Effect-site concentration of remimazolam at loss and recovery of responsiveness during general anesthesia: a simulation study

Kim Kyung Mi,Bang Ji-Yeon,Lee Jong Min,Yang Hong Seuk,최병문,노규정 대한마취통증의학회 2022 Anesthesia and pain medicine Vol.17 No.3

Background: The objective of this study was to investigate the effect-site concentration (Ce) of remimazolam at loss of response (LOR) and recovery of response (ROR) in patients underwent general anesthesia using simulation. In addition, the relationships between patient’s factors and simulated Ce at LOR and ROR were examined.Methods: The medical records of 81 patients who underwent elective surgery under general anesthesia using remimazolam with simulation of Ce between August 4, 2021 and October 12, 2021, were retrospectively reviewed. Remimazolam was administered as an induction dose of 6 or 12 mg/kg/h until the patient became unresponsive, followed by 0.32 mg/kg/h to maintain BIS values below 60. Simultaneously, simulations of manual infusion mode were performed using Asan Pump software and the Ce of remimazolam was simulated using the Schüttler model. Whenever infusion rate of remimazolam was manually changed, the simulated Ce was confirmed almost simultaneously. LOR and ROR, defined as unresponsive and eye-opening to verbal commands, respectively, were recorded in the Asan Pump program.Results: The median (1Q, 3Q) simulated Ce at LOR and ROR were 0.7 (0.5, 0.9) and 0.3 (0.2, 0.4) g/ml, respectively. LOR was achieved in 1.9 min after remimazolam infusion with cumulative doses of 0.3 mg/kg. There was a significant relationship between age and simulated Ce at ROR (Ce at ROR = –0.0043 × age + 0.57, r = 0.30, P = 0.014). Conclusions: For optimal dosage adjustment, simulating Ce while administering remimazolam with a weight-based dose during anesthesia is helpful. Elderly patients may recover from anesthesia at lower Ce of remimazolam.

Remimazolam: pharmacological characteristics and clinical applications in anesthesiology

김경미 대한마취통증의학회 2022 Anesthesia and pain medicine Vol.17 No.1

A novel ultra-short-acting benzodiazepine (BDZ), remimazolam (CNS 7056), has been designed by ‘soft drug’ development to achieve a better sedative profile than that of the current drugs. Notably, the esterase linkage in remimazolam permits rapid hydrolysis to inactivate metabolites by non-specific tissue esterase and induces a unique and favorable pharmacological profile, including rapid onset and offset of sedation and a predictable duration of action. Similar to other BDZs, its sedative effects can be reversed using flumazenil, a BDZ antagonist. The pharmacokinetics and pharmacodynamics of remimazolam are characterized by relatively high clearance, small steady-state volume of distribution, short elimination half-life, short context-sensitive half-life, and fast onset and recovery, indicating rapid elimination, minimal tissue accumulation, and good control. In addition, remimazolam possesses a superior safety profile, including low liability for cardiorespiratory depression and injection pain, making it a preferred hypnotic agent in various clinical settings. Early clinical investigations suggest that remimazolam is well tolerated and effective for procedural sedation and for induction and maintenance of general anesthesia. To date, however, the clinical use of remimazolam has been confined to a few volunteer studies and a limited number of clinical investigations. Therefore, further studies regarding its recovery issues or postoperative complications, characteristics of electroencephalogram changes, and cost-benefit analyses are required to facilitate its widespread use.

Comparison of remimazolam and desflurane in emergence agitation after general anesthesia for nasal surgery: a prospective randomized controlled study

Cho Sung-Ae,Ahn So-min,권우진,성태윤 대한마취통증의학회 2024 Korean Journal of Anesthesiology Vol.77 No.4

Background: Remimazolam is an ultrashort-acting benzodiazepine. Few studies have evaluated the effects of remimazolam-based total intravenous anesthesia (TIVA) on emergence agitation (EA). This study aimed to compare the incidence and severity of EA between TIVA using remimazolam and desflurane. Methods: This prospective randomized controlled study enrolled 76 patients who underwent nasal surgery under general anesthesia. Patients were randomized into two groups of 38 each: desflurane-nitrous oxide (N2O) (DN) and remimazolam-remifentanil (RR) groups. The same protocol was used for each group from induction to emergence, except for the use of different anesthetics during maintenance of anesthesia according to the assigned group: desflurane and nitrous oxide for the DN group and remimazolam and remifentanil for the RR group. The incidence of EA as the primary outcome was evaluated using three scales: Ricker Sedation-Agitation Scale, Richmond Agitation-Sedation Scale, and Aono’s four-point agitation scale. Additionally, hemodynamic changes during emergence and postoperative sense of suffocation were compared. Results: The incidence of EA was significantly lower in the RR group than in the DN group in all three types of EA assessment scales (all P < 0.001). During emergence, the change in heart rate differed between the two groups (P = 0.002). The sense of suffocation was lower in the RR group than in the DN group (P = 0.027). Conclusions: RR reduced the incidence and severity of EA in patients undergoing nasal surgery under general anesthesia. In addition, RR was favorable for managing hemodynamics and postoperative sense of suffocation.

레미마졸람을 사용하여 전신마취로 고관절 수술을 시행한 환자에서의 섬망 발생: 후향적 연구

강승재(Seung Jae Kang),전인정(In Jung Jun),김원(Won Kim),장윤영(Yoon Young Chang),손보경(Bo Kyung Sohn),이동우(Dong Woo Lee) 대한사회정신의학회 2023 사회정신의학 Vol.28 No.2

목적 :본 연구는 고관절 수술 환자를 대상으로, 최근 국내에 도입되어 사용하고 있는 레미마졸람을 마취에 사용한 환자들을 대상으로 섬망 발생률 및 섬망 발생 관련 인자들을 파악하고자 하였다. 방법 : 2021년 3월 1일부터 2022년 10월 31일까지 레미마졸람을 사용하여 마취 후 고관절 골절 수술을 받은 60세 이상의 환자들의 임상 정보를 바탕으로 후향적 연구를 진행하였다. 입원 시부터 퇴원 전까지의 섬망 발생률 및 과거력, 현병력 및 사회력, 수술 전후의 혈액검사 결과 등을 수집하여 섬망 발생과 유의미한 연관이 있는 요인들을 분석하였다. 결과 : 전체 106명 중 수술 후 섬망이 발생한 환자는 46명(43.40%)이었다. 카이 제곱 검정 및 t-test 결과 연령(p=0.004), 교육년수(p=0.028), 뇌졸중 과거력(p=0.016), 정신과적 과거력(p=0.015), 수술 전 전해질 불균형 여부(p=0.036) 및 수술 전 혈당(p=0.023)이 수술 후 섬망 발생한 군과 그렇지 않은 군 간에 유의미한 차이가 있었다. 로지스틱 회귀분석을 실시한 결과 연령이 증가할수록(B=0.083, OR=1.086, 95% CI=1.007-1.172, p=0.032), 뇌졸중의 과거력이 있는 경우(B=1.312, OR=3.714, 95% CI=1.066-12.939, p=0.039), 수술 전 전해질 불균형이 있는 경우(B=1.028, OR=2.796, 95% CI=1.021-7,659, p=0.046), 수술 전 혈당이 높은 경우(B=0.019, OR=1.019, 95% CI=1.004-1.034, p=0.014) 섬망 발생 위험도가 더 높았다. 결론 :본 연구 결과, 60세 이상의 노인 환자들에게 최근 승인된 레미마졸람을 사용하여 정형외과 고관절 수술을 하였을 때 섬망의 발생률이 기존에 비슷한 군들을 대상으로 한 연구들과 간접적으로 비교하였을 때, 기존 마취제를 사용한 결과와 크게 다르지 않다는 것을 알 수 있었다. 또한 본 연구를 통해 파악된 레미마졸람 사용 시 수술 후 섬망 발생을 일으킬 수 있는 위험 요인들을 고려하고 개선 가능한 요인들은 적극 개입하여 섬망 발생을 예방할 필요가 있다. Objectives: This study aims to determine the incidence of delirium and delirium-related factors in patients undergoing hip surgery who were under remimazolam, a drug recently introduced and used in Korea. Methods: This is a retrospective study based on clinical information of patients aged ≥60 years who underwent hip fracture surgery after anesthesia with remimazolam from March 1, 2021 to October 31, 2022. We investigated the incidence of delirium during the admission period and delirium-related factors by analyzing the current medical and social history, and pre- and postoperative blood tests results. Results: Of the 106 patients, 46 (43.40%) developed postoperative delirium. Chi-square and t-tests showed that age (p=0.004), years of education (p=0.028), history of stroke (p=0.016), psychiatric history (p=0.015), presence of preoperative electrolyte imbalance (p=0.036), and preoperative blood glucose levels (p=0.023) were significantly different between those who developed postoperative delirium and those who did not. In logistic regression analysis, the risk of the occurrence of delirium was significantly related to increasing age (B=0.083, OR=1.086, 95% CI=1.007-1.172, p=0.032), history of stroke (B=1.312, OR=3.714, 95% CI=1.066-12.939, p=0.039), preoperative electrolyte imbalance (B=1.028, OR=2.796, 95% CI=1.021-7,659, p=0.046), and high preoperative blood sugar levels (B=0.019, OR=1.019, 95% CI=1.004-1.034, p=0.014). Conclusion: This study found that the incidence of delirium following orthopedic hip surgery using remimazolam was not significantly different from that using conventional anesthetics if indirectly compared to previous studies in similar populations. Moreover, if we use remimazolam, we should consider the delirium-related factors and treat modifiable factors for delirium prevention

Clinical profile of a new anesthetic: remimazolam

Lee Myoungjin,Kim Sang Hun 조선대학교 의학연구원 2023 Medical Bilogical Science and Engineering Vol.6 No.1

Remimazolam is a novel ultrashort-acting benzodiazepine that acts on g-aminobutyric acid A receptor. It has been approved for use as a general anesthetic and sedative. This medication is recommended for inducing and maintaining anesthesia using continuous intravenous infusion; however, bolus dosing of remimazolam can also be adopted. Continuous intravenous infusion should be started at a rate of 6 or 12 mg/kg/h until loss of consciousness is achieved. Subsequently, this infusion rate should be decreased at a rate of 1 mg/kg/h as appropriate to maintain proper anesthetic depth (maximum allowable rate, 2 mg/kg/h). These recommended doses show more stable hemodynamics than those of propofol. The clinical profiles of anesthesia induction and maintenance are comparable between remimazolam and propofol. Although remimazolam has a slightly longer anesthetic induction time than propofol, the results are not inferior to each other. Recovery profiles show somewhat contradictory results, but the effects of remimazolam and propofol are comparable. Whether the bispectral index or other anesthetic depth indices are suitable for monitoring the sedative effect of remimazolam remains controversial. The appropriate ranges of electroencephalography (EEG) indices for remimazolam are unclear, but it has higher EEG indices than propofol. Thus, co-administration of opioids with a low dose of remimazolam is recommended to maintain the appropriate ranges for patients. Despite the favorable effects of remimazolam, the risk of re-sedation should always be considered after remimazolam reversal, especially when using flumazenil. Thus, remimazolam is considered comparable with propofol for inducing general anesthesia.

Determination of the 95% effective dose of remimazolam to achieve loss of consciousness during anesthesia induction in different age groups

Oh Juyeon,박성용,이숙영,Song Ju Yeol,Lee Ga Yun,Park Ji Hyun,조한범 대한마취통증의학회 2022 Korean Journal of Anesthesiology Vol.75 No.6

Background: Remimazolam is a new ultra short-acting benzodiazepine originally developed as an improved version of midazolam. Recent studies have demonstrated non-inferiority of remimazolam to propofol in general anesthesia. However, to date, few studies have investigated the induction bolus dose of remimazolam required to achieve general anesthesia. We aimed to determine the 95% effective dose (ED95) of remimazolam bolus required to achieve loss of consciousness (LOC) and the appropriate doses for different age groups. Methods: Patients aged 20–79 years with the American Society of Anesthesiologists physical status of I or II were enrolled in this study. A total of 120 patients were included representing young, middle-aged, and elderly groups. Loss of eyelash reflex and verbal response after the administration of remimazolam was considered successful LOC. The ED95 of remimazolam was determined using a biased coin up-and-down design with sequential allocation and the isotonic regression method. Results: The ED95 of remimazolam for induction of general anesthesia was 0.367 mg/kg (95% CI [0.277, 0.392]) in the young group, 0.369 mg/kg (95% CI [0.266, 0.394]) in the middle-aged group, and 0.249 mg/kg (95% CI [0.199, 0.288]) in the elderly group. During the study period, none of the patients required rescue medications for hypotension or bradycardia. Conclusions: This study investigated the ED95 of remimazolam bolus for anesthesia induction. The precise dosing of the ED95 can help maintain hemodynamic stability during the induction of anesthesia.

Comparison of postoperative nausea and vomiting between remimazolam and propofol: a propensity score-matched, retrospective, observational, single-center cohort study

Suzuki Yuji,Kawashima Shingo,Makino Hiroshi,Doi Matsuyuki,Nakajima Yoshiki 대한마취통증의학회 2023 Korean Journal of Anesthesiology Vol.76 No.2

Background: Remimazolam is a novel ultrashort-acting benzodiazepine that has recently become available for general anesthesia. However, the incidence of postoperative nausea and vomiting (PONV) associated with remimazolam remains unknown. In this propensity score-matched, retrospective, observational study, we compared the rates of PONV between remimazolam and propofol.Methods: In this retrospective observational study, propensity score-matching was performed to minimize selection bias. Patients who received total intravenous anesthesia with remimazolam or propofol at the Hamamatsu University Hospital between August 2020 and July 2021 were enrolled in the study. Data on patient demographics, anesthetic agents, and PONV within the first 24 h were collected and analyzed.Results: Of the 1,239 patients who met the study selection criteria, 585 received remimazolam and 684 received propofol. After propensity score matching, 333 matched pairs were further analyzed. Patient demographics and the anesthetic agents used were comparable between the matched cohorts. The incidence of PONV was significantly higher in the remimazolam group than in the propofol group (35% vs. 21%, P < 0.001).Conclusions: The incidence of PONV is higher with remimazolam anesthesia than with propofol anesthesia. The findings of this study require confirmation in larger prospective randomized controlled trials.

Effective concentration of remifentanil for successful i-gel insertion during remimazolam induction

Choi Jung Ju,정월선,장영진,Yoo Seungbeom,곽현정 대한마취통증의학회 2023 Korean Journal of Anesthesiology Vol.76 No.3

Background: Remifentanil can be used as adjuvants during remimazolam induction without neuromuscular blockade. We evaluated the 95% effective concentration (EC) of remifentanil effect-site concentration (Ce) for the successful insertion of an i-gel using the biased-coin up-and-down method in adult patients during remimazolam induction. Methods: Forty 19–65 year-old patients scheduled to undergo surgery using i-gel were enrolled. Anesthesia was induced using remimazolam infusion (12 mg/kg/h). Simultaneously, remifentanil was infused at a predetermined Ce. After 5 min of anesthesia induction, the i-gel was inserted. The 95% EC (EC95) of remifentanil in each patient was determined using a biased-coin up-and-down method based on a successful insertion in a preceding patient. The step size of remifentanil Ce was 0.4 ng/ml. If the insertion failed, remifentanil Ce was increased in the next patient. Following successful insertions, the corresponding concentration decreased in subsequent patients with a probability of 1/19 or was maintained with a probability of 18/19. The time from remimazolam infusion initiation to a bispectral index (BIS) < 60 (time to BIS60) and hemodynamic variables were measured and recorded.Results: The EC95 (95% CI) of Ce was 2.07 (1.94, 2.87) ng/ml. The overall time to BIS60 was 154.0 ± 39.9 s. No patient experienced significant hypotension or bradycardia during remimazolam induction.Conclusions: The EC95 of remifentanil Ce was 2.07 (1.94, 2.87) ng/ml for successful i-gel insertion during remimazolam induction at 12 mg/kg/h without hemodynamic instability in adult patients. Future studies should measure remifentanil Ce in elderly patients or using remimazolam at various infusion doses.

Remimazolam – current knowledge on a new intravenous benzodiazepine anesthetic agent

김성협,Fechner Jörg 대한마취통증의학회 2022 Korean Journal of Anesthesiology Vol.75 No.4

Intravenous anesthetic agents such as midazolam, propofol, and ketamine are routinely used to provide anesthesia and sedation. They have been shown to effectively induce and maintain amnesia, sedation, and hypnosis in various patient groups and clinical settings. However, all anesthetic agents have the potential to cause unwanted side effects such as hemodynamic instability, respiratory depression, or slow recovery due to prolonged post-procedural sedation. Remimazolam, a recently approved benzodiazepine for general anesthesia and procedural sedation in Korea, has been successfully used for these purposes. To date, inconclusive knowledge has been obtained regarding the use of remimazolam in different patient populations and under various surgical conditions. With respect to the specific pharmacokinetic and pharmacodynamic characteristics of remimazolam, the use of remimazolam is expected to increase providing safe general anesthesia and sedation. This review aims to provide an overview of the basic and clinical pharmacology of remimazolam and to compare it with midazolam and propofol.

Patient-controlled sedation using remimazolam during third molar extraction: a case report

박경남,감명환,서광석,김현정,유승화 대한치과마취과학회 2024 Journal of Dental Anesthesia and Pain Medicine Vol.24 No.1

Dental sedation plays a pivotal role in alleviating patient anxiety during various procedures. Remimazolam, a benzodiazepine derivative, stands out for its distinctive attributes, particularly its rapid onset of sedation coupled with a brief duration, making it an invaluable option for dental applications. The patient was admitted for the extraction of impacted third molars via patient-controlled sedation and not only demonstrated stable vital signs but also expressed a high level of satisfaction with the procedure. An in-depth analysis of plasma remimazolam concentrations and changes in the Patient State Index revealed negative correlation patterns, highlighting the inherent potential of remimazolam in achieving effective sedation. This expanded research scope aims to provide a more nuanced understanding of the pharmacological responses to remimazolam in dental sedation scenarios. This case report offers valuable insights into the evolving landscape of dental sedation methodologies and paves the way for a more informed and evidence-based approach to the use of remimazolam in patient-controlled sedation.