Pharmacokinetic–pharmacodynamic model for propofol for broad application in anaesthesia and sedation

Eleveld, Douglas J.; Colin, Pieter; Absalom, Anthony; Struys, Michel

doi:10.1016/j.bja.2018.01.018

Cited by 177 publications

(198 citation statements)

References 46 publications

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“…Eleven individuals representing a distribution of ages from 37 weeks PMA to 3 years (Table ) were taken from an existing data base . Propofol plasma concentrations were simulated for each of these individuals based on their covariates (age, weight, height, fat‐free mass) using the pharmacokinetic parameter set published by Eleveld and colleagues . The Steur regimen recommended a 3‐5 mg.kg −1 induction dose.…”

Section: Methodsmentioning

confidence: 99%

“…A pharmacokinetic‐pharmacodynamic (PKPD) parameter set that is theoretically applicable to neonates, infants and children, has recently been published by Eleveld and colleagues . The authors analyzed propofol PK data and BIS data from 1033 patients of a wide age range (27 weeks postmenstrual age to 88 years) with data obtained from 30 published studies.…”

Section: Introductionmentioning

confidence: 99%

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A manual propofol infusion regimen for neonates and infants

Morse

Hannam

Cortínez

et al. 2019

Pediatric Anesthesia

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Aims Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3 years undergoing anesthesia. We assessed the performance of these regimens using reported age‐specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens. Methods Simulations using a reported general purpose pharmacokinetic propofol model were used to predict propofol blood plasma concentrations during manual infusion regimens recommended for children 0‐3 years. Simulated steady state concentrations were 6‐8 µg.mL−1 in the first 30 minutes that were not sustained during 100 minutes infusions. Pooled clinical data (n = 161, 1902 plasma concentrations) were used to determine an alternative pharmacokinetic parameter set for propofol using nonlinear mixed effects models. A new manual infusion regimen for propofol that achieves a steady‐state concentration of 3 µg.mL−1 was determined using a heuristic approach. Results A manual dosing regimen predicted to achieve steady‐state plasma concentration of 3 µg.mL−1 comprised a loading dose of 2 mg.kg−1 followed by an infusion rate of 9 mg.kg−1.h−1 for the first 15 minutes, 7 mg.kg−1.h−1 from 15 to 30 minutes, 6 mg.kg−1.h−1 from 30 to 60 minutes, 5 mg.kg−1.h−1 from 1 to 2 hours in neonates (38‐44 weeks postmenstrual age). Dose increased with age in those aged 1‐2 years with a loading dose of 2.5 mg.kg−1 followed by an infusion rate of 13 mg.kg−1.h−1 for the first 15 minutes, 12 mg.kg−1.h−1 from 15 to 30 minutes, 11 mg.kg−1.h−1 from 30 to 60 minutes, and 10 mg.kg−1.h−1 from 1 to 2 hours. Conclusion Propofol clearance increases throughout infancy to reach 92% that reported in adults (1.93 L.min.70 kg−1) by 6 months postnatal age and infusion regimens should reflect clearance maturation and be cognizant of adverse effects from concentrations greater than the target plasma concentration. Predicted concentrations using a published general purpose pharmacokinetic propofol model were similar to those determined using a new parameter set using richer neonatal and infant data.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A manual propofol infusion regimen for neonates and infants

Morse

Hannam

Cortínez

et al. 2019

Pediatric Anesthesia

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“…These neonates were all sedated using propofol as part of an INSURE (intubation, surfactant, and extubation) procedure. The neonates are characterized by median (range) postmenstrual ages (PMA) of 30 (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) weeks and a median (range) dose of propofol (Diprivan 1%; AstraZeneca, Brussels, Belgium) of 1.0 (0.5-4.5) mg·kg −1 . In the present analysis, the neonates are stratified into three groups, based on PMA, since this is a major covariate of propofol clearance in the absence of variability in postnatal age (PNA) [24].…”

Section: Datasetmentioning

confidence: 99%

“…Propofol is a threecompartment drug, characterized by a short α and β (median estimates of 1 and 13 minutes, resp.) and a long γ half-life (median estimate of 350 minutes) [26,27]. The pharmacodynamic effects are primarily associated with the first (α) and second (β) exponential half-life, which indicates that the effect of propofol at the end of the analysis window is minimal.…”

Section: Datasetmentioning

confidence: 99%

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Using Graph Theory to Assess the Interaction between Cerebral Function, Brain Hemodynamics, and Systemic Variables in Premature Infants

et al. 2018

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Graphs can be used to describe a great variety of real-world situations and have therefore been used extensively in different fields. In the present analysis, we use graphs to study the interaction between cerebral function, brain hemodynamics, and systemic variables in premature neonates. We used data from a propofol dose-finding and pharmacodynamics study as a model in order to evaluate the performance of the graph measures to monitor signal interactions. Concomitant measurements of heart rate, mean arterial blood pressure, arterial oxygen saturation, regional cerebral oxygen saturation-measured by means of near-infrared spectroscopy-and electroencephalography were performed in 22 neonates undergoing INSURE (intubation, surfactant administration, and extubation). The graphs used to study the interaction between these signal modalities were constructed using the RBF kernel. Results indicate that propofol induces a decrease in the signal interaction up to 90 minutes after propofol administration, which is consistent with clinical observations published previously. The clinical recovery phase is mainly determined by the EEG dynamics, which were observed to recover much slower compared to the other modalities. In addition, we found a more pronounced loss in cerebral-systemic interactions with increasing propofol dose.

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The Drug Titration Paradox: Correlation of More Drug With Less Effect in Clinical Data

Schnider

Minto

Filipovic

2021

Clin Pharma and Therapeutics

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While analyzing clinical data where an anesthetic was titrated based on an objective measure of drug effect, we observed paradoxically that greater effect was associated with lesser dose. With this study we sought to find a mathematical explanation for this negative correlation between dose and effect, to confirm its existence with additional clinical data, and to explore it further with Monte Carlo simulations. Automatically recorded dosing and effect data from more than 9,000 patients was available for the analysis. The anesthetics propofol and sevoflurane and the catecholamine norepinephrine were titrated to defined effect targets, i.e., the processed electroencephalogram (Bispectral Index, BIS) and the blood pressure. A proportional control titration algorithm was developed for the simulations. We prove by deduction that the average dose-effect relationship during titration to the targeted effect will associate lower doses with greater effects. The finding of negative correlations between propofol and BIS, sevoflurane and BIS, and norepinephrine and mean arterial pressure confirmed the titration paradox. Monte Carlo simulations revealed two additional factors that contribute to the paradox. During stepwise titration toward a target effect, the slope of the dose-effect data for the population will be "reversed," i.e., the correlation between dose and effect will not be positive, but will be negative, and will be "horizontal" when the titration is "perfect." The titration paradox must be considered whenever data from clinical titration (flexible dose) studies are interpreted. Such data should not be used naively for the development of dosing guidelines.

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Pharmacokinetic–pharmacodynamic model for propofol for broad application in anaesthesia and sedation

Abstract: We developed a PK-PD model to predict the propofol concentrations and BIS for broad, diverse population. This should be useful for TCI in anaesthesia and sedation.

Cited by 177 publications

References 46 publications

A manual propofol infusion regimen for neonates and infants

A manual propofol infusion regimen for neonates and infants

Using Graph Theory to Assess the Interaction between Cerebral Function, Brain Hemodynamics, and Systemic Variables in Premature Infants

The Drug Titration Paradox: Correlation of More Drug With Less Effect in Clinical Data

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