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Pharmacokinetics and Pharmacodynamics of Midazolam and Metabolites in Nonventilated Infants after Craniofacial Surgery

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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 μm with a high interindividual variability of 89%. Using the Bispectral Index, in 57% of the infants the effect of midazolam could not be characterized.

Conclusion:

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.

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