The aim of this prospective, animal study was to compare brain tissue oxygen tension (PbtO(2)) with cerebral near infrared spectroscopy (NIRS) and mixed venous oxygen saturation (SVO(2)) 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 PbtO(2) and microdialysis metabolites. The NIRS sensor was placed overlying the forehead to measure cerebral regional saturation index (rSO(2)i) while SVO(2) 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 rSO(2)i and SVO(2) correlated only marginally with PbtO(2) (R(2)=0.32 and R(2)=0.26, respectively) while the correlation between rSO(2)i and SVO( 2) was significantly stronger (R(2)=0.59). Cerebral metabolites and rSO(2)i were significantly altered during attenuation of PbtO( 2), p<0.05). A subset of animals, following exposure to hypoxia, experienced markedly delayed recovery of both rSO(2)i and PbtO( 2) despite rapid normalization of SVO(2). 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, rSO(2)i correlated better with PbtO(2) (R(2)=0.76). These findings suggest that, in our ECMO model, rSO(2)i and SVO( 2) correlate reasonably well with each other, but not necessarily with brain PbtO(2) and that NIRS-derived rSO(2)i may more accurately reflect cerebral tissue hypoxia in sicker animals.