Despite the successful clinical translation of therapeutic hypothermia for perinatal encephalopathy into routine care, treatment is only partially effective. It is likely that this reflects the formidable challenges of initiating treatment for neonatal encephalopathy within a few hours after birth. In randomized controlled trials, cooling has been typically initiated at a mean 4 to 5 h after birth. This is clearly not optimal given accumulating evidence that cooling is significantly more effective when it can be initiated before 3hr. In this review we propose that given the consistent evidence that milder hypoxic-ischemic injury is associated with slower evolution of damage, any future clinical trials of delayed treatment starting more than 6hr after an insult should target infants with milder encephalopathy. We then critically examine the evidence that erythropoietin is one of the most promising preclinical candidates either for co-treatment with the mild therapeutic hypothermia or to support neuroregeneration after the therapeutic window for acute neuroprotection.
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