Objective-To compare the effects of pH-stat and alpha-stat management prior to deep hypothermic circulatory arrest (DHCA) followed by a period of low flow (two rates) cardiopulmonary bypass (CPB) on cortical oxygenation and selected regulatory proteins: Bax, Bcl-2, Caspase-3 and phospho-Akt.Design-Piglets were placed on CPB, cooled with pH-stat or alpha-stat management to 18°C over 30 min, subjected to 30 min DHCA and 1h low flow at 20 (LF-20) or 50 ml/kg/min (LF-50), rewarmed to 37°C, separated from CPB, and recovered for 6 h.Subjects-Newborn piglets, 2-5 days old, randomly assigned to experimental groups.Measurements and main results-Cortical oxygen was measured by oxygen-dependent quenching of phosphorescence; proteins were measured by western blots. The means from 6 experiments ± standard error (SEM) are presented as % of alpha-stat. Significance was by t-test. For LF-20, cortical oxygenation was similar for alpha-stat and pH-stat, whereas for LF-50 it was significantly better using pH-stat. For LF-20, the measured proteins were not different except for Bax in the cortex (214±24%, p=0.006) and hippocampus (118% ± 6%, p=0.024) and Caspase 3 in striatum (126% ± 7%, p=0.019). For LF-50, in pH-stat group: In cortex, Bax and Caspase-3 were lower (72±8%, p=0.001 and 72±10%, p=0.004, respectively) and pAkt was higher (138±12%, p=0.049). In hippocampus, Bcl-2 and Bax were not different but pAkt was higher 212±37% (p=0.005) and Caspase 3 lower (84 ± 4%, p=0.018). In striatum, Bax and pAkt did not differ but Bcl-2 increased (146±11%, p=0.001) and Caspase-3 decreased (81±11%, p=0.042).Conclusions-In this DHCA-LF model, when flow was 20ml/kg/min there was little difference between alpha-stat and pH-stat management. However for LF-50, pH-stat management resulted in better cortical oxygenation during recovery and Bax, Bcl-2, pAkt and Caspase-3 changes consistent with lesser activation of pro-apoptotic signaling with pH-stat than with alpha-stat.