Population pharmacokinetics of dexmedetomidine in infants after open heart surgery.
BACKGROUND
Dexmedetomidine is a highly selective alpha(2)-agonist with hypnotic, analgesic, and anxiolytic properties. In adults, it provides sedation while preserving respiratory function facilitating extubation. Only limited pharmacokinetic data are available for pediatric patients. The primary aim of this study was to determine the pharmacokinetics of dexmedetomidine in infants after open heart surgery.


METHODS
We evaluated 36 infants, aged 1 to 24 months, after open heart surgery. Cohorts of 12 infants requiring mechanical ventilation after open heart surgery were enrolled sequentially to 1 of the 3 initial loading dose-continuous IV infusion (CIVI) regimens: 0.35-0.25, 0.7-0.5, or 1-0.75 microg/kg-microg/kg/h. The initial loading dose was administered over 10 minutes immediately postoperatively followed by a CIVI of up to 24 hours. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics.


RESULTS
Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight on drug clearance, intercompartmental clearance, central and peripheral volume of distributions, total bypass time as a covariate on clearance and central volume of distribution, and age and ventricular physiology as covariates on clearance. Infants demonstrated a clearance of 28.1 mL/min/kg(0.75), intercompartmental clearance of 93.4 mL/min/kg(0.75), central volume of distribution of 1.2 L/kg, and peripheral volume of distribution of 1.5 L/kg.


CONCLUSIONS
Dexmedetomidine clearance increased with weight, age, and single-ventricle physiology, whereas total bypass time was associated with a trend toward decreasing clearance, and central volume of distribution increased as a function of total bypass time. The dependence of clearance on body weight supports current practice of weight-based dexmedetomidine dosing, whereas the clinical impact of the remaining covariate effects requires further investigation. Initial loading doses in the range of 0.35 to 1 microg/kg over 10 minutes and CIVI of 0.25 to 0.75 microg/kg/h were well tolerated in this infant population.
Su
Felice
F
Division of Clinical Pharmacology and Therapeutics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Nicolson
Susan C
SC
Gastonguay
Marc R
MR
Barrett
Jeffrey S
JS
Adamson
Peter C
PC
Kang
David S
DS
Godinez
Rodolfo I
RI
Zuppa
Athena F
AF
D000375:Aging / Q000502:physiology; D000465:Algorithms; D006348:Cardiac Surgical Procedures; D015331:Cohort Studies; D003198:Computer Simulation; D016638:Critical Illness; D020927:Dexmedetomidine / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006330:Heart Defects, Congenital / Q000150:complications / Q000601:surgery*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics*; D007223:Infant; D016014:Linear Models; D008297:Male; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D011153:Population; D011237:Predictive Value of Tests; D012449:Safety
D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine