Cooling for newborns with hypoxic ischaemic encephalopathy

Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects.

To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects.

The standard search strategy of the Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007) was used. Randomised controlled trials evaluating therapeutic hypothermia in term newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal hand searching.

Randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic newborn infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies were included. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome.

Three review authors independently selected, assessed the quality of and extracted data from the included studies. Authors were contacted for further information. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals.

Eight randomised controlled trials were included in this review, comprising 638 term infants with moderate/ severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age [typical RR 0.76 (95% CI 0.65, 0.89), typical RD -0.15 (95% CI -0.24, -0.07), NNT 7 (95% CI 4, 14)]. Cooling also resulted in statistically significant reductions in mortality [typical RR 0.74 (95% CI 0.58, 0.94), typical RD -0.09 (95% CI -0.16, -0.02), NNT 11 (95% CI 6, 50)] and in neurodevelopmental disability in survivors [typical RR 0.68 (95% CI 0.51, 0.92), typical RD -0.13 (95% CI -0.23, -0.03), NNT 8 (95% CI 4, 33)]. Some adverse effects of hypothermia included an increase in the need for inotrope support of borderline significance and a significant increase in thrombocytopaenia.

There is evidence from the eight randomised controlled trials included in this systematic review (n = 638) that therapeutic hypothermia is beneficial to term newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. However, this review comprises an analysis based on less than half of all infants currently known to be randomised into eligible trials of cooling. Incorporation of data from ongoing and completed randomised trials (n = 829) will be important to clarify the effectiveness of cooling and to provide more information on the safety of therapeutic hypothermia, but could also alter these conclusions. Further trials to determine the appropriate method of providing therapeutic hypothermia, including comparison of whole body with selective head cooling with mild systemic hypothermia, are required.