Normobaric hyperoxia improves cerebral blood flow and oxygenation, and inhibits peri-infarct depolarizations in experimental focal ischaemia

Normobaric hyperoxia is under investigation as a treatment for acute ischaemic stroke. In experimental models, normobaric hyperoxia reduces cerebral ischaemic injury and improves functional outcome. The mechanisms of neuroprotection are still debated because, (i) inhalation of 100% O-2 does not significantly increase total blood O-2 content; (ii) it is not known whether normobaric hyperoxia increases O-2 delivery to the severely ischaemic cortex because of its short diffusion distance; and (iii) hyperoxia may reduce collateral cerebral blood flow (CBF) to ischaemic penumbra because it can cause vasoconstriction. We addressed these issues using real-time two-dimensional multispectral reflectance imaging and laser speckle flowmetry to simultaneously and non-invasively determine the impact of normobaric hyperoxia on CBF and oxygenation in ischaemic cortex. Ischaemia was induced by distal middle cerebral artery occlusion (dMCAO) in normoxic (30% inhaled O-2, arterial pO(2) 134 +/- 9 mm Hg), or hyperoxic mice (100% inhaled 02 starting 15 min after dMCAO, arterial pO(2) 312 +/- 10 mm Hg). Post-ischaemic normobaric hyperoxia caused an immediate and progressive increase in oxyhaemoglobin (oxyHb) concentration, nearly doubling it in ischaernic core within 60 min. In addition, hyperoxia improved CBF so that the area of cortex with <= 20% residual CBF was decreased by 45% 60 min after dMCAO. Furthermore, hyperoxia reduced the frequency of peri-infarct depolarizations (PIDs) by more than 60%, and diminished their deleterious effects on CBF and metabolic load. Consistent with these findings, infarct size was reduced by 45% in the hyperoxia group 2 days after 7S min transient dMCAO. Our data show that normobaric hyperoxia increases tissue 02 delivery, and that novel mechanisms such as CBF augmentation, and suppression of PlDs may afford neuroprotection during hyperoxia.