BACKGROUND Posttransplantation lung reperfusion injury continues to be a major problem. We have shown that controlling the initial period of reperfusion limits this injury after 2 hours of warm lung ischemia. The effectiveness of this modality, however, is unknown after longer periods of cold ischemia, which more closely mimics the clinical situation. METHODS After baseline measurements, 10 pigs had the left lung flushed with a modified Euro-Collins solution, explanted, stored at 4 degrees C for 24 hours, and transplanted into 10 other pigs. Five (group 1) underwent uncontrolled reperfusion created by removal of the vascular clamps after implantation of the new left lung, mimicking the clinical situation. The other five (group 2) underwent controlled reperfusion, which we performed by taking blood from the femoral artery, mixing it with a crystalloid solution (using a mixer heater) to make the blood hyperosmolar, alkalotic, and substrate-enriched, and pumping it through a leukocyte-depleting filter into the transplanted lung for 10 minutes at a pressure of 20 to 30 mm Hg before removing the pulmonary artery clamp. The right pulmonary artery and bronchus were then ligated, and left lung function was assessed each hour for 4 hours and compared with baseline. RESULTS Controlled reperfusion (group 2) minimized the reperfusion injury, preserving posttransplant pulmonary compliance (92% +/- 1% versus 68% +/- 1%; p < 0.001), reducing the rise in pulmonary vascular resistance (27% +/- 2% versus 166% +/- 3%; p < 0.001), improving oxygenation (PO2, 425 +/- 14 versus 82 +/- 11 mm Hg; p < 0.001), and lowering myeloperoxidase activity (0.22 +/- 0.02 versus 0.45 +/- 0.02 deltaOD/mg protein per minute; p < 0.001) and tissue edema (83.0% +/- 0.3% versus 84.9% +/- 0.3%; p < 0.001) compared with uncontrolled reperfusion, which resulted in an injury so severe that 3 of 5 pigs died before the 4-hour measurements. CONCLUSIONS After 24 hours of cold ischemia uncontrolled reperfusion results in a severe pulmonary reperfusion injury. This injury is almost completely avoided by controlling the composition (modified solution and white blood cell filter) and conditions (pressure) of the reperfusion. Because this experiment mimics the clinical situation, it suggests surgeons should begin to use this modality to limit reperfusion injury after lung transplantation.