Moderate hypothermia to treat perinatal asphyxial encephalopathy

Perinatal asphyxial encephalopathy is associated with high morbidity and mortality rates and thus represents a major burden for patients, families and society. There is therefore an urgent need to improve outcomes in infants affected by this condition. Experimental evidence suggests that reducing body temperature to 3 to 5°C below the normal level may decrease the incidence of cerebral injury and may improve neurologic function after asphyxia. Moreover, preliminary clinical studies have found no serious adverse effects of cooling. Two randomized, controlled trials, namely the CoolCap trial and the National Institute of Child Health and Human Development (NICHD) trial, have reported outcomes among infants at 18 months of age who had asphyxial encephalopathy, after slightly different cooling regimens. Only the NICHD trial showed a significant reduction in the composite primary outcome of death or disability with hypothermia. However, neither trial had sufficient power to detect significant differences in important individual neurological outcomes; several systematic reviews and an expert workshop did not reach a consensus in recommending hypothermia as standard treatment.
An English group has recently published on the New England Journal of Medicine the results of the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), aimed to clarify the role of hypothermia. In this multicenter study, infants who were less than 6 hours of age and had a gestational age of at least 36 weeks and perinatal asphyxial encephalopathy were randomized to intensive care plus cooling of the body to 33.5°C for 72 hours or to intensive care alone. The primary outcome was death or severe disability at 18 months of age. Secondary outcomes included 12 neurologic outcomes and 14 other adverse outcomes. Overall, 163 infants underwent intensive care with cooling, and 162 were assigned to 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. There was no statistical difference between groups for either outcome. However, infants in the cooled group had an increased rate of survival without neurologic abnormality (RR=1.57; 95%CI: 1.16-2.12; p=0.003). Among survivors, cooling reduced risks of cerebral palsy (RR=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). Adverse events were mostly minor and none of them was associated with cooling.
In conclusion, although no difference was observed in the combined rates of death and severe disability, the addition of cooling to standard intensive care resulted in a significant improvement in several secondary neurologic outcomes among survivors. Whether this improvement may be maintained in the longer term needs further investigations.

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