Dataset Information

The relationship between the effect-site concentration of propofol and sedation scale in children: a pharmacodynamic modeling study.

ABSTRACT:

Background

Continuous infusion of propofol has been used to achieve sedation in children. However, the relationship between the effect-site concentration (C_e) of propofol and sedation scale has not been previously examined. The objective of this study was to investigate the relationship between the C_e of propofol and the University of Michigan Sedation Scale (UMSS) score in children with population pharmacodynamic modeling.

Methods

A total of 30 patients (aged 3 to 6 years) who underwent surgery under general anesthesia with propofol and remifentanil lasting more than 1 h were enrolled in this study. Sedation levels were evaluated using the UMSS score every 20 s by a 1 μg/mL stepwise increase in the C_e of propofol during the induction of anesthesia. The pharmacodynamic relationship between the C_e of propofol and UMSS score was analyzed by logistic regression with nonlinear mixed-effect modeling.

Results

The estimated C_e50 (95% confidence interval) of propofol to yield UMSS scores equal to or greater than n were 1.84 (1.54-2.14), 2.64 (2.20-3.08), 3.98 (3.66-4.30), and 4.78 (4.53-5.03) μg/mL for n = 1, 2, 3, and 4, respectively. The slope steepness for the relationship of the C_e versus sedative response to propofol (95% confidence interval) was 5.76 (4.00-7.52).

Conclusions

We quantified the pharmacodynamic relationship between the C_e of propofol and UMSS score, and this finding may be helpful to predict the sedation score at the target C_e of propofol in children.

Trial registration

http://www.clinicaltrials.gov (No.: NCT03195686 , Date of registration: 22/06/2017).

SUBMITTER: Jang YE

PROVIDER: S-EPMC8427954 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOptimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines.MethodsA prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10.ResultsA three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 μg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW.ConclusionThis is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.