piperidines and Hypoventilation

Smooth emergence or cough prevention is a clinically important concern in patients undergoing laryngomicroscopic surgery (LMS). The purpose of this study was to estimate the effective concentration of remifentanil in 95% of patients (EC95) for the prevention of emergence cough after LMS under propofol anesthesia using the biased coin design (BCD) up-down method.A total of 40 adult patients scheduled to undergo elective LMS were enrolled. Anesthesia induction and maintenance were performed with target-controlled infusion of propofol and remifentanil. Effective effect-site concentration (Ce) of remifentanil in 95% of patients for preventing emergence cough was estimated using a BCD method (starting from 1 ng/mL with a step size of 0.4 ng/mL). Hemodynamic and recovery profiles were observed after anesthesia.According to the study protocol, 20 patients were allocated to receive remifentanil Ce of 3.0 ng/mL, and 20 patients were assigned to receive lower concentrations of remifentanil, from 1.0 to 2.6 ng/mL. Based on isotonic regression with a bootstrapping method, EC95 (95% CI) of remifentanil Ce for the prevention of emergence cough from LMS was found to be 2.92 ng/mL (2.72-2.97 ng/mL). Compared with patients receiving lower concentrations of remifentanil, the incidence of hypoventilation before extubation and extubation time were significantly higher in those receiving remifentanil Ce of 3.0 ng/mL. However, hypoventilation incidence after extubation and staying time in the recovery room were comparable between the 2 groups.Using a BCD method, the EC95 of remifentanil Ce for the prevention of emergence cough was estimated to be 2.92 ng/mL (95% CI: 2.72-2.97 ng/mL) after LMS under propofol anesthesia.

Topics: Adult; Airway Extubation; Anesthesia; Anesthesia Recovery Period; Anesthetics, Intravenous; Cough; Dose-Response Relationship, Drug; Female; Humans; Hypoventilation; Laryngoscopy; Male; Microsurgery; Middle Aged; Piperidines; Propofol; Remifentanil

Rats are most frequently used to fulfill ICH S7A requirements for respiratory safety pharmacology. We hypothesized that the models used to assess respiratory safety pharmacology present different ventilatory responses to bronchoconstriction, bronchodilation and respiratory depression. Respiratory monitoring was performed with head-out plethysmographs for rats, masks for dogs and bias airflow helmets for monkeys. Respiratory rate (RR), tidal volume (TV) and minute volume (MV) were recorded. Forty rats, 18 dogs and 8 monkeys were acclimated to the respiratory monitoring equipment. Animals received saline (IV), albuterol (inhalation), methacholine (IV) and remifentanil (IV). Albuterol increased TV in all species. Methacholine decreased TV and MV in monkeys. In dogs, methacholine increased TV, RR and MV. In rats, methacholine increased TV and decreased RR. Remifentanil induced central respiratory depression in all species with decreased MV, except in rats. Dogs presented a biphasic response to remifentanil with hypoventilation followed by delayed hyperventilation. The monkeys presented similar responses to humans which may be due to biologic similarities. Dogs and rats presented clinically significant ventilatory alterations following positive control drugs. Although, the response to bronchoconstriction in dogs and rats was different from humans, the two species presented ventilatory changes that highlight the potential adverse effect of test articles.

Topics: Albuterol; Animals; Bronchoconstrictor Agents; Bronchodilator Agents; Dogs; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hyperventilation; Hypoventilation; Macaca fascicularis; Male; Methacholine Chloride; Pharmaceutical Preparations; Piperidines; Rats; Remifentanil; Respiration; Respiratory Function Tests; Respiratory Insufficiency; Species Specificity