title: Pharmacokinetics and pharmacodynamics of midazolam and metabolites in nonventilated infants after craniofacial surgery.
abstract: BACKGROUND
  Because information on the optimal dose of midazolam for sedation of nonventilated infants after major surgery is scant, a population pharmacokinetic and pharmacodynamic model is developed for this specific group.
  
  
  METHODS
  Twenty-four of the 53 evaluated infants (aged 3-24 months) admitted to the Pediatric Surgery Intensive Care Unit, who required sedation judged necessary on the basis of the COMFORT-Behavior score and were randomly assigned to receive midazolam, were included in the analysis. Bispectral Index values were recorded concordantly. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD).
  
  
  RESULTS
  For midazolam, total clearance was 0.157 l/min, central volume was 3.8 l, peripheral volume was 30.2 l, and intercompartmental clearance was 0.30 l/min. Assuming 60% conversion of midazolam to 1-OH-midazolam, the volume of distribution for 1-OH-midazolam and 1-OH-midazolamglucuronide was 6.7 and 1.7 l, and clearance was 0.21 and 0.047 l/min, respectively. Depth of sedation using COMFORT-Behavior could adequately be described by a baseline, postanesthesia effect (Emax model) and midazolam effect (Emax model).The midazolam concentration at half maximum effect was 0.58 mum with a high interindividual variability of 89%. Using the Bispectral Index, in 57% of the infants the effect of midazolam could not be characterized.
  
  
  CONCLUSIONS
  In nonventilated infants after major surgery, midazolam clearance is two to five times higher than in ventilated children. From the model presented, the recommended initial dosage is a loading dose of 1 mg followed by a continuous infusion of 0.5 mg/h during the night for a COMFORT-Behavior of 12-14 in infants aged 1 yr. Large interindividual variability warrants individual titration of midazolam in these children.
authors.affiliation: Department of Clinical Pharmacy, St. Antonius Hospital, The Netherlands. r.peeters@antoniusmesosgroep.nl
authors.forename: Mariska Y M
authors.initials: MY
authors.lastname: Peeters
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Prins
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
authors.forename: Joost
authors.initials: J
authors.lastname: Dejongh
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathôt
authors.forename: Celesta
authors.initials: C
authors.lastname: Warris
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000375:Aging / Q000378:metabolism; D001711:Biotransformation; D004569:Electroencephalography / Q000187:drug effects; D005145:Face / Q000601:surgery*; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007223:Infant; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D015203:Reproducibility of Results; D012886:Skull / Q000601:surgery*
chemical_list: D006993:Hypnotics and Sedatives; D008874:Midazolam