The aim of the present study was to assess the veno-arterial difference in pCO2 (delta pCO2) as an indicator of ischemia compared to the arteriovenous O2 difference (AVDO2). Staircase cerebral blood flow (CBF) reductions were obtained in seven domestic pigs by inducing intracranial hypertension: CBF 100%, 50-60% of baseline, 20-30% of baseline. ICP, MAP, CPP and CBF (Laser-Doppler method) were continuously recorded. The superior sagittal sinus was punctured to determine AVDO2 and delta pCO2. AVDO2 was 5.9 (+/- 1.78, range 3.3-7.4), 7.01 (+/- 1.31, range 5-8.9) and 8.17 (+/- 1.51, range 6.0-11.3) ml/100 ml in the three CBF steps (p = 0.001). CBF impairment was accompanied by the following increases in delta pCO2: from 10 (+/- 4, range 4-15) mmHg to 14.5 (+/- 4.11, range 10-27) mmHg, and to 31.2 (+/- 9.0, range 17-39) mmHg (p < 0.001). When CBF declines AVDO2 increases, indicating greater extraction of O2 to satisfy the aerobic metabolism. However, this mechanism can no longer compensate once a critical CBF threshold is reached. delta pCO2 rises slowly during moderate CBF reduction because of defective washout; the rise is impressive during marked CBF impairment when anaerobic metabolism takes place with proton buffering in CO2 and H2O. Therefore, when the brain's ability to compensate for low blood flow is exceeded, CO2 production outweighs O2 extraction.