"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 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.
Iwata
Osuke
O
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
Iwata
Sachiko
S
Thornton
John S
JS
De Vita
Enrico
E
Bainbridge
Alan
A
Herbert
Linda
L
Scaravilli
Francesco
F
Peebles
Donald
D
Wyatt
John S
JS
Cady
Ernest B
EB
Robertson
Nicola J
NJ
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