title: "Therapeutic time window" duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets.
abstract: 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 degrees 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 degrees C (n=7), and (iii) HI-33 degrees C (n=10). HI-35 degrees C and HI-33 degrees 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.
authors.affiliation: Centre for Perinatal Brain Research, Institute for Women's Health, University College London, and Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK. o.iwata@orbix.uk.net
authors.forename: Osuke
authors.initials: O
authors.lastname: Iwata
authors.forename: Sachiko
authors.initials: S
authors.lastname: Iwata
authors.forename: John S
authors.initials: JS
authors.lastname: Thornton
authors.forename: Enrico
authors.initials: E
authors.lastname: De Vita
authors.forename: Alan
authors.initials: A
authors.lastname: Bainbridge
authors.forename: Linda
authors.initials: L
authors.lastname: Herbert
authors.forename: Francesco
authors.initials: F
authors.lastname: Scaravilli
authors.forename: Donald
authors.initials: D
authors.lastname: Peebles
authors.forename: John S
authors.initials: JS
authors.lastname: Wyatt
authors.forename: Ernest B
authors.initials: EB
authors.lastname: Cady
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Robertson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000473:pathology / Q000628:therapy*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D009410:Nerve Degeneration / Q000209:etiology* / Q000517:prevention & control*; D011897:Random Allocation; D012720:Severity of Illness Index; D013552:Swine; D013997:Time Factors