A PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATION OF MILRINONE IN ADULTS UNDERGOING CARDIAC-SURGERY

Milrinone can reverse acute postischemic myocardial dysfunction after cardiopulmonary bypass, although neither the appropriate bolus dose nor its pharmacokinetics has been established for cardiac surgical patients. Consenting patients undergoing cardiac surgery received milrinone (25, 50, or 75 mu g/kg) in an open-label, dose-escalating study if their cardiac index was <3 L . min(-1). m(-2) after separation from bypass. Heart rate, mean arterial blood pressure, pulmonary capillary wedge pressure, and cardiac index were determined before and after the administration of milrinone. Timed blood samples were obtained for measurement of milrinone plasma concentrations and pharmacokinetic analysis. Twenty-nine of 60 consenting patients had cardiac indices <3 L . min(-1). m(-2) after separation from bypass, received milrinone, and completed the protocol. All three bolus doses of milrinone significantly increased cardiac index. The 50- and 75-mu g/kg doses produced significantly larger increases in cardiac index than the 25-mu g/kg dose; however, the 75-mu g/kg dose did not produce a significantly larger increase in cardiac index than did the 50-mu g/kg dose. Two of 10 patients receiving milrinone 25 mu g/kg, but no patient receiving either 50 or 75 mu g/kg, required early epinephrine rescue when the cardiac index failed to increase by >15%. The 75-mu g/kg dose was associated with a case of ventricular tachycardia. The three-compartment model better described milrinone drug disposition than the two-compartment model by both visual inspection and Schwartz-Bayesian criterion. There was only limited evidence of dose-dependence, so data from all three doses are reported together (and normalized to the 50-mu g/kg dose). Data from one patient was discarded (samples mislabeled). Using mixed-effects nonlinear regression (for n = 28), the following volumes were determined for the three compartments: V-1 = 11.1 L, V-2 16.9 L, and V-3 = 363 L. Similarly, the following clearances were estimated for the three compartments: Cl-1 0.067 L/min, Cl-2 = 1.05 L/min, and Cl-3 = 0.31 L/min. The 50-mu g/kg loading dose appeared more potent than the 25-mu g/kg dose, and, as potent, but with possibly fewer side-effects than the 75-mu g/kg dose. The short context-sensitive half-times of 6.7 or 10.2 min after 1- or 10-min bolus infusions underscore the need for prompt institution of a maintenance infusion when milrinone concentrations must be maintained. Simulations based on our best drug disposition using this study's variables predict a context-sensitive half-time of 4.9 h for plasma milrinone concentrations after a 50-mu g/kg bolus I-min infusion with an immediate 24-h maintenance infusion of 0.5 mu g . min(-1). kg(-1).