title: Modeling Respiratory Depression Induced by Remifentanil and Propofol during Sedation and Analgesia Using a Continuous Noninvasive Measurement of pCO2.
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 (ke 0) 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 ke 0 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.
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Hannam
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Borrat
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: José F
authors.initials: JF
authors.lastname: Valencia
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: Erik W
authors.initials: EW
authors.lastname: Jensen
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: Angela
authors.initials: A
authors.lastname: Pedroso
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: Jenifer
authors.initials: J
authors.lastname: Muñoz
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellví-Bel
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.).
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain (J.A.H., I.F.T.); Department of Anaesthesiology, School of Medicine, University of Auckland, Auckland, New Zealand (J.A.H.); Systems Pharmacology Effect Control and Modeling Research Group, Department of Anesthesia, Hospital CLINIC de Barcelona, Barcelona, Spain (X.B., J.F.V., A.P., P.L.G.); Electronic Engineering Program, School of Engineering. Universidad de San Buenaventura, Cali, Colombia (J.F.V.); Centre for Biomedical Engineering Research, Universitat Politècnica de Catalunya, Barcelona, Spain (E.W.J.); Gastroenterology Department, Hospital CLINIC, CIBERehd, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (J.M., S.C.-B., A.C.); Department of Anesthesia and Perioperative Care, University of California, San Francisco, California (P.L.G.); and Neuroimmunology Research Group, Institut d'investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (P.L.G.) plgambus@hospitalclinic.org.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Gambús
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000009:adverse effects; D001785:Blood Gas Monitoring, Transcutaneous / Q000379:methods; D002245:Carbon Dioxide / Q000097:blood*; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D016343:Monitoring, Intraoperative / Q000379:methods*; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D015742:Propofol / Q000008:administration & dosage* / Q000009:adverse effects; D000077208:Remifentanil; D012131:Respiratory Insufficiency / Q000097:blood* / Q000139:chemically induced / Q000175:diagnosis
chemical_list: D000701:Analgesics, Opioid; D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; D010880:Piperidines; D002245:Carbon Dioxide; D000077208:Remifentanil; D015742:Propofol