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

Young-Eun Jang, Sang-Hwan Ji, Ji-Hyun Lee, Eun-Hee Kim, Jin-Tae Kim, Hee-Soo Kim, Young-Eun Jang, Sang-Hwan Ji, Ji-Hyun Lee, Eun-Hee Kim, Jin-Tae Kim, Hee-Soo Kim

Abstract

Background: Continuous infusion of propofol has been used to achieve sedation in children. However, the relationship between the effect-site concentration (Ce) of propofol and sedation scale has not been previously examined. The objective of this study was to investigate the relationship between the Ce 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 Ce of propofol during the induction of anesthesia. The pharmacodynamic relationship between the Ce of propofol and UMSS score was analyzed by logistic regression with nonlinear mixed-effect modeling.

Results: The estimated Ce50 (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 Ce versus sedative response to propofol (95% confidence interval) was 5.76 (4.00-7.52).

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

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

Keywords: Anesthesia; Anesthetics; Pharmacodynamics; Pharmacokinetics; Sedation.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
UMSS score vs Ce of propofol. This figure shows a scattered plot of observation of the University of Michigan Sedation Scale (UMSS) score versus effect-site concentration (Ce) of propofol
Fig. 2
Fig. 2
Estimation of probabilities of UMSS score. 2A depicts the estimation of the probability that the University of Michigan Sedation Scale (UMSS) score is n or more (n = 1, 2, 3, 4) according to the effect-site concentration (Ce) of propofol. Probabilities were calculated for Ce50UMSS ≥ n with a pharmacodynamic model using the Laplace method. 2B shows the probability for each specific UMSS score according to Ce of propofol. Detailed calculation methods are presented in the methods section. The probabilities for UMSS scores = 1, 2, and 3 show a single peak, and the probability of UMSS score = 4 shows a gradual increase as the Ce of propofol increases. Ce50UMSS ≥ n, the steady-state effect-site concentration of propofol with a 50% probability of UMSS score being equal to or greater than n
Fig. 3
Fig. 3
Observed vs predicted distribution of UMSS. The proportions of each observed and predicted University of Michigan Sedation Scale (UMSS) score according to the range of the effect-site concentration (Ce) of propofol are shown. 3A is for observed and 3B is for predicted UMSS score. The predicted UMSS score was determined as the score with the highest probability for a given Ce of propofol. Each section of Ce is set such that the values rounded from the first decimal place are included in the same section
Fig. 4
Fig. 4
Comparison of predicted Ce of propofol between models. Bland-Altman plots showing the agreement between the estimation of Ce of propofol by the Kim and Choi’s model, and Ce of propofol by the Kataria model (4A) and by the Paedfusor model (4B). The differences were obtained by subtracting predictions by the Kataria model or the Paedfusor model from predictions by the Kim and Choi’s model. Lines for 95% limits of agreements were drawn

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