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The aim of this prospective, animal study was to compare brain tissue oxygen tension (PbtO2) with cerebral near infrared spectroscopy (NIRS) and mixed venous oxygen saturation (SVO2) during venoarterial extracorporeal membrane oxygenation (VA ECMO) in a porcine model. This was accomplished using twelve immature piglets with surgically implanted catheters placed in the superficial cerebral cortex to measure brain PbtO2 and microdialysis metabolites. The NIRS sensor was placed overlying the forehead to measure cerebral regional saturation index (rSO2i) while SVO2 was measured directly from the ECMO circuit. Animals were placed on VA ECMO followed by an initial period of stabilization, after which they were subjected to graded hypoxia and recovery. Our results revealed that rSO2i and SVO2 correlated only marginally with PbtO2 (R2=0.32 and R2=0.26, respectively) while the correlation between rSO2i and SVO2 was significantly stronger (R2=0.59). Cerebral metabolites and rSO2i were significantly altered during attenuation of PbtO2, p<0.05). A subset of animals, following exposure to hypoxia, experienced markedly delayed recovery of both rSO2i and PbtO2 despite rapid normalization of SVO2. Upon further analysis, these animals had significantly lower blood pressure (p=0.001), lower serum pH (p=0.01), and higher serum lactate (p=0.02). Additionally, in this subgroup, rSO2i correlated better with PbtO2 (R2=0.76). These findings suggest that, in our ECMO model, rSO2i and SVO2 correlate reasonably well with each other, but not necessarily with brain PbtO2 and that NIRS-derived rSO2i may more accurately reflect cerebral tissue hypoxia in sicker animals.