“Therapeutic time window” duration decreases with increasing severity of cerebral hypoxia–ischaemia under normothermia and delayed hypothermia in newborn piglets

Objective: For optimal neuroprotection following transient perinatal hypoxia–ischaemia (HI), therapy should start before overt secondary energy failure and its irreversible neurotoxic cascade. Hypothermia is a promising neuroprotective intervention that also prolongs the therapeutic time window (“latent-phase”; the period between re-establishment of apparently normal cerebral metabolism after HI, and the start of secondary energy failure). The influences of HI severity on latent-phase duration and regional neuroprotection are unclear. Under normothermia and delayed whole-body cooling to 35 and 33 °C we aimed to assess relationships between HI severity and: (i) latent-phase duration; (ii) secondary-energy-failure severity; and (iii) neuronal injury 48 h following HI. Methods: Newborn piglets were randomized to: (i) HI-normothermia (n = 12), (ii) HI-35 °C (n = 7), and (iii) HI-33 °C (n = 10). HI-35 °C and HI-33 °C piglets were cooled between 2 and 26 h after HI. Insult and secondary-energy-failure severity and latent-phase duration were evaluated using phosphorus magnetic resonance spectroscopy and compared with neuronal death in cortical-grey and deep-grey matter. Results: More severe HI was associated with shorter latent-phase (p = 0.002), worse secondary energy failure (p = 0.023) and more cortical-grey-matter neuronal death (p = 0.016). Conclusions: Latent-phase duration is inversely related to insult severity; latent-phase brevity may explain the apparently less effective neuroprotection following severe cerebral HI.