This study tests the hypothesis that reoxygenation injury is produced when cardiopulmonary bypass is initiated in immature hypoxemic piglets and that it causes cardiopulmonary dysfunction that can be avoided by intravenous metabolic treatment before and during cardiopulmonary bypass. Of 18 immature Yorkshire-Duroc piglets (aged < 3 weeks), six were anesthetized, instrumented, and observed for 5 hours (control animals). Twelve piglets underwent up to 2 hours of hypoxemia (arterial oxygen tension = 20 to 30 mm Hg) before initiation of reoxygenation on cardiopulmonary bypass. Six received an intravenous metabolic infusion solution (mercaptopropionyl glycine, catalase, aspartate, glutamate, glucose/insulin), which was started before and continued during cardiopulmonary bypass. Hypoxia produced an initial hyperdynamic response (39% increase in cardiac index; p < 0.05) followed by progressive hemodynamic deterioration, necessitating premature initiation of bypass in 8 of 12 hypoxemic piglets (67%). Reoxygenation-induced injury (assessed 30 minutes after cardiopulmonary bypass) was characterized by 39% reduction of stroke work index (p < 0.05), increased myocardial lipid peroxidation (79% increase of conjugated dienes; p < 0.05), 254% increase in pulmonary vascular resistance index (p < 0.05), 22% decrease in static lung compliance (p < 0.05), and 50% decrease in arterial/alveolar oxygen tension ratio (p < 0.05). These reoxygenation changes were avoided by intravenous metabolic treatment. We conclude that the reoxygenation of immature hypoxemic piglets by initiating cardiopulmonary bypass results in cardiopulmonary dysfunction that may increase vulnerability to subsequent ischemia (i.e., aortic crossclamping). The cardiopulmonary reoxygenation changes are preventable by intravenous metabolic treatment before and during cardiopulmonary bypass needed for cardiac repair.