New Horizons in Mild Hypoxic-ischemic Encephalopathy: A Standardized Algorithm to Move past Conundrum of Care

Hypoxic-ischemic encephalopathy (HIE) presents clinically with a neonatal encephalopathy (NE) whereby the mild spectrum is difficult to classify immediately after birth. For decades trials have focused exclusively on infants with moderate-severe HIE s, as these infants were easier to identify after birth and had the highest risk of adverse outcomes. Twenty years after those trials, the PRIME study finally solved the first part of the conundrum by providing a definition of mild HIE in the first 6 hours. There is strong biological plausibility and preclinical evidence supporting the efficacy of therapeutic hypothermia (TH) but there is a lack of comparative clinical data to establish the risk-benefit in mild HIE. The fundamental question of how best to manage mild HIE remains unanswered. This review will summarize (1) the evidence that neonates with mild HIE are at significant risk for adverse outcomes, (2) the gaps/controversies in management, and (3) an algorithm of care is proposed to ensure standardized management of mild HIE and the direction of future trials.