RT Journal Article SR Electronic T1 Modeling Respiratory Depression Induced by Remifentanil and Propofol during Sedation and Analgesia Using a Continuous Noninvasive Measurement of pCO2 JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 563 OP 573 DO 10.1124/jpet.115.226977 VO 356 IS 3 A1 Jacqueline A. Hannam A1 Xavier Borrat A1 Iñaki F. Trocóniz A1 José F. Valencia A1 Erik W. Jensen A1 Angela Pedroso A1 Jenifer Muñoz A1 Sergi Castellví-Bel A1 Antoni Castells A1 Pedro L. Gambús YR 2016 UL http://jpet.aspetjournals.org/content/356/3/563.abstract AB 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.