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      Median Effective Dose of Dexmedetomidine Inducing Bradycardia in Elderly Patients Determined by Up-and-Down Sequential Allocation Method

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          Abstract

          Purpose: When dexmedetomidine is used in elderly patients, high incidence of bradycardia is reported. Given age-related physiological changes in this population, it is necessary to know the safety margin between the loading dose of dexmedetomidine and bradycardia. Therefore, we conducted this study to investigate the median effective dose (ED50) of dexmedetomidine causing bradycardia in elderly patients.

          Methods: Thirty patients with ages over 65 years undergoing elective general surgery were enrolled. The Dixon and Massay sequential method were applied to determine the loading dose of dexmedetomidine, starting from 1.0 µg/kg. The dose for the follow-up subjects increased or decreased according to the geometric sequence with the common ratio 1.2, based on the 'negative' or 'positive' response of the previous subject. Positive mean that the subject developed bradycardia during the test. Hemodynamic data including heart rate and systolic blood pressure were recorded. The level of sedation was assessed with the Observer Assessment of Alertness and Sedation Scale (OAA/S).

          Results: Bradycardia occurred in 13 patients (43.3%). The ED50 of dexmedetomidine causing bradycardia was 1.97 µg/kg (95% CI, 1.53-2.53 µg/kg). OAA/S scores at 10 min after the beginning of the dexmedetomidine infusion and 10 min after the termination of dexmedetomidine administration showed no significant differences between the positive and negative groups ( P > 0.05).

          Conclusion: The ED50 of dexmedetomidine causing bradycardia in our cohort was higher than clinical recommended dose. A higher loading dose appears acceptable for a faster onset of sedation under careful hemodynamic monitoring.

          Trial registration: ChiCTR 15006368.

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          Most cited references29

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          Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

          Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2:α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolized into inactive metabolites by glucuronidation and hydroxylation. A high inter-individual variability in dexmedetomidine pharmacokinetics has been described, especially in the intensive care unit population. In recent years, multiple pharmacokinetic non-compartmental analyses as well as population pharmacokinetic studies have been performed. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Results regarding other covariates remain inconclusive and warrant further research. Although initially approved for intravenous use for up to 24 h in the adult intensive care unit population only, applications of dexmedetomidine in clinical practice have been widened over the past few years. Procedural sedation with dexmedetomidine was additionally approved by the US Food and Drug Administration in 2003 and dexmedetomidine has appeared useful in multiple off-label applications such as pediatric sedation, intranasal or buccal administration, and use as an adjuvant to local analgesia techniques.
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            Early Sedation with Dexmedetomidine in Critically Ill Patients

            Dexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit (ICU). The use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied.
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              Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes.

              Dexmedetomidine (DMED) is a novel clonidine-like compound known to have sedative, analgesic, and cardiovascular stabilizing qualities. DMED is a more highly selective alpha 2-adrenergic agonist than clonidine. This investigation examined the hemodynamic effects of four selected iv doses in consenting healthy male volunteers. In a randomized, double-blind, placebo-controlled trial subjects received 0 (n = 9), 0.25 (n = 6) 0.5 (n = 6), 1.0 (n = 6), or 2.0 (n = 10) micrograms/kg of DMED by infusion (2 min). ECG, heart rate (HR), arterial blood pressure (MABP), bioimpedance cardiac output (CO), and plasma catecholamines concentrations (CA) were monitored from 90 min before to 360 min after infusion. Plasma DMED concentrations were measured. DMED produced a maximum decrease in MABP at 60 min of 14%, 16%, 23%, and 27% for the 0.25, 0.5, 1.0, and 2.0 micrograms/kg groups, respectively (P < .05). At 330 min MABP remained below baseline by 8% and 17% at the two largest doses (P < .05). Both HR and CO decreased maximally by both 17% at 105 min. The two largest doses produced a transient (peak at 3 min lasting < 11 min) increased in MABP (16 +/- 2.5 and 24 +/- 10 mmHg, respectively; P < .05) with a concomitantly reduced CO (41%, 2 micrograms/kg; P < .05) and HR (22%, 2 micrograms/kg; P < .05), whereas systemic vascular resistance doubled. Even the lowest dose decreased CA immediately to values close to 20 pg/ml for 5 h. A 2-min iv infusion of DMED produced a transient increase in MABP and a longer lasting decrease in MABP and CA. These DMED doses were well tolerated in the healthy volunteers.
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                Author and article information

                Journal
                Int J Med Sci
                Int J Med Sci
                ijms
                International Journal of Medical Sciences
                Ivyspring International Publisher (Sydney )
                1449-1907
                2022
                13 June 2022
                : 19
                : 6
                : 1065-1071
                Affiliations
                [1 ]Department of Anesthesiology, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, Shanghai, China.
                [2 ]Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
                Author notes
                ✉ Corresponding authors: Jin-Chao Song, M.D. Department of Anesthesiology, Shidong Hospital of Shanghai, University of Shanghai for Science and Technology, Shiguang Road, No. 999 Shanghai, China. Phone: (86) 21-25066782. E-mail: sjch2013@ 123456163.com ; Yu-Gang Lu, M.D. Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China. E-mail: luyugang@ 123456tongji.edu.cn .

                *These authors contributed equally to this work.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                ijmsv19p1065
                10.7150/ijms.71380
                9254370
                35813293
                c5188992-6cc6-4f14-8e4f-6e5e3d001aac
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 24 January 2022
                : 15 May 2022
                Categories
                Research Paper

                Medicine
                dexmedetomidine,bradycardia,elderly patient,intravenous anaesthesia,adverse effects
                Medicine
                dexmedetomidine, bradycardia, elderly patient, intravenous anaesthesia, adverse effects

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