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      Optimal effect-site concentration of remifentanil for preventing cough during removal of the double-lumen endotracheal tube from sevoflurane-remifentanil anesthesia : A prospective clinical trial

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          Abstract

          Opioids are used as a treatment for coughing. Recent studies have reported an antitussive effect of remifentanil during recovery from general anesthesia by suppressed coughing. The coughing reflex may differ throughout the respiratory tract from the larynx to the bronchi. But the proper dose of remifentanil to prevent cough during double-lumen tube (DLT) extubation is unknown.

          Twenty-five ASA physical status 1 and 2 patients, 20 to 65 years of age who were undergoing video-assisted thoracoscopic lung surgery requiring 1-lung ventilation were enrolled. The effective effect-site concentration (Ce) of remifentanil for 50% and 95% of patients (EC 50 and EC 95) for preventing cough was determined using the isotonic regression method with a bootstrapping approach, following the Dixon up-and-down method. Recovery profiles and hemodynamic values after anesthesia were compared between patients with cough and patients without cough.

          EC 50 and EC 95 of remifentanil was 1.670 ng/mL [95% confidence interval (95% CI) 1.393–1.806] and 2.275 ng/mL (95% CI 1.950–2.263), respectively. There were no differences in recovery profiles and hemodynamic values after anesthesia between patients with/without cough. No patients suffered respiratory complications during the emergence period.

          Remifentanil can be a safe and reliable method of cough prevention during emergence from sevoflurane anesthesia after thoracic surgery requiring DLT. EC 50 and EC 95 of remifentanil that suppresses coughing is 1.670 and 2.275 ng/mL, respectively.

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          Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.

          Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short-acting opioid remifentanil. Sixty-five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant-rate infusion of 1 to 8 micrograms.kg-1.min-1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y. The parameters for the simple three-compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were Ke0 = 0.516 min-1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and Ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic-pharmacodynamic model performed better than did the simple model when applied prospectively. This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.
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            Advances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research.

            Sequential design methods for binary response variables exist for determination of the concentration or dose associated with the 50% point along the dose-response curve; the up-and-down method of Dixon and Mood is now commonly used in anesthesia research. There have been important developments in statistical methods that (1) allow the design of experiments for the measurement of the response at any point (quantile) along the dose-response curve, (2) demonstrate the risk of certain statistical methods commonly used in literature reports, (3) allow the estimation of the concentration or dose-the target dose-associated with the chosen quantile without the assumption of the symmetry of the tolerance distribution, and (4) set bounds on the probability of response at this target dose. This article details these developments, briefly surveys current use of the up-and-down method in anesthesia research, reanalyzes published reports using the up-and-down method for the study of the epidural relief of pain during labor, and discusses appropriate inferences from up-and-down method studies.
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              Dose finding using the biased coin up-and-down design and isotonic regression.

              We are interested in finding a dose that has a prespecified toxicity rate in the target population. In this article, we investigate five estimators of the target dose to be used with the up-and-down biased coin design (BCD) introduced by Durham and Flournoy (1994, Statistical Decision Theory and Related Topics). These estimators are derived using maximum likelihood, weighted least squares, sample averages, and isotonic regression. A linearly interpolated isotonic regression estimate is shown to be simple to derive and to perform as well as or better than the other target dose estimators in terms of mean square error and average number of subjects needed for convergence in most scenarios studied.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                June 2016
                17 June 2016
                : 95
                : 24
                : e3878
                Affiliations
                [a ]Department of Anesthesiology and Pain Medicine
                [b ]Office of Biostatistics, Ajou University, School of Medicine, Suwon, Korea.
                Author notes
                []Correspondence: Sung Yong Park, Department of Anesthesiology and Pain Medicine, Ajou University, School of Medicine, 5 Wonchon-Dong, Youngtong-Gu, Suwon 443-721, Korea (e-mail: anepark@ 123456hanmail.net ).
                Article
                03878
                10.1097/MD.0000000000003878
                4998462
                27310976
                12883090-fdd5-428d-8162-bdbae6440a1c
                Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

                History
                : 5 April 2016
                : 9 May 2016
                : 16 May 2016
                Categories
                3300
                Research Article
                Clinical Trial/Experimental Study
                Custom metadata
                TRUE

                anesthesia,complications,extubation trachea,pharmacology,remifentanil

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