Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery.
BACKGROUND
To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described.


METHODS
After craniofacial surgery, 22 of the 44 evaluated infants (aged 3-17 months) in the pediatric intensive care unit received propofol (2-4 mg . kg-1 . h-1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD).


RESULTS
In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 . (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index.


CONCLUSIONS
Propofol clearance is two times higher in nonventilated healthy children than reported in the literature for ventilated children and adults. Based on the model, the authors advise a propofol dose of 30 mg/h in a 10-kg infant to achieve values of 12-14 on the COMFORT-Behavior scale and 70-75 on the Bispectral Index during the night. Wide pharmacodynamic variability emphasizes the importance of dose titration.
Peeters
Mariska Y M
MY
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. mym.peters@kf-antoniusmesosgroep.nl
Prins
Sandra A
SA
Knibbe
Catherijne A J
CA
DeJongh
Joost
J
van Schaik
Ron H N
RH
van Dijk
Monique
M
van der Heiden
Ilse P
IP
Tibboel
Dick
D
Danhof
Meindert
M
D003398:Craniosynostoses / Q000601:surgery*; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015742:Propofol / Q000493:pharmacokinetics* / Q000494:pharmacology
D006993:Hypnotics and Sedatives; D015742:Propofol