Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock

Objectives: The objectives of this study were to determine the pharmacokinetics of milrinone lactate in pediatric patients with septic shock and to determine whether a relationship exists between steady-state plasma milrinone concentrations and changes in hemodynamic variables. Study design: This was a randomized, double-blind placebo-controlled, interventional study. In study phase 1 patients were randomized and underwent loading and infusion with milrinone lactate (50 mu g/kg, then 0.5 mu g/kg/min), and invasive hemodynamic values were determined. Steady-state was determined by obtaining plasma samples at 30, 15, and 0 minutes before the end of the milrinone infusion. Study phase 2 started when milrinone was discontinued by the patient care team. Steady-state was reaffirmed and plasma samples were obtained at 0.5, 1, 2, 4, 6, and 8 hours after the end of the infusion. Results: The average plasma concentration at steady-state (Css avg) and total body clearance for phase 1 were 81.3 +/- 38.6 ng/ml (mean +/- SD) and 0.0106 +/- 0.0053 L/kg/min, respectively (n = 9). All but two patients underwent reloading with milrinone. In phase 2 Css avg and total body clearance were 65.8 +/- 42.1 ng/ml and 0.0110 +/- 0.0096 L/kg/min, respectively (n = 11). The average time of infusion was 51 +/- 21 hours. Eight patients were evaluated for phase 2 elimination. The mean elimination rate constant was 0.0091 +/- 0.0061 min(-1) (n = 8). The median half-life was 1.47 hours (range, 0.62 to 10.85 hours). All patients had creatinine clearances greater than 61 ml/min/1.73 m(2). The volume of distribution at steady-state was 1.47 +/- 1.03 L/kg. No correlation existed between age and the elimination rate constant or the volume of distribution at steady-state. All patients achieved at least a 20% change in cardiac index and systemic vascular resistance index while maintaining a Css avg of 35 to 160 ng/ml. No adverse effects were noted. All patients achieved primary hemodynamic end points (cardiac index and systemic vascular resistance index) during the milrinone infusion. Conclusions: Loading doses of 75 mu g/kg milrinone lactate and starting infusion rates of 0.75 to 1.0 mu g/kg/min for patients with normal renal function should be used; the infusion rate should then be titrated to effect. We recommend that for every increase of 0.25 mu g/kg/min, a 25 mu g/kg bolus dose be given. Because the median half-life is 1.47 hours, immediate hemodynamic effects may not be seen unless appropriate loading doses and infusion adjustments are made.