Abstract
Respiratory depression is a common adverse effect of propofol and remifentanil. We aimed to develop a model for respiratory depressant effects of propofol with remifentanil in patients undergoing endoscopy with sedation. Data were available for 136 patients undergoing endoscopy with sedation. Participants randomly received infusions of propofol and remifentanil. Predicted plasma concentrations, outputted by infusion pumps, were available. Transcutaneous arterial pressure of carbon dioxide (pCO2) was measured. Data were analyzed using nonlinear mixed-effects modeling methods. Covariate relationships were investigated for age, noxious stimuli (endoscopy tube insertion), and A118G genotype for the µ-opioid receptor (OPRM1). Participants had a median (range) age of 64.0 (25.0–88.0) years, weight of 70.0 (35.0–98.0) kg, and height of 164.0 (147.0–190.0) cm. Seven percent were recessive homozygous for OPRM1 polymorphism. An indirect-effect model with a “modulator” compartment best described pCO2 data (P < 0.001) over a direct-effect model. Remifentanil inhibited pCO2 removal with an IC50 of 1.13 ng/ml and first-order rate constant (ke0) of 0.28 minute−1. Propofol affected the modulator compartment with an IC50 of 4.97 µg/ml (no effect-site compartment). Propofol IC50 and remifentanil ke0 were reduced with increasing age. Noxious stimuli and genotype were not significant covariates. An indirect-effect model with a rebound mechanism can describe remifentanil- and propofol-induced changes in pCO2 in patients undergoing noxious procedures. The model may be useful for identifying optimal dosing schedules for these drugs in a combination that provides adequate sedation but avoids respiratory depression.
Footnotes
- Received June 18, 2015.
- Accepted December 10, 2015.
Primary laboratory of origin:
The Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (responsible for modeling and analysis)
Systems Pharmacology Effect Control and Modeling (SPEC-M) Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (responsible for study design, conduct and data).
This work was supported by the Hospital CLINIC de Barcelona, Spain [Grant 3664]; the Fondo de Investigaciones Sanitarias, Health Department, Government of Spain [Grants PI/050072, PS09/01209, and FIS PI14/00173]; the Ministerio de Economia y Competitividad [Grant 2010-19273]; the Agència de Gestió d’Ajuts Universitaris i de Recerca [Grant 2009 849]; and the Research Agency of the Government of Colombia, COLCIENCIAS [Grant 297-2015].
This work was previously presented as follows: [Poster] Hannam JA, Trocóniz IF, Borrat X, and Gambús PL (2015) A model for the respiratory effects of remifentanil and propofol during sedation and analgesia. 24th Population Approach Group in Europe Meeting; June 2-5, 2015. Hersonissos, Crete, Greece.
↵This article has supplemental material available at (jpet.aspetjournals.org).
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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