Less is more: standardizing preclinical hypothermia to advance neonatal neuroprotection

Therapeutic hypothermia (TH) has been the only effective treatment for neonatal hypoxic-ischemic encephalopathy (HIE) for nearly two decades, yet roughly half of cooled infants still die or develop major neurological impairment. 1 This unmet need has driven a robust preclinical pipeline aimed at identifying adjunct therapies that can be layered onto hypothermia. 2 , 3 The challenge, as Ibrahim and colleagues articulate in their study, 4 is that the preclinical “control arm” against which these candidates are benchmarked is itself a moving target. Hypothermia protocols in rodent models of HIE vary widely in duration, depth, and timing, complicating cross-study comparisons and clouding the interpretation of potential additive benefit. By systematically comparing commonly used cooling durations — 2, 3, and 5 hours — within a single controlled Rice-Vannucci framework, the authors provide the field with a much-needed reference protocol grounded in direct comparison rather than convention.