Cooling for newborns with hypoxic ischaemic encephalopathy

Abstract

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. We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm 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, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross‐references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. 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. Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta‐analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm 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 0.75 (95% CI 0.68 to 0.83); typical RD ‐0.15, 95% CI ‐0.20 to ‐0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD ‐0.09 (95% CI ‐0.13 to ‐0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD ‐0.13 (95% CI ‐0.19 to ‐0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm 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. Hypothermia should be instituted in term and late preterm infants with moderate‐to‐severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention. Refroidissement pour les nouveau-nés présentant une encéphalopathie hypoxique ischémique Les études menées sur les animaux nouveau‐nés et les études pilotes chez les humains donnent à penser qu'une hypothermie légère suite à une hypoxie‐ischémie péripartum chez les nouveau‐nés peut réduire les séquelles neurologiques sans effets indésirables. Déterminer l'effet de l'hypothermie thérapeutique chez les nouveau‐nés présentant une asphyxie encéphalopathique sur la mortalité, l'incapacité neurodéveloppementale à long terme et les effets secondaires cliniquement importants. Nous avons utilisé la stratégie de recherche standard du Groupe thématique Cochrane sur la néonatologie tel que décrit dans The Cochrane Library (numéro 2, 2007). Les essais contrôlés randomisés évaluant l'hypothermie thérapeutique chez les nouveau‐nés nés à terme ou peu prématurés présentant une encéphalopathie hypoxique ischémique ont été identifiés en effectuant des recherches dans The Oxford Database of Perinatal Trials, le registre Cochrane des essais contrôlés ‐ Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, numéro 2), MEDLINE (de 1966 à juin 2007), les revues précédentes comprenant des références croisées, des résumés, des conférences, des actes de symposiums, auprès d'informateurs experts et en effectuant des recherches manuelles dans des journaux. La dernière mise à jour de cette recherche a été effectuée en mai 2012. Nous avons inclus des essais contrôlés randomisés comparant l'utilisation de l'hypothermie thérapeutique aux soins standard chez les nourrissons encéphalopathiques...