Remimazolam: its clinical pharmacology and evolving role in anesthesia and sedation practice.

PURPOSE OF REVIEW: Remimazolam is a novel benzodiazepine anesthetic/sedative, designed as a rapidly metabolized carboxylic acid. Since its recent launch, the role of remimazolam in modern anesthesia and sedation practice is still evolving. This review aims to outline the clinical pharmacology and clinical utility of remimazolam to elucidate its potential advantages and limitations. RECENT FINDINGS: Remimazolam is "short-acting" but not ultra-short-acting compared with propofol based on context-sensitive decrement times. But compared to propofol, the availability of the benzodiazepine antagonist, flumazenil, is considered an advantage, particularly in certain emergency situations such as in patients with difficult airways. However, because flumazenil is shorter acting than remimazolam when remimazolam accumulates or is present in a high concentration, the reappearance of remimazolam sedation may occur after the initial reversal of anesthesia/sedation from flumazenil administration. Although it is beneficial that remimazolam causes less respiratory depression and hypotension than propofol, serious respiratory depression and hypotension can still occur. Remimazolam administration causes minimal or no pain on injection. Remimazolam is associated with less postoperative nausea and vomiting than inhaled anesthetics, but propofol is clearly superior in this regard. The anesthetic/sedative effects may be prolonged by severe hepatic impairment; remimazolam tolerance can occur in long-term benzodiazepine users. SUMMARY: Remimazolam may be beneficial to use in procedural sedation and general anesthesia for patients with difficult airways or hemodynamic instability. Further clinical studies with remimazolam are warranted to identify the potential benefits in other settings and patient populations.

Hypotension after general anaesthesia induction using remimazolam or propofol in geriatric patients undergoing sevoflurane anaesthesia with remifentanil: a single-centre, double-blind, randomised controlled trial.

BACKGROUND: The occurrence of hypotension after induction of general anaesthesia is common in geriatric patients, and should be prevented to minimise perioperative complications. Compared with propofol, remimazolam potentially has a lower incidence of hypotension. This study aimed to compare the incidence of hypotension after general anaesthesia induction with remimazolam or propofol in geriatric patients. METHODS: This single-centre, double-blind, randomised trial enrolled 90 patients aged ≥80 yr who received general anaesthesia for scheduled surgery. Patients were randomised to receive remimazolam (12 mg kg-1 h-1) or propofol (0.025 mg kg-1 s-1) for anaesthesia induction, with remifentanil and sevoflurane. The presence or absence of hypertension on the ward served as the stratification factor. The incidence of hypotension after the induction of general anaesthesia, defined as a noninvasive mean arterial pressure of <65 mm Hg measured every minute from initiation of drug administration to 3 min after tracheal intubation, was the primary outcome. Subgroup analysis was performed for the primary outcome using preoperative ward hypertension, clinical frailty scale, Charlson Comorbidity Index, and age. RESULTS: Three subjects were excluded before drug administration, and 87 subjects were included in the analysis. The incidence of hypotension was 72.1% (31/43) and 72.7% (32/44) with remimazolam or propofol, respectively. No statistically significant differences (adjusted odds ratio, 0.96; 95% confidence interval, 0.37-2.46; P=0.93) were observed between groups. Subgroup analysis revealed no significant differences between groups. CONCLUSIONS: Compared with propofol, remimazolam did not reduce the incidence of hypotension after general anaesthesia induction in patients aged ≥80 yr. CLINICAL TRIAL REGISTRATION: UMIN000042587.

What are standard monitoring devices for anesthesia in future?

Monitoring the patient's physiological functions is critical in clinical anesthesia. The latest version of the Japanese Society of Anesthesiologists' Guidelines for Safe Anesthesia Monitoring, revised in 2019, covers various factors, including electroencephalogram monitoring, oxygenation, ventilation, circulation, and muscle relaxation. However, with recent advances in monitoring technologies, the information provided has become more detailed, requiring practitioners to update their knowledge. At a symposium organized by the Journal of Anesthesia in 2023, experts across five fields discussed their respective topics: anesthesiologists need to interpret not only the values displayed on processed electroencephalogram monitors but also raw electroencephalogram data in the foreseeable future. In addition to the traditional concern of preventing hypoxemia, monitoring for potential hyperoxemia and the effects of mechanical ventilation itself will become increasingly important. The importance of using AI analytics to predict hypotension, assess nociception, and evaluate microcirculation may increase. With the recent increase in the availability of neuromuscular monitoring devices in Japan, it is important for anesthesiologists to become thoroughly familiar with the features of each device to ensure its effective use. There is a growing desire to develop and introduce a well-organized, integrated "single screen" monitor.

Anesthesia management for thoracoscopic resection of a huge intrathoracic meningocele: a case report.

BACKGROUND: Diagnosed intrathoracic meningocele is an uncommon complication of neurofibromatosis type 1. We report an anesthesia management for a rare case undergoing thoracoscopic resection of a huge intrathoracic meningocele. CASE PRESENTATION: A 51-year-old woman was scheduled for thoracoscopic meningectomy under general anesthesia. We monitored intrathecal pressure during anesthesia to prevent a decrease in intrathecal pressure. During surgery, the intrathecal pressure occasionally increased by around 5 cmH2O immediately after the insertion of the drainage tube and occasionally decreased by up to 10 cmH2O during the careful slow aspiration of the cerebrospinal fluid (CSF). The pressure rapidly recovered after the interruption of the procedures. She was discharged on postoperative day 4 without major complications. CONCLUSIONS: The CSF pressure was fluctuated by procedures during thoracoscopic resection of a huge meningocele. A CSF pressure monitoring was useful to detect the sudden change of CSF pressure immediately, which can cause intracranial hemorrhage.

Monitored Anesthesia Care Under a Combination of Low-Dose Remimazolam Infusion and Flumazenil Antagonism: A Case Report.

Remimazolam is a novel benzodiazepine known for its short-acting properties. The safe use of flumazenil antagonism following remimazolam infusion remains a subject of debate. We present a case of monitored anesthesia care managed to be safe through low-dose remimazolam infusion and flumazenil antagonism. Pharmacokinetic simulations revealed that low-dose remimazolam was practically useful as one of the components of multimodal sedation/analgesia. Subsequent sedation with the readministration of remimazolam after a dose of flumazenil could also be attained.

Hypotension after general anesthesia induction using remimazolam in geriatric patients: Protocol for a double-blind randomized controlled trial.

INTRODUCTION: In geriatric patients, hypotension is often reported after general anesthesia induction using propofol. Remimazolam is a novel short-acting sedative. However, the incidence of hypotension after general anesthesia induction using remimazolam in geriatric patients remains unclear. This study aims to compare the incidence of hypotension associated with remimazolam and propofol in patients aged ≥80 years. METHODS: This single-center, double-blind, randomized, two-arm parallel group, standard treatment-controlled, interventional clinical trial will include 90 patients aged ≥80 years undergoing elective surgery under general anesthesia who will be randomized to receive remimazolam or propofol for induction. The primary outcome is the incidence of hypotension after general anesthesia induction, occurring between the start of drug administration and 3 min after intubation. We define hypotension as mean blood pressure <65 mmHg. The primary outcome will be analyzed using the full analysis set. The incidence of hypotension in the two groups will be compared using the Mantel-Haenszel χ2 test. Subgroup analysis of the primary outcome will be performed based on the Charlson comorbidity index, clinical frailty scale, hypertension in the ward, and age. Secondary outcomes will be analyzed using the Fisher's exact test, Student's t test, and Mann-Whitney U test, as appropriate. Logistic regression analysis will be performed to explore the factors associated with the incidence of hypotension after anesthesia induction. DISCUSSION: Our trial will determine the efficacy of remimazolam in preventing hypotension and provide evidence on the usefulness of remimazolam for ensuring hemodynamic stability during general anesthesia induction in geriatric patients. TRIAL REGISTRATION: The study has been registered with UMIN Clinical Trials Registry (UMIN000042587), on June 30, 2021.

Equilibration rate constant, ke0, to determine effect-site concentration for the Masui remimazolam population pharmacokinetic model in general anesthesia patients.

Effect-site concentration is widely used to determine drug dosage in anesthesia practice. To obtain effect-site concentration, a pharmacokinetic model with a corresponding equilibration rate constant between plasma and effect-site, ke0, is necessary. Remimazolam, a novel short-acting benzodiazepine, has been approved as anesthetic/sedative. Recently, a remimazolam pharmacokinetic model has been published using a large dataset including wide range of subject characteristics (416 males and 246 females, age 18-93 years, total body weight 34-149 kg, height 133-204 cm, body mass index 14-61 kg m-2, ASA physical status: I-IV, and Asian, White, American African, and 2 other races). This Masui model can be applicable to various patients, but a pharmacodynamic model including ke0 was not developed simultaneously. A previous article has indicated that the time to peak effect of drug after its bolus should be used to determine ke0 for a pharmacokinetic model without simultaneous development of corresponding pharmacodynamic model. The ke0 value can be calculated using numerical analysis but not algebraic solution. We provide the detail method of the numerical analysis and a tool to have ke0 value easily for the Masui remimazolam PK model. Additionally, we provide a multiple regression model to have ke0 value for the PK model.

A population pharmacokinetic model of remimazolam for general anesthesia and consideration of remimazolam dose in clinical practice.

BACKGROUND: Remimazolam besylate is a novel short-acting benzodiazepine. An appropriate pharmacokinetic model of remimazolam is desirable in anesthesia practice. The aim of the study was to develop a pharmacokinetic model using plasma samples from patients anesthetized with remimazolam. Influence of patient characteristics, context-sensitive decrement-times, and dose regimens were also examined. METHODS: Data were obtained from four trials on patients, and seven trials on healthy volunteers. The characteristics of 416 male and 246 female subjects were as follows: age, 18-93 years; body weight, 34-149 kg; and American Society of Anesthesiologists physical status (ASA-PS), I-IV. 2231 arterial and 3200 venous samples were used for the final model. The equilibration rate constant between arterial plasma and effect-site was estimated using the concept of time to peak effect. The final model was used to generate context-sensitive decrement times and dose regimens for general anesthesia. RESULTS: A three-compartment model plus virtual venous compartment with allometric scaling of adjusted body weight (ABW), age, sex, and ASA-PS as covariates were selected as the final model. Elimination clearance was lower in males, and in subjects with higher ABW and ASA-PS scores. Approximately 10% or 20% higher dose rate was necessary in females than in males or ASA-PS I/II than III/IV patient. The context-sensitive half-time for effect-site concentration in a 55-year-old, 70-kg, 170-cm male or female ASA-PS I/II patient after > 6-h infusion was 16.7 or 15.9 min. CONCLUSION: Remimazolam pharmacokinetic model for general anesthesia was successfully developed. ABW, ASA-PS, and sex has a considerable impact on the remimazolam concentration.

Mortality Risk Stratification Using Cluster Analysis in Patients With Myositis-Associated Interstitial Lung Disease Receiving Initial Triple-Combination Therapy.

Objective: To stratify patients with polymyositis/dermatomyositis-associated interstitial lung disease (ILD) who were initially treated with an intensive regimen consisting of high-dose corticosteroids, a calcineurin inhibitor, and intravenous cyclophosphamide (triple-combo therapy) into subgroups based on mortality outcomes by a cluster analysis using a large-scale multicenter retrospective cohort of Japanese patients with myositis-associated ILD (JAMI). Methods: Two-step cluster analysis of preclustering and subsequent hierarchical clustering was conducted in 185 patients who received triple-combo therapy in an unbiased manner. Initial predictors for mortality previously reported in patients with myositis-associated ILD were used as variables and included age, sex, disease duration, classification of myositis, requirement of supplemental oxygen, anti-aminoacyl tRNA synthetase (ARS) antibody, anti-melanoma differentiation-associated gene 5 (MDA5) antibody, and serum levels of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6). The cluster model was further applied to 283 patients who received conventional regimens consisting of corticosteroids with or without a single immunosuppressive agent (dual-combo therapy or monotherapy). Cumulative survival rates were compared using Kaplan-Meier analysis, and the log-rank test was used to test for significant differences between two groups. Results: We developed a cluster model consisting of 6 clusters, which were categorized by age at onset, clinically amyopathic dermatomyositis, CRP, KL-6, requirement of supplemental oxygen, anti-ARS antibody, and anti-MDA5 antibody. This model was judged to be of good quality based on the silhouette measure of cohesion and separation of 0.6. These clusters were regrouped into three subsets based on low (<10%), moderate (10-50%), and high (>50%) mortality rates. The performance of the clustering was generally replicated in patients who received initial dual-combo therapy or monotherapy. Survival benefits of triple-combo therapy over dual-combo therapy or monotherapy were not observed in any of the clusters. Conclusion: We successfully developed a cluster model that stratified patients with myositis-associated ILD who were treated with initial triple-combo therapy into subgroups with different prognoses, although this model failed to identify a patient subgroup that showed survival benefits from triple-combo therapy over dual-combo therapy or monotherapy.

Lateral position for difficult intubation in a patient with history of hemiglossectomy and flap reconstruction: a case report.

BACKGROUND: Reconstructive head and neck surgery can alter upper airway anatomy. We report a difficult intubation in a patient with a history of hemiglossectomy and reconstruction. CASE PRESENTATION: A 65-year-old female patient, who had undergone hemiglossectomy with the flap reconstruction, underwent video-assisted thoracoscopic esophagectomy for esophageal cancer. After the loss of consciousness during anesthesia induction, we failed to perform direct and oral fiberoptic intubation using a video laryngoscope and nasal fiberoptic intubation without or with video laryngoscope assistance in the supine position. Finally, shifting the patient to the left-lateral position allowed successful nasal fiberoptic intubation. Postoperatively, we were informed that she was unable to sleep in the supine position because of airway obstruction and therefore always slept on her side. CONCLUSION: Preanesthetic evaluation of the influence of body position on the airway patency during sleep or sedation may aid in airway management.

Remimazolam Tolerance in Long-term Benzodiazepine Users: A Case Report of 2 Cases.

A 60-year-old woman with a 5-year history of anxiolytic use, a diazepam-equivalent daily dose of 15 mg, was scheduled for esophageal stent removal. She was given remimazolam (0.5 mg/kg) but remained fully alert. She only lost consciousness with propofol (40 mg). A 61-year-old man with a 1-year history of anxiolytic use, diazepam-equivalent daily dose of 20 mg, was scheduled for hand tumor resection. He was given remimazolam (0.3 mg/kg) but remained fully alert. He only lost consciousness after desflurane inhalation. In a patient with a history of long-term benzodiazepine use, anesthetic or sedative agents aside from remimazolam should be considered.

Pharmacokinetics and effects on clinical and physiological parameters following a single bolus dose of propofol in common marmosets (Callithrix jacchus).

The objectives of this study were (a) to establish a population pharmacokinetic model and (b) to investigate the clinical and physiological effects of a single bolus dose of propofol in common marmosets. In Study 1, pharmacokinetic analysis was performed in six marmosets under sevoflurane anaesthesia. 8 mg/kg of propofol was administrated at a rate of 4 mg kg-1  min-1 . Blood samples were collected 2, 5, 15, 30, 60, 90, 120 or 180 min after starting propofol administration. Plasma concentration was measured, and population pharmacokinetic modelling was performed. A two-compartment model was selected as the final model. The population pharmacokinetic parameters were as follows: V1  = 1.14 L, V2  = 77.6 L, CL1  = 0.00182 L/min, CL2  = 0.0461 L/min. In Study 2, clinical and physiological parameters were assessed and recorded every 2 min after 12 mg/kg of propofol was administrated at a rate of 4 mg kg-1  min-1 . Immobilization was sustained for 5 min following propofol administration without apparent bradycardia. While combination of propofol and sevoflurane caused apnoea in Study 1, apnoea was not observed following single administration of propofol in Study 2. These data provide bases for further investigation on intravenous anaesthesia using propofol in common marmosets.

Interpretation of laboratory tests for prevention of the SARS-CoV-2 transmission.

With the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), medical providers should take care to prevent the transmission of SARS-CoV-2 in hospitals including super-spreading. Understanding super-spreading would be useful to reduce future transmission. Some publications have shown clusters of SARS-CoV-2 such as at choir practice and in hospitals. Aerosol can be considered as a primary transmission route. As SARS-CoV-2 stability in aerosol is similar to SARS-CoV-1 with the higher reproductive number of SARS-CoV-2 than SARS-CoV-1, another factor causes rapidly spread-out, e.g. a higher discharge ratio from infected people or a higher viral intake ratio to human body. A basic research suggests higher infectivity of SARS-CoV-2 in the nose than the peripheral lung. Universal masking would be important to prevent the exposure of SARS-CoV-2 droplet to uninfected people. To detect SARS-CoV-2 infection, laboratory tests such as reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays are applied. Although sensitivity and specificity are provided for the ability of the test, positive or negative prediction values are useful to indicate the possiblity of infection or non-infection in clinical practice. We have to realize that the positive and negative prediction values depend on the sensitivity, specificity, and infection probability of the patient.

Propofol suppresses the His-ventricular conduction in paediatric patients.

WHAT IS KNOWN AND OBJECTIVE: Propofol is the most commonly used intravenous anaesthetic worldwide and is considered to be safe for all ages. However, there have been some reports that propofol induces severe atrioventricular (AV) blocks in humans and some studies demonstrated that propofol suppressed the cardiac conduction system in animals. A precise mechanism by which the block is induced has not been elucidated yet in humans. The objective of this study was to investigate the effects of propofol on the cardiac conduction system and the cardiac autonomic nervous balance in children. METHODS: We enrolled 23 paediatric patients (age: 6-15 years; males: 16, females: 7) who were scheduled to undergo radiofrequency catheter ablation (RFCA) under general anaesthesia. Anaesthesia was induced with 2 mg/kg propofol and 0.5 µg/kg/min remifentanil, and tracheal intubation was performed with the aid of 1 mg/kg rocuronium. Anaesthesia was maintained with 5-7 mg/kg/h propofol and 0.2 µg/kg/min remifentanil during the RFCA. After the completion of the RFCA, anaesthesia was further maintained with 5 mg/kg/h propofol and 0.2 µg/kg/min remifentanil for at least 10 min (LC: low propofol concentration state), followed by the injection of 2 mg/kg propofol and the infusion of 10 mg/kg/h propofol for 10 min (HC: high propofol concentration state). The sinus node recovery time (SNRT), sinoatrial conduction time (SACT), atrial-His (AH) interval and the His-ventricular (HV) interval were measured at the end of both the LC and HC. Cardiac autonomic regulation was simultaneously assessed based on heart rate variability. RESULTS AND DISCUSSION: Propofol significantly suppressed intrinsic cardiac HV conduction, but did not affect the SNRT, SACT or the AH interval. As HV blocks, which occur below the His bundle, are often life-threatening, the HV conduction delay may be a cause of severe AV blocks induced by propofol. Propofol directly suppressed parasympathetic nerve activity, and sympathetic nerve activity was also suppressed. WHAT IS NEW AND CONCLUSION: These results indicate that propofol suppresses the HV conduction and might help to elucidate the mechanism by which propofol causes lethal AV blocks.

Risk Prediction Modeling Based on a Combination of Initial Serum Biomarker Levels in Polymyositis/Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: To establish predictive models for mortality in patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) using a combination of initial serum biomarker levels. METHODS: The Multicenter Retrospective Cohort of Japanese Patients with Myositis-Associated ILD (JAMI) database of 497 incident cases of PM/DM-ILD was used as a derivation cohort, and 111 cases were additionally collected as a validation cohort. Risk factors predictive of all-cause mortality were identified by univariate and multivariable Cox regression analyses using candidate serum biomarkers as explanatory variables. The predictive models for mortality were generated in patients with and those without anti-melanoma differentiation-associated gene 5 (MDA-5) antibody, using a combination of risk factors. Cumulative survival rates were assessed using Kaplan-Meier analysis, and were compared between subgroups using the Breslow test. RESULTS: In the derivation cohort, C-reactive protein (CRP) and Krebs von den Lungen 6 (KL-6) levels were identified as independent risk factors for mortality in both anti-MDA-5-positive and anti-MDA-5-negative patients. We then developed a prediction model based on anti-MDA-5 antibody status, CRP level, and KL-6 level, termed the "MCK model," to identify patients at low (<15%), moderate (15-50%), or high (≥50%) risk of mortality, based on the number of risk factors. The MCK model successfully differentiated cumulative survival rates in anti-MDA-5-positive patients (P < 0.01 for low versus moderate risk and P = 0.03 for moderate versus high risk) and in anti-MDA-5-negative patients (P < 0.001 for low versus moderate risk). The utility of the MCK model was replicated in the validation cohort. CONCLUSION: Our findings indicate that an evidence-based risk prediction model using CRP and KL-6 levels combined with anti-MDA-5 antibody status might be useful for predicting prognosis in patients with PM/DM-ILD.

Severe hyponatremia with seizures and confirmed mild brain edema by hysteroscopic myomectomy: a case report.

BACKGROUND: Hyponatremia can be developed during hysteroscopic surgery with electrolyte-free irrigation fluid. We experienced severe hyponatremia with postoperative seizures and confirmed mild brain edema. CASE PRESENTATION: A quadragenarian female patient underwent a 2-h hysteroscopic myomectomy with electrolyte-free fluid for uterine distension under general anesthesia. Plasma sodium level of 84.1 mmol/L 100 min after the start of surgery indicated excessive absorption of the irrigation fluid. Acute severe hyponatremia was diagnosed with significant edema in the conjunctiva, lip, and extremities. She was treated with a continuous infusion of hypertonic saline. However, seizures and cerebral edema developed 7 h later. The patient recovered without neurological deficits at postoperative day 2. CONCLUSION: The electrolyte-free irrigation fluid can be absorbed rapidly during hysteroscopic surgery. Its interruption with hyponatremia should be considered against prolonged surgery. Especially under general anesthesia, caution should be exercised because the typical symptoms of hyponatremia such as nausea and confusion are blinded.

Individual pharmacometric analysis for sugammadex reversal and re-administration of neuromuscular blockade.

Sugammadex is an innovative reversal agent for neuromuscular blockade (NMB) induced by rocuronium. Although there is a case that re-paralysis is necessary after sugammadex administration, limited reports can be found on the sugammadex dosage for reversal from profound paralysis after induction and immediate re-paralysis following such reversal in detail. We experienced a case in which NMB reversal was required in a short period after paralysis for induction due to the discovery of anisocoria. We successfully re-induced general anesthesia with tracheal intubation soon after. To examine the validity of the dosing, we performed a pharmacometric analysis. A pharmacokinetic-pharmacodynamic model was developed for the patient based on a published pharmacokinetic-pharmacodynamic model for rocuronium and sugammadex. The developed model appropriately describes the train of four ratio observed. In this case, the dose of approximately 8 mg/kg sugammadex but not the conventional dose of 16 mg/kg would be enough for immediate reversal after induction. For the re-paralysis 30 min after NMB reversal, not 1.4 mg/kg but 2.2 mg/kg rocuronium was an adequate dose. Taking individual differences including given dose and time intervals in consideration, NMB monitoring should be used to determine the necessary dose of rocuronium and sugammadex in such situations.