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Mei Wang,1,2 Tianqi Wang,1 Nan Wu,2 Yutao Zhang,3,4 Jindi Jia,1 Shengguo Zhao,1,2 Jie Yan,1,2 Airong Wang,1 Dajiang Yuan1,5 1College of Anesthesiology, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Department of Anesthesiology, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 3College of Second Clinical Medical, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 4Department of Orthopedics, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 5Department of the Party Committee, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, People’s Republic of ChinaCorrespondence: Dajiang Yuan, Department of the Party Committee, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi, People’s Republic of China, Tel +86-186-3617-1219, Email yuandajiang@sina.comPurpose: To investigate whether patient-controlled sedation (PCS) with remimazolam provides more precise sedation control and superior overall outcomes compared to conventional sedation (CS) in elderly patients undergoing lower limb surgery under spinal anesthesia.Patients and Methods: 120 patients aged ≥ 65 years (ASA physical status II~III) were randomized to receive either PCS (n=60) or CS (n=60). PCS received a loading dose (1 mg), background infusion (0.75 mg·h− 1), and patient-demand boluses (0.5 mg; lockout interval 60s). CS received a loading dose (0.05~0.1 mg·kg− 1) followed by a continuous infusion (0.1~0.3 mg·kg− 1·h− 1). The primary outcome was the proportion of patients who maintained optimal sedation, defined as a Ramsay Sedation Scale score of 3~4 with supportive bispectral index (BIS) monitoring. Secondary outcomes included onset/recovery time, hemodynamics, drug consumption, adverse events, and satisfaction.Results: The proportion maintaining optimal sedation was higher in the PCS group (100% vs 88.3%, P < 0.05). PCS also showed lower total drug use, shorter recovery time (both P < 0.001), and higher scores for comfort, satisfaction, and cooperation (all P < 0.05). Hemodynamic stability was better in the PCS group, with higher mean arterial pressure at T2 through T6 timepoints (mean difference 4.5 mmHg, P = 0.019) and a lower hypotension incidence (10.0% vs 23.3%, P = 0.050).Conclusion: For elderly patients undergoing lower limb surgery under spinal anesthesia, patient-controlled sedation with remimazolam facilitates more precise sedation control. It ensures a higher proportion of optimal sedation depth while reducing drug consumption, accelerating recovery, and enhancing patient comfort and satisfaction. Under the conditions of this study, this approach constitutes a safe, effective, and individualized sedation strategy.Keywords: remimazolam, patient-controlled sedation, elderly, spinal anesthesia

Yuling Tang,1,2,* Menghong Long,1,2,* Yuhang Gao,1,2 Ana Kowark,3 Mark Coburn,3 Hengjun Wan,1,2 Yiyun Li,1,2 Xiaoxia Duan1 1Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany*These authors contributed equally to this workCorrespondence: Xiaoxia Duan, Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China, Tel +86 13568635458, Email duanxiaoxia@swmu.edu.cnPurpose: Hyperlipidemia increases postoperative delirium (POD) risk via neuroinflammation; however, effective pharmacological interventions to mitigate POD in this population remain limited. Remimazolam has been reported to reduce perioperative stress and modulate neuroinflammatory responses. We investigated the effect of remimazolam on POD incidence in surgical patients with hyperlipidemia.Patients and Methods: In this retrospective cohort study, we enrolled 1123 patients with hyperlipidemia who underwent surgery under general anesthesia with or without remimazolam at a single institution. The primary outcome measure was POD incidence within 3 days postoperatively. To assess the impact of remimazolam on POD, a target trial emulation framework was applied to enhance control of confounders and strengthen causal inference. We additionally investigated the dose–response relationship between remimazolam exposure and POD.Results: POD incidence in the remimazolam group was 13.8%, which was 7.2% lower than that in the non-remimazolam group (P< 0.01). Additionally, delirium severity (median score: 9 vs 10, P< 0.01) and cognitive impairment incidence at 6 months postoperatively (4.4% vs 8.3%, P< 0.05) were lower in the remimazolam group. The target trial emulation further confirmed the protective effects of remimazolam on POD (adjusted risk difference [aRD]: − 5.3%, P=0.016), delirium severity (aRD: − 2.238, P< 0.001), and cognitive dysfunction incidence at 6 months postoperatively (aRD: − 3.97%, P=0.019). Dose–response analysis showed a significant reduction in POD incidence when the total remimazolam dose was ≥ 10.29 mg or the maintenance rate was ≥ 0.51 mg kg− 1 h− 1.Conclusion: Remimazolam significantly reduced POD incidence and severity in patients with hyperlipidemia and improved cognitive function at 6 months postoperatively. However, prospective studies are needed to confirm these findings.Keywords: remimazolam, postoperative delirium, hyperlipidemia, target trial emulation, dose–response, neuroprotection

To evaluate factors affecting variability in response to remimazolam in general anesthesia. Plasma concentration-time data from 11 Phase 1–3 clinical trials were pooled for the population pharmacokinetic (popPK) analysis and concentration-bispectral index (BIS) data were pooled from 8 trials for popPK-PD analysis. A 3-compartment model with allometric exponents on clearance and volume described remimazolam concentrations over time. An effect compartment model with an inhibitory sigmoid Emax model was fit to the concentration-BIS data. Simulations were performed to assess sedation in general anesthesia and post-surgical sedation in healthy and sensitive populations. General anesthesia and post-surgical sedation. 689 subjects included in popPK and 604 subjects included in popPK-PD. Most subjects (>85%) were ASA Class 1 or 2, with the remaining subjects being ASA Class 3. Serial plasma concentrations and BIS scores. Standard intra-operative monitoring. PopPK model included an effect of extracorporeal circulation, ASA class, and sex on PK and a time-dependent clearance (~30% lower at 24 h) that was not related to cumulative dose. Co-administered remifentanil had a synergistic decrease in BIS with remimazolam. Remimazolam IC50 increased with cumulative dose. Onset was faster in overweight subjects and slower in Asian subjects. If using a weight-based regimen, simulations showed that remimazolam 6 mg/kg/h until loss of consciousness followed by 1 mg/kg/h during general anesthesia and 0.25 mg/kg/h for post-surgical sedation for up to 24 h is optimal, regardless of ASA class or sensitivity of subjects. If using a weight-based regimen, results illustrated an appropriate regimen of remimazolam for general anesthesia and post-surgical sedation in general and sensitive populations, although lower doses can be considered in elderly patients with a significant disease burden or in ASA Class 3 patients. The time-dependent change in clearance is not clinically relevant for up to 24 h. •PK-PD used to find remimazolam dose in general anesthesia for weight-based regimen.•Most covariate effects were small and did not change the dosing recommendations.•No dose adjustments required; but consider dose reduction in medically complex elderly patients.•Consider dose reduction in ASA Class 3 patients with significant disease burden.

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.

Background: The primary objective of this study was to compare the risk of hypotension, as well as the induction and recovery characteristics between remimazolam and propofol in patients receiving surgery under general anesthesia. Methods: The Embase, Medline, Google scholar, and the Cochrane Library databases were searched from inception to March 2022 for randomized controlled trials The primary outcome was the risk of post-induction hypotension between the two agents, while the secondary outcomes included anesthetic depth, induction efficacy, time to loss of consciousness (LOC), hemodynamic profiles, time to eye opening, extubation time as well as the incidence of injection pain and postoperative nausea/vomiting (PONV). Results: Meta-analysis of eight studies published from 2020 to 2022 involving 738 patients revealed a significantly lower risk of post-induction hypotension with the use of remimazolam compared to that with propofol [risk ratio (RR) = 0.57, 95% confidence interval (CI): 0.43 to 0.75, p < 0.0001, I 2 = 12%, five studies, 564 patients]. After anesthetic induction, the anesthetic depth measured by bispectral index (BIS) was lighter in the remimazolam group than that in the propofol group (MD = 9.26, 95% confidence interval: 3.06 to 15.47, p = 0.003, I 2 = 94%, five studies, 490 patients). The time to loss of consciousness was also longer in the former compared to the latter (MD = 15.49 s, 95%CI: 6.53 to 24.46, p = 0.0007, I 2 = 61%, three studies, 331 patients). However, the use of remimazolam correlated with a lower risk of injection pain (RR = 0.03, 95%CI: 0.01 to 0.16, p < 0.0001, I 2 = 0%, three studies, 407 patients) despite comparable efficacy of anesthetic induction (RR = 0.98, 95%CI: 0.9 to 1.06, p = 0.57, I 2 = 76%, two studies, 319 patients). Our results demonstrated no difference in time to eye opening, extubation time, and risk of PONV between the two groups. Conclusion: Remimazolam was associated with a lower risk of post-induction hypotension after anesthetic induction compared with propofol with similar recovery characteristics. Further studies are required to support our findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/ ; Identifier: CRD42022320658.

The quality of recovery (QoR) of remimazolam-based and propofol-based total intravenous anesthesia was compared as measured by QoR-15 scores. A prospective, double-blind, randomized controlled, non-inferiority trial. An operating room, a post-anesthesia care unit (PACU), and a hospital ward. Female patients (n = 140; 20–65 years) scheduled for open thyroidectomy were enrolled and randomly assigned to the remimazolam or propofol group. The remimazolam group received continuous remimazolam infusions and effect-site target-controlled remifentanil infusions. The propofol group received effect-site target-controlled infusions of propofol and remifentanil. The primary outcome was QoR-15 on postoperative day 1 (POD1). The mean difference between the groups was compared against a non-inferiority margin of −8. Secondary outcomes were QoR-15 on POD2, hemodynamic data, time to lose and recover consciousness, sedation score upon PACU admission, pain, and postoperative nausea and vomiting profiles at the PACU and ward. Group-time interaction effects in hemodynamic data and QoR-15 were analyzed using a linear mixed model. The total QoR-15 score on POD1 in the remimazolam group was non-inferior to that in the propofol group (mean [SD] 111.2 [18.8] vs. 109.1 [18.9]; mean difference [95% CI] 2.1 [−4.2, 8.5]; p = 0.002 for non-inferiority). The QoR-15 score on POD2 was comparable between the groups, and no group-time interaction was observed. At the end of anesthesia, after extubation, and upon arrival at the PACU, mean arterial pressure was significantly higher in the remimazolam group. Remimazolam group was more sedated at the time of admission to PACU. Pain intensity and the requirement for analgesics were lower in the remimazolam group than in the propofol group. Remimazolam-based total intravenous anesthesia provided a similar QoR to propofol. Remimazolam and propofol can be used interchangeably for general anesthesia in female patients undergoing thyroid surgery. •Evidence regarding quality of recovery after remimazolam-based total intravenous anesthesia has been limited.•Remimazolam-based total intravenous anesthesia was explored in female patients undergoing open thyroidectomy.•Remimazolam-based total intravenous anesthesia demonstrated similar quality of recovery to propofol.•Hypotensive incidence at cessation of anesthetics was lower in patients administered with remimazolam compared to propofol.•Remimazolam-based total intravenous anesthesia was associated with reduced pain intensity and analgesic requirement.

ObjectiveThis study aimed to evaluate remimazolam’s anesthetic efficacy and impact on postoperative cognitive function in breast cancer patients undergoing radical mastectomy.MethodsA total of 80 patients were randomized into two groups: Group R (remimazolam, n = 40) and Group EP (etomidate–propofol mixture, n = 40). Mean arterial pressure (MAP) and heart rate (HR) were recorded at T₀ (pre-induction), T₁ (post-intubation), T₂ (1 h intraoperation), and T₃ (post-extubation). Pain, measured using the visual analog scale (VAS), was assessed upon awakening and at PACU discharge. Cognitive function, measured using the Mini-Mental State Examination/Montreal Cognitive Assessment (MMSE/MoCA), was evaluated on postoperative days 1 and 3. Recovery times and adverse events were also compared between groups.ResultsBaseline characteristics were comparable between groups (p > 0.05). At T₁, HR was lower in Group R than in Group EP (p < 0.05). At T₂, MAP was higher in Group R (p < 0.05). VAS scores showed no intergroup differences postoperatively (p > 0.05). MMSE and MoCA scores were significantly higher in Group R at postoperative days 1 and 3 (p < 0.05). Following flumazenil antagonism, eye-opening and extubation times were shorter in Group R than in Group EP (p < 0.05). The overall adverse event rate was significantly lower in Group R (12.5% vs. 32.5%, p < 0.05).ConclusionRemimazolam provides effective anesthesia for elderly female patients undergoing radical mastectomy, offering superior hemodynamic stability at key time points, faster recovery, fewer adverse events, and significantly better preservation of early postoperative cognitive function compared with an etomidate–propofol mixture.Clinical trial registration numberidentifier ChiCTR2500106237.

BACKGROUND: Remimazolam is a novel ultrashort-effect benzodiazepine. In 2020, the US Food and Drug Administration approved it for procedural sedation. Remimazolam is beneficial for consistent sedation and quick recovery in painless gastrointestinal endoscopy. Propofol is one of the most commonly used intravenous anesthetics in clinical practice. Recently, only a few studies have compared propofol with remimazolam for general anesthesia induction. OBJECTIVES: The purpose of our systematic review and meta-analysis was to compare the hemodynamic effects of remimazolam and propofol during the induction of general anesthesia. STUDY DESIGN: Systematic review and meta-analysis of randomized, controlled trials. METHODS: The authors retrieved the PubMed, Embase, Cochrane Library, and Web of Science databases for studies published through September 30, 2022, which reported relevant prospective randomized controlled trials (RCTs) comparing remimazolam with propofol for general anesthesia. The primary outcome was hemodynamic changes, including the absolute value of fluctuation of mean arterial pressure (delta MAP) and heart rate delta HR). The secondary outcomes were the following 2 indicators: the occurrence of total adverse events and the quality of recovery from general anesthesia at 24 hours postsurgery. RevMan 5.4.1 (The Nordic Cochrane Centre for The Cochrane Collaboration) and trial sequential analysis were used to execute the statistical analyses. The different domains of bias were judged by the Cochrane risk of the bias assessment tool. RESULTS: The authors identified 189 papers in PubMed, Embase, Cochrane Library, and Web of Science. Eight articles with 964 patients were selected. The included studies had moderate quality. For primary outcomes, the lower delta HR (mean difference [MD] = -4.99; 95% CI, -7.97 to -2.00; I² = 41.6%; P = 0.001] and delta MAP (MD = -5.91; 95% CI. -8.57 to -3.24; I² = 0%; P < 0.0001) represent more stable hemodynamic characteristics in the remimazolam group. Regarding secondary outcomes, a considerably lower incidence of total adverse events was noted in the remimazolam group than that for the propofol group (odds ratio [OR] = 0.40; 95% CI, 0.28 to 0.58; I² = 63%; P < 0.00001). In comparison to the propofol group, remimazolam achieved an advantage score of quality of recovery -15 in 24 hours postsurgery (MD = 5.31, 95% CI, 1.51 to 9.12; I² = 87%; P = 0.006). LIMITATION: Firstly, there are only a handful of published RCTs on the administration of remimazolam in general anesthesia. In addition, due to patient privacy, we could not extract individual patient data, therefore we could not combine and assess any variations in patient characteristics. CONCLUSION: Evidence suggests that remimazolam has a lower hemodynamic effect during general anesthesia and fewer perioperative adverse effects after general anesthesia than propofol; however, which agent is superior regarding quality benefit in postoperative recovery based on the studies included here remains inconclusive. Additional RCTs with updated meta-analyses to enlarge the sample size and properly analyze the benefit-to-risk ratio to patients are needed to determine the evidence for such a relatively new medicine. KEY WORDS: Remimazolam, propofol, general anesthesia, hemodynamic, adult

Remimazolam is an ultrashort-acting benzodiazepine, which has been indicated to be effective in endoscopic surgery and general anaesthesia. Research on its use in outpatient dental procedures remains limited. This triple-blinded randomized clinical trial was designed to determine whether the quality of postoperative recovery is better with continuous intravenous remimazolam administration compared with midazolam administration for impacted wisdom tooth extraction in patients with dental anxiety. This study was a randomized, parallel triple-blinded, superiority trial conducted between 30 April 2022 and 24 June 2024. Participants aged ≥18 years who exhibited dental anxiety and who were eligible for impacted wisdom tooth extraction in an outpatient setting were included in this study. Participants were randomly assigned at a 1:1 ratio to receive either a continuous intravenous infusion of remimazolam or midazolam. The primary outcome was the time to recover full alertness. The secondary outcome was postoperative anterograde amnesia. A total of 150 participants were randomized in this study, with 75 patients assigned to the remimazolam group and 75 patients assigned to the midazolam group. The time to complete alertness was significantly shorter in the remimazolam group than in the midazolam group (3.0 ± 3.6 min vs 4.7 ± 5.2 min, mean difference, -1.9 min; 95% CI, -3.3min to -0.4 min; P = 0.013). The odds of immediate and delayed anterograde amnesia were much reduced with remimazolam administration compared with midazolam administration (immediate: 0.14, 95% CI, 0.05 to 0.34, delayed: 0.07, 95% CI, 0.03 to 0.15, both P < 0.001). For patients with dental anxiety, remimazolam offers not only faster recovery, but also a much better restoration of memory function compared with midazolam. https://clinicaltrials.gov/study/NCT05350085.