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Detection of cerebral hypoxia-ischemia (H-I) and prevention of brain injury remains problematic in critically ill neonates. Near-infrared spectroscopy (NIRS), a noninvasive bedside technology could fill this role, although NIRS cerebral O2 saturation (ScO2) viability-time thresholds for brain injury have not been determined. We investigated the relationship between H-I duration at ScO2 35%, a viability threshold which causes neurophysiological impairment, to neurological outcome.Forty-six fentanyl-midazolam anesthetized piglets were equipped with NIRS and cerebral function monitor (CFM) to record ScO2 and electrocortical activity (ECA). After carotid occlusion, inspired O2 was adjusted to produce H-I (ScO2 35% with decreased ECA) for 1, 2, 3, 4, 6 or 8 h in different groups, followed by survival to assess neurological outcome by behavioral and histological examination.For H-I lasting 1 or 2 h, ECA and ScO2 during reperfusion rapidly returned to normal and neurological outcomes were normal. For H-I more than 2–3 h, ECA was significantly decreased and ScO2 was significantly increased during reperfusion, suggesting continued depression of tissue O2 metabolism. As H-I increased beyond 2 h, the incidence of neurological injury increased linearly, approximately 15% per h.A viability-time threshold for H-I injury is ScO2 of 35% for 2–3 h, heralded by abnormalities in NIRS and CFM during reperfusion. These findings suggest that NIRS and CFM might be used together to predict neurological outcome, and illustrate that there is a several hour window of opportunity during H-I to prevent neurological injury.