Population pharmacokinetic-pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents

Abstract

Background: Optimal 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.

Methods: A 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.

Results: A 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.

Conclusion: This 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.

Trial registration: ClinicalTrials.gov NCT00948597.

Keywords: anesthetics i.v.; bariatric; bispectral index; obese; pediatric; pharmacodynamics; pharmacokinetics; propofol; simulation.

© 2015 John Wiley & Sons Ltd.

Figures

Figure 1

Propofol concentration and BIS-time plots for the study cohort. Time 0 is the start of propofol infusion. Panel A shows measured propofol concentrations over time from 26 patients with actual measurements marked by open ended-circles (≈ 14 samples/patient). Panel B represents BIS data in 1-minute increments from 23 subjects in the cohort (≈ 144 data points/patient). BIS data from 3 subjects were excluded from analysis because sevoflurane was used for anesthetic induction in one individual who did not want to have their venous catheter placed while awake (ID: 8); and inability to retrieve all recorded data from the BIS monitor for the remaining two (ID: 3 and 25).

Figure 2

Prediction Corrected Visual Predictive Check of PK (propofol concentrations) and PD (BIS) based on developed PK/PD models. Prediction Corrected Visual Predictive Check is presented as means of simulation diagnostics for the (A) 3-Compartmental PK model and (B) Pharmacokinetic-Pharmacodynamic model. The PK and PK/PD model were simulated n=1000 times and the dependent variable was subject to prediction and variance correction to account of differences due to titrated individual dosing and differences in length of surgery. The darker solid black line represents the median prediction corrected observations and darker dashed black lines present the 5th and 95th percentiles of the prediction corrected observations. Similarly, the thinner solid black line represents the model simulated median values and the thinner dashed black lines present the 5th and 95th percentiles of the same. The shaded grey area in the middle represents 90% confidence interval for the model simulated median values while the lighter shaded grey areas represent the 90% confidence interval for the model simulated 5th/95th percentiles (bottom and top shaded areas). The prediction corrected observations are represented by grey circles. Time after most recent dose/infusion rate change was used as the independent variable.

Figure 3

Predictions of plasma propofol concentrations and BIS, based on simulations using proposed propofol dosing regimen for a representative SO (median age, height and weight from our study) and lean adolescent (50th percentile weight, same height and age). Panel A represents predicted propofol concentrations and Panel B represents BIS values during and after maintenance of propofol anesthesia over a 60 minute period, for a hypothetical obese (Total Body Weight = 130 kg, Adjusted Body Weight = 78.7 kg) and lean (Total Body Weight = 53.4 kg, Adjusted Body Weight = 48.1 kg) female of the same age (15.7 years of age) and height (166 cm). In each panel, median predictions based on our developed PK/PD model for the obese adolescent is given by the black line; the Eleveld-Cortinez PK/PD model based prediction for the obese adolescent is given by the gray colored line, and the lean adolescent is represented by the dotted line. The dosing regimen proposed maintains adequate propofol concentrations and BIS levels in conjunction with either model.