Abstract
Multiple randomized controlled trials of hypothermia for moderate or severe neonatal hypoxic-ischemic encephalopathy (HIE) have uniformly demonstrated a reduction in death or disability at early childhood evaluation. These initial trials along with other smaller studies established hypothermia as a standard of care in the neonatal community for moderate or severe HIE. The results of the initial trials have identified gaps in knowledge. This article describes 3 randomized controlled trials of hypothermia (second-generation trials) to address refinement of hypothermia therapy (longer and/or deeper cooling), late initiation of hypothermia (after 6 hours following birth), and use of hypothermia in preterm newborns.