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We studied the cardiovascular and metabolic changes occurring during orthotopic liver transplantation in nine patients. The operative management of these patients can be divided into an initial dissection phase, an anhepatic phase when the hepatic artery, portal vein, and inferior vena cava are cross-clamped, arid the phase after the release of these clamps. On clamping the inferior vena cava, the systolic arterial pressure decreased from 134 ± 9 to 104 ± 8 mm Hg, the pulmonary artery pressure decreased from 25 ± 4 to 17 ± 4 mm Hg, the mean pulmonary wedge pressure decreased from 11.9 ± 1.9 to 6.8 ± 1.2 mm Hg, and cardiac index decreased from 5.3 ± 0.3 to 2.7 ± 0.2 L·min−1·m−2. There were compensatory increases in systemic vascular resistance from 806 ± 52 to 1448 ± 109 dyne·cm·sec−5 and in pulmonary vascular resistance from 78 ± 13 to 122 ± 25 dyne·cm·sec−5. Removal of these clamps was followed by an initial depression in cardiac output that returned to preclamping values. Profound metabolic alterations were encountered during these phases. Hydrogen ion concentration increased from a mean of 39 ± 2 to 45 ± 2 nmol/L during cross-clamping, with a further increase to 55 ± 3 nmol/L after the initial perfusion of the new liver. Serum potassium levels increased significantly only on release of the clamps, from a mean of 3.8 ± 0.3 to a peak of 5.3 ± 0.6 mmol. With the reduction in pulmonary blood flow during the period of caval clamping, the endtidal arterial carbon dioxide difference increased. These changes were independent of minute ventilation and returned to control levels by the end of the procedure. Blood glucose levels increased throughout initial stages of the operation from 12 ± 2 to 26 ± 3 mmol/L, but decreased by the end of surgery to 22 ± 2 mmol/L. These changes were due to a combination of hemodynamic effects of inferior cava clamping and the biochemical consequence of the introduction of the preserved liver into the circulation.