In adults, exposure to prolonged hypercarbia results in a normalization of the extravascular brain pH associated with a reduction in brain blood flow (BBF). Following prolonged hypercarbia, sudden normalization of the arterial PCO2also produces a change in the extravascular brain pH to an alkaline state, resulting in a marked decrease in BBF. We examined these physiologic phenomena in newborn subjects by exposing seven awake, spontaneously breathing newborn piglets to 4 h of sustained hypercarbia (PaCO2: 60-70 mm Hg) followed by a 45-min normocarbic period. Total and regional BBF, cardiac output (radionuclide-labeled microsphere method), arterial blood pressure, plasma catecholamine and lactate concentrations, blood gases, oxygen contents, and hematocrits were measured during a baseline period, at V2, 2, and 4 h of sustained hypercarbia and V* and 3A h following an abrupt onset of normocarbia. The initial 2.5-fold increase in total BBF during hypercarbia persisted for 2 h and at 4 h decreased significantly below the level of the 30-min hypercarbic measurement, although the values still remained 2-fold above the baseline values. Brain tissue pH was reduced at the onset of hypercarbia, remaining unchanged throughout the hypercarbic period. Both total BBF and brain tissue pH returned to baseline values following the return to normocarbia. Changes in regional BBF were similar to that of total BBF with the exception of the boundary zone (periventricular area in the frontoparietal region of the cerebrum, adjacent to the caudate nucleus) and the parietal area (site of the brain tissue pH electrode), where a significant decrease from the peak hyperemia was not observed. Choroid plexus blood flow demonstrated a small initial increase over normocarbic baseline values. Plasma bicarbonate concentrations did not change during the studies. Following the onset of hypercarbia, heart rate and cardiac output increased significantly whereas plasma lactate concentrations decreased significantly. There was also an increase in the percentage of cardiac output distributed to the brain. The increase in cardiac output persisted throughout the hypercarbic period and returned to baseline levels during normocarbia. Mean arterial blood pressure increased significantly at the 4-h hypercarbic period and this increase persisted during normocarbia. We conclude that in newborn piglets 1) hypercarbia resulted in cerebral hyperperfusion, accompanied by marked fall in brain tissue