
Comments. We now have the long-awaited TOBY trial results. This is the third large RCT that showed benefit from moderate hypothermia for neonatal encephalopathy. The previous trials were the NICHD (see 6-040) and Cool Cap (see 6-039) studies. The TOBY trial found that cooled infants had increased survival without neurologic abnormality, reduced risk of cerebral palsy, and improved scores on the Bailey MDI and PDI developmental indices. While there were minor differences between study protocols and results, the basic results of all 3 trials were very similar. Hypothermia works, and should be offered to all term and near-term babies with moderate or severe neonatal encephalopathy. This therapy should no longer be considered investigational. ABK
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