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Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery
C Ramamoorthy1, G D Anderson, G D Williams
1Department of Anesthesiology, University of Washington School of Medicine, Seattle, USA. chandra@u.washington.edu
Insights
Milrinone pharmacokinetics in pediatric cardiac surgery patients showed faster clearance and larger distribution volumes than in adults. Dosing adjustments are recommended due to differing infant and child kinetics, with thrombocytopenia being a key side effect.
Area of Science:
- Pediatric Cardiology
- Pharmacokinetics
- Critical Care Medicine
Background:
- Pediatric dosing of medications like milrinone often relies on adult data.
- Infants and children exhibit distinct pharmacokinetic profiles compared to adults.
- Understanding milrinone's behavior in pediatric patients undergoing cardiac surgery is crucial for effective treatment.
Purpose of the Study:
- To investigate the pharmacokinetics and side effects of milrinone in infants and children after open heart surgery.
- To evaluate milrinone binding to cardiopulmonary bypass (CPB) circuitry.
- To compare milrinone kinetics in pediatric patients with established adult data.
Main Methods:
- Prospective, open-label study involving two milrinone dosing groups (small and large dose).
- Blood samples collected at multiple time points to determine milrinone concentrations.
- Pharmacokinetic analysis using traditional and nonlinear mixed effects modeling, including a two-compartment model.
Main Results:
- Steady-state plasma levels were within the adult therapeutic range for both dose groups.
- Infants showed significantly lower milrinone clearance (3.8 mL/kg/min) compared to children (5.9 mL/kg/min).
- Thrombocytopenia occurred in 58% of patients, with risk increasing with infusion duration; no milrinone binding to CPB circuitry was observed.
Conclusions:
- Milrinone exhibits different pharmacokinetic properties in infants and children compared to adults, including a larger volume of distribution and faster clearance.
- Pediatric dosing of milrinone requires adjustment to account for these age-related kinetic differences.
- Thrombocytopenia is a significant complication associated with milrinone use in this population.
Unlabelled:
We investigated the pharmacokinetics and side effects of milrinone in infants and children (< or = 13 yr) after open heart surgery in this prospective, open-label study. Milrinone binding to cardiopulmonary bypass (CPB) circuitry was also examined in out two groups. Children in the small dose group (n = 11) received two 25-microg/kg boluses with a final infusion rate of 0.5 microg kg(-1) x min(-1); those in the large dose group (n = 8) received a 50-microg/kg bolus and a 25-microg/kg bolus with a final infusion rate of 0.75 microg x kg(-1) x min(-1). Blood samples for milrinone concentration were drawn 30 min after each bolus, at steady state, and after discontinuing the milrinone infusion. Pharmacokinetics were evaluated using traditional and nonlinear mixed effects modeling analysis. Milrinone kinetics best fit a two-compartment model. Steady-state plasma levels in the small and large dose groups were within the adult therapeutic range (113 +/- 39 and 206 +/- 74 ng/mL, respectively). The volumes of distribution (Vbeta) in infants (0.9 L/kg) and children (0.7 L/kg) were not different, but infants had significantly lower milrinone clearance (3.8 vs 5.9 mL x kg(-1) x min(-1)). Thrombocytopenia (defined as platelet count < or = 100,000 mm(-3)) occurred in 58%, and the risk increased significantly with duration of infusion. Tachyarrythmias were noted in two patients. Milrinone did not bind to CPB circuitry. We conclude that milrinone is cleared more rapidly in children than in adults. The major complication was thrombocytopenia.
Implications:
Most pediatric dosing is based on data published for adults. Infants and children have kinetics that differ from adults. We studied the distribution of I.V. milrinone in infants and children after open heart surgery. Milrinone had a larger volume of distribution and a faster clearance in infants and children than in adults, and dosing should be adjusted accordingly.