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 no r its pharmacokinetics has been established for cardiac surgical patie nts. Consenting patients undergoing cardiac surgery received milrinone (25, 50, or 75 mu g/kg) in an open-label, dose-escalating study if th eir cardiac index was <3 L . min(-1). m(-2) after separation from bypa ss. Heart rate, mean arterial blood pressure, pulmonary capillary wedg e pressure, and cardiac index were determined before and after the adm inistration of milrinone. Timed blood samples were obtained for measur ement 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 compl eted the protocol. All three bolus doses of milrinone significantly in creased cardiac index. The 50- and 75-mu g/kg doses produced significa ntly larger increases in cardiac index than the 25-mu g/kg dose; howev er, the 75-mu g/kg dose did not produce a significantly larger increas e in cardiac index than did the 50-mu g/kg dose. Two of 10 patients re ceiving milrinone 25 mu g/kg, but no patient receiving either 50 or 75 mu g/kg, required early epinephrine rescue when the cardiac index fai led to increase by >15%. The 75-mu g/kg dose was associated with a cas e of ventricular tachycardia. The three-compartment model better descr ibed milrinone drug disposition than the two-compartment model by both visual inspection and Schwartz-Bayesian criterion. There was only lim ited evidence of dose-dependence, so data from all three doses are rep orted together (and normalized to the 50-mu g/kg dose). Data from one patient was discarded (samples mislabeled). Using mixed-effects nonlin ear 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. Si milarly, the following clearances were estimated for the three compart ments: 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 a fter 1- or 10-min bolus infusions underscore the need for prompt insti tution 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 infusio n with an immediate 24-h maintenance infusion of 0.5 mu g . min(-1). k g(-1).