Psychomotor Recovery Following Remimazolam-induced Sedation and the Effectiveness of Flumazenil as an Antidote

Chen, Xia; Sang, Nuoer; Song, Kaicheng; Zhong, Wen; Wang, Hongyun; Jiang, Ji; Huang, Yuguang; Hu, Pei

doi:10.1016/j.clinthera.2020.02.006

Cited by 72 publications

(69 citation statements)

References 24 publications

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“…The pharmacokinetics of remimazolam were linear with dose, and its systemic clearance of 70.3 L/h was approximately three times that seen with midazolam. The steady-state volume of distribution was 88.1 L, terminal half-life 0.75 h, and mean residence time 0.51 h. Phase I single ascending dose trials of remimazolam besylate ( Doi, 2014 ; Sheng et al, 2020 ) and remimazolam tosylate ( Chen et al, 2020b ) in Japanese and Chinese subjects report a similar profile to the initial phase I study with linear pharmacokinetics, high clearance, and short half-life. Pharmacokinetic analysis of remimazolam besylate administered by continuous infusions has been reported from volunteer studies ( Sheng et al, 2020 ; Schüttler et al, 2020 ).…”

Section: Remimazolammentioning

confidence: 82%

“…Analysis of the pharmacokinetics of the acid metabolite, CNS 7054, has usually been conducted simultaneously with that of remimazolam. A profile of a small volume of distribution together with a longer mean residence time and slower clearance compared to remimazolam is routinely reported in man and large animals ( Mutter et al, 2006 ; Upton et al, 2010 ; Antonik et al, 2012 ; Pesic et al, 2020b ; Pesic et al, 2020a ; Schüttler et al, 2020 ; Sheng et al, 2020 ; Chen et al, 2020b ). For example, Antonik et al ( Antonik et al, 2012 ) report an apparent clearance of 4.22 L/h, a volume of distribution of 17.5 L, a half-life of 2.89 h, and a mean residence time of 3.6–5.1 h. The pharmacokinetics of CNS 7054 has been reported to fit best to a two-compartment model in sheep ( Upton et al, 2010 ) and man (with a transit compartment to account for metabolite formation) ( Schüttler et al, 2020 ).…”

Section: Remimazolammentioning

confidence: 99%

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Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Kilpatrick¹

2021

Front. Pharmacol.

128

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A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990’s by Glaxo Wellcome. The program focussed on the identification of ester-based benzodiazepine derivatives that are rapidly broken down by esterases. Remimazolam was identified as one of the lead compounds. The project at Glaxo was shelved for strategic reasons at the late lead optimization stage. Via the GSK ventures initiative, the program was acquired by the small biotechnology company, TheraSci, and, through successive acquisitions, developed as the besylate salt at CeNeS and PAION. The development of remimazolam besylate has been slow by industry standards, primarily because of the resource limitations of these small companies. It has, however, recently been approved for anesthesia in Japan and South Korea, procedural sedation in the United States, China, and Europe, and for compassionate use in intensive care unit sedation in Belgium. A second development program of remimazolam was later initiated in China, using a slightly different salt form, remimazolam tosylate. This salt form of the compound has also recently been approved for procedural sedation in China. Remimazolam has the pharmacological profile of a classical benzodiazepine, such as midazolam, but is differentiated from other intravenous benzodiazepines by its rapid conversion to an inactive metabolite resulting in a short onset/offset profile. It is differentiated from other intravenous hypnotic agents, such as propofol, by its low liability for cardiovascular depression, respiratory depression, and injection pain. The benzodiazepine antagonist flumazenil can reverse the effects of remimazolam in case of adverse events and further shorten recovery times. The aim of this review is to provide an analysis of, and perspective on, published non-clinical and clinical information on 1) the pharmacology, metabolism, pharmacokinetics, and pharmacodynamic profile of remimazolam, 2) the profile of remimazolam compared with established agents, 3) gaps in the current understanding of remimazolam, 4) the compound’s discovery and development process and 5) likely future developments in the clinical use of remimazolam.

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Section: Remimazolammentioning

confidence: 82%

Section: Remimazolammentioning

confidence: 99%

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Kilpatrick¹

2021

Front. Pharmacol.

128

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“…Remimazolam has the advantages of rapid onset, a short elimination half-life, and drug metabolism that is independent of liver and kidney function [23]; moreover, it has a speci c antagonist, namely, umazenil [24]. Compared with midazolam, remimazolam provides effective procedural sedation, and the success rate and recovery rate are higher than those of midazolam.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Remimazolam Besylate Versus Propofol during Hysteroscopy: Single‐centre Randomized Controlled Trial

Zhang¹,

Li²,

Liu³

2021

Preprint

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Background: Remimazolam besylate is a new type of benzodiazepine that has the characteristics of quick effects, short maintenance and recovery times, and no accumulation. Compound opioids can have a sedative effect in some endoscopic examinations. This trial was conducted to confirm the efficacy and safety of remimazolam besylate versus propofol during hysteroscopy.Methods: Patients undergoing hysteroscopy were randomly assigned to either the remimazolam (Group R, n=41) or the propofol group (Group P, n=41). Group R was administered an induction dosage of 0.2 mg/kg/min and a maintenance dosage of 1 mg/kg/h. Group P was started at 1.5-2.0 mg/kg propofol for up to 60-100 s and then maintained at 3.0-6.0 mg/kg/h. In both groups, remifentanil was infused using a target-controlled infusion system with a target concentration of 1.5 ng/ml and titrated during the procedure. The incidence rates of body movement and various adverse events in both groups were compared.Results: Eighty-two patients were included in this study. The incidence of adverse events in Group R (8.5%) was significantly lower than that in Group P (36.6%) (P < 0.05). Injection pain, postoperative dizziness and low SpO2 were the most common adverse events (P < 0.05). Compared with Group P patients, Group R patients recovered faster, had a shorter residence time in the PACU, and exhibited a higher quality of recovery (P < 0.05).Conclusion: Remimazolam besylate can provide safe and effective sedation for hysteroscopy. The depth of sedation is sufficient and effective, and the quality of recovery is high. Moreover, adverse events such as haemodynamic fluctuation, excessive sedation depth, low SpO2 and injection pain caused by propofol are largely avoided.Trial registrationThis study was approved by the Clinical Research Ethics Committee of Mengcheng County No.1 People's Hospital (2020MYL20003) and registered at http:// www.chictr.org.cn (15/09/2020, ChiCTR-2000038252). The study protocol is performed in the relevant guidelines.

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“…Effective communication between the patient and medical personnel during recovery is crucial. Administration of flumazenil after remimazolam allows rapid psychomotor recovery from sedation [14], even in patients with muscular dystrophy [15]. The administration of flumazenil after remimazolam anesthesia may be useful to assist in achieving good communication with hearing impaired patients.…”

Section: Discussionmentioning

confidence: 99%

General anesthesia with remimazolam in a patient with mitochondrial encephalomyopathy: a case report

2021

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Background Systemic anesthetic management of patients with mitochondrial disease requires careful preoperative preparation to administer adequate anesthesia and address potential disease-related complications. The appropriate general anesthetic agents to use in these patients remain controversial. Case presentation A 54-year-old woman (height, 145 cm; weight, 43 kg) diagnosed with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes underwent elective cochlear implantation. Infusions of intravenous remimazolam and remifentanil guided by patient state index monitoring were used for anesthesia induction and maintenance. Neither lactic acidosis nor prolonged muscle relaxation occurred in the perioperative period. At the end of surgery, flumazenil was administered to antagonize sedation, which rapidly resulted in consciousness. Conclusions Remimazolam administration and reversal with flumazenil were successfully used for general anesthesia in a patient with mitochondrial disease.

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Psychomotor Recovery Following Remimazolam-induced Sedation and the Effectiveness of Flumazenil as an Antidote

Abstract: Purpose: Remimazolam tosylate (HR-7056) is a novel ester-type benzodiazepine with ultrafast onset of effect. The compound is being developed for sedation induction and maintenance during NCT03444480. (Clin Ther. 2020;42:614e624) © 2020 Elsevier Inc.

Cited by 72 publications

References 24 publications

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Efficacy and Safety of Remimazolam Besylate Versus Propofol during Hysteroscopy: Single‐centre Randomized Controlled Trial

General anesthesia with remimazolam in a patient with mitochondrial encephalomyopathy: a case report

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