Perinatal hypoxic-ischemic brain injury remains one of the most desperate conditions in modern pediatric practice. The potentially devastating and lifelong consequences of this condition are accentuated by the frustrating impotence of current therapeutic options. In recent years remarkable experimental advances have elucidated many of the cellular and vascular mechanisms of hypoxic-ischemic brain injury. This in turn has facilitated the design of rational, focused, and mechanism-based rescue therapies in animal models.¹ Unfortunately, translation of this experimental progress to human clinical trial has been confined in large part to the adult stroke population, and has been slow to trickle down to the asphyxiated newborn infant. Perhaps the most exciting neuroprotective strategy to emerge from the laboratory in recent years has been the use of mild sustained hypothermia.^2-12 In this month's issue, Gunn et al¹³ report promising data from a prospective trial of this technique in asphyxiated term infants. The feasibility and safety data reported in this randomized study support the advance of this technique toward larger-scale clinical trials in the human newborn with hypoxic-ischemic encephalopathy.

For decades, the pursuit of safe and effective neuroprotection for the asphyxiated newborn infant has been impeded by certain features intrinsic to both the insult (ie, hypoxia-ischemia/reperfusion [HI/R]) and the substrate (ie, the immature brain).¹ The complex concatenation of cellular events triggered by a cerebral HI/R insult evolves rapidly through a series of amplifying cascades and eventually crosses the threshold of irreversible injury. Although our concepts of the reversibility of neuronal injury are changing, there is clearly a therapeutic window of opportunity beyond which intervention rapidly becomes ineffective.¹⁴ The second major constraint has been our ongoing inability to interrogate the neurologic well-being of the fetus, thereby delaying the diagnosis of cerebral HI/R insults and . . . [Full Text of this Article]