Therapeutic hypothermia in the prevention of hypoxic-ischaemic encephalopathy: new categories to be enrolled

Therapeutic hypothermia is now the standard of care for brain injury control in term infants with perinatal hypoxic ischemic encephalopathy (HIE). Accumulated evidence shows a reduction in mortality and long-term neurodevelopmental disability at 12-24 months of age, with more favourable effects in the less severe forms of HIE. Only few trials recruited newborns <36 weeks gestational age, or mild-to-moderate encephalopathy with base deficit (BD) <16. The new categories of patients to be enrolled should include (late) preterm infants, neonates with unexpected postnatal collapse, and newborns with stroke. Preterm HIE: Therapeutic hypothermia shows a good safety profile in clinical studies, and no adverse effects were noted in the preterm fetal animal model. Recently, it has been shown that mild hypothermia in preterm newborns with necrotizing enterocolitis (NEC) and multiple organ dysfunction syndrome (MODS) does not increase mortality, bleeding, infection, or need for inotropes in cooled newborns. A pilot study (NCT00620711) is currently recruiting newborns of > 32 but < 36 weeks gestation with standard criteria for HIE. Postnatal Collapse: The postnatal collapse (PNC) is a rare (0.03-0.5/1000 live births) but life-threatening hypoxic-ischemic event. No clinical trials of therapeutic hypothermia have specifically addressed to PNC. Nevertheless, a beneficial effect of brain cooling is expectable, and it has been proposed to include in brain hypothermia trials the infants with PNC fulfilling the entry criteria for HIE. Stroke: Perinatal arterial ischemic stroke is the most common cause of cerebral palsy (CP) in term and near-term newborn. In a systematic review and meta-analysis of animal studies of focal cerebral ischemia, hypothermia reduced the infarct size by 44%. No specific neuroprotective interventions are available for the management of acute perinatal stroke. Hypothermia may decrease seizures in newborns with encephalopathy and a focal infarct, potentially improving the long-term outcome for these infants. Concluding remarks: Future studies of therapeutic hypothermia should include the categories of newborns excluded from the published clinical trials, that is infants <36 weeks gestation, PNC or stroke, or admitted outside of the established 6-hour window, and with encephalopathy not imputable to HIE. New entry criteria will allow significant number of newborns to benefit from the treatment.