Neonatal neuroprotection for hypoxic–ischemic brain injury remains elusive. Preclinical studies of mild hypothermia in multiple animal models in several species (primarily, rodents, piglets, and sheep) showed significant benefit, and this therapy was therefore brought to clinical trials. Some of the preclinical trials showed little or no benefit, and these experiments allowed investigators to better define parameters in which hypothermia was effective. Important factors included timing and duration of therapy, depth of cooling, and use of anesthetics or morphine to prevent shivering. Multiple randomized controlled clinical trials of therapeutic hypothermia have now been completed, and meta-analyses of these trials definitively show benefit for infants with moderate to severe hypoxic–ischemic encephalopathy, with the number needed to treat between 7 and 9 (1,2). In general, the benefits of hypothermia were greater in animal experiments than in human trials. This discrepancy is probably because preclinical experiments are carried out in otherwise healthy animals under controlled settings with the type, degree, and timing of injury all known. Used clinically, hypothermia improves both survival and the neurologic outcomes of those who survive, but the effect is only modest. Fifteen percent of cooled neonates with moderate to severe neonatal encephalopathy due to presumed hypoxia–ischemia still die, with 25% of qualifying infants suffering severe long-term neurodevelopmental impairment. Hence, the search continues for therapies that will further improve outcomes.

Erythropoietin (Epo) has great potential to be such an agent. In published preclinical studies, Epo has neuroprotective and neuroregenerative effects in the brain, with improvement rates after neonatal brain injury ranging from 34 to 79% (3). Mechanisms of Epo neuroprotection include receptor-mediated, cell-specific effects that occur both early and late in the healing process, and nonspecific effects that also modulate the response to injury. Epo has anti-inflammatory (4,5,6), antiexcitotoxic (7), antioxidant (8), and antiapoptotic (9) effects on neurons and oligodendrocytes (10). It also promotes neurogenesis (11,12) and angiogenesis (13), which are essential for injury repair and normal neurodevelopment. Epo effects are dose dependent, and multiple doses are more effective than single doses (9,14,15). The studies by Fang et al. (16) and Fan et al. (17) published in this issue both question whether Epo plus hypothermia might be more protective than either Epo or hypothermia alone. Surprisingly, the study by Fang et al. showed no benefit of 8 h of hypothermia; Epo treatment improved the histopathological outcome in males only, and combined therapy showed no benefit (or harm). In contrast, the study by Fan et al. showed neuroprotection after 3 h of hypothermia (greater effect in females than in males), improvement in sensorimotor function (but not amelioration of histopathological damage) with Epo alone, and combined therapy showed only modest benefit in sensorimotor function (observed in males only). How can we resolve these differences, and why are these studies discordant with previously published work?

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