title: Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 microg/kg, then 0.5 microg/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 m2. 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 microg/kg milrinone lactate and starting infusion rates of 0.75 to 1.0 microg/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 microg/kg/min, a 25 microg/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.
authors.affiliation: Division of Pediatric Critical Care, University of Texas Southwestern Medical Center and Children's Medical Center of Dallas, 75235-9063, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Lindsay
authors.forename: P
authors.initials: P
authors.lastname: Barton
authors.forename: S
authors.initials: S
authors.lastname: Lawless
authors.forename: L
authors.initials: L
authors.lastname: Kitchen
authors.forename: A
authors.initials: A
authors.lastname: Zorka
authors.forename: J
authors.initials: J
authors.lastname: Garcia
authors.forename: A
authors.initials: A
authors.lastname: Kouatli
authors.forename: B
authors.initials: B
authors.lastname: Giroir
mesh_terms: D000293:Adolescent; D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007223:Infant; D020105:Milrinone; D011446:Prospective Studies; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology; D014665:Vasodilator Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002316:Cardiotonic Agents; D011728:Pyridones; D014665:Vasodilator Agents; D020105:Milrinone