Abstract

Remimazolam is a recently approved benzodiazepine for procedural sedation in Taiwan. It is a new type of short-acting γ-aminobutyric acid receptor agonist with the characteristics of non-organ-dependent metabolism, no injection pain, and inactive metabolites. Remimazolam has a mild cardiopulmonary suppressive effect, showing good effectiveness and safety in clinical applications, especially in the elderly, critically ill patients, or patients with hepatic and renal insufficiency. This review aims to provide an overview of the specific basic and clinical pharmacology of remimazolam and provide scientific support for the clinical application of this novel sedative drug in procedural sedation.

Keywords

benzodiazepine, procedural sedation, remimazolam

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Introduction

Remimazolam is a rapidly metabolized benzodiazepine approved for procedural sedation in 2022 in Taiwan. Remimazolam is derived from midazolam, synthesized by introducing a side chain of methyl-propionate, which has the metabolic potential¹ of benzene sulfonic acid and toluenesulfonic acid.² It is rapidly metabolized by unspecific esterases (predominantly carboxylesterase 1A) mainly localized in the human liver to CNS7054, a so-called inactive metabolite with a 300–400 times reduced binding affinity at the γ-aminobutyric acid (GABA) type A receptor.³ Remimazolam has multiple advantages, including a mild cardiopulmonary suppressive effect and hepatic and renal function-independent metabolism.⁴ After its approval for procedural sedation in Taiwan, further clinical experience with remimazolam and evidence-based approaches for dosing and drug handling are needed for the safe and efficient use of remimazolam in different patient populations. This review describes the progress of the clinical application of remimazolam in procedural sedation and introduces its methods and advantages.

Pharmacological Characteristics

Remimazolam selectively has a high affinity for cerebral GABA receptors but shows no significant selectivity for receptor subtypes and no off-target activity. Remimazolam binding to receptors can lead to chloride influx and neural cell membrane hyperpolarization, thereby suppressing neuronal activity and exerting sedative, anterograde amnesia, and anticonvulsant effects.² An animal study showed that remimazolam could suppress the firing of neurons in the substantia nigra pars reticulata (a region that receives GABA afferent innervation from the striatum), lead to the loss of the righting reflex and sedative effect.^1,2

A clinical study revealed that after a 1 minute single intravenous injection of remimazolam at 0.01–0.35 mg/kg in a healthy volunteer, the systemic clearance was 70.3 L/h, three times higher than that of midazolam at 0.075 mg/kg. Additionally, this study showed a steady-state volume of 88.1 L following remimazolam administration, a terminal half-life of 0.75 hours, and a mean duration of 0.51 hours.⁴ The dose of remimazolam has a linear relationship with its pharmacokinetics, and the clearance characteristics conform to the first-order pharmacokinetic model and independent of body weight. In addition, the specific chemical structure of remimazolam makes its metabolism nonspecific, degradable by a wide range of tissue esterases, and independent of cytochrome-dependent hepatic pathways. In this situation, its sedative effect is short-acting and recovery time is short.⁵ Studies have also shown that long-term or high-dose infusion of remimazolam is associated with lower risk of accumulation and prolonged efficacy.⁶

Procedural Sedation

A summary of published remimazolam clinical trials for procedural sedation is presented in Table 1^7-20.

Gastrointestinal Endoscopy

Phase IIa clinical study in 2015 reported that a single dose of remimazolam had an increased sedative effect on gastroscopy. An increase in the dose (0.1–0.2 mg/kg) resulted in shorter times to onset but led to the disappearance of the effect.⁷ In a subsequent Phase IIb study in 2016, a comparative analysis was done between remimazolam and midazolam regarding the sedative effect during colonoscopy.⁸ In that study, 162 patients were randomly administered remimazolam or midazolam. The results showed that more than 82.5% of patients receiving a loading dose of remimazolam achieved adequate sedation, which was much higher than that of patients receiving midazolam (46.3%). Additionally, the success rate of sedation was significantly higher after remimazolam administration throughout the procedure (92.5%–97.5% vs. 75%), and had a shorter onset time (2.23–3.03 vs. 4.8 min). According to the Hopkins Verbal Learning Test–Revised (HVLT-R), which defines good recovery of neuropsychiatric function with little change from baseline, the scores of patients receiving remimazolam were significantly higher than those receiving midazolam (−3.8 to −5.2 vs. −8.7), suggesting a shorter time to return to normal neuropsychiatric function in this population.

To examine the efficacy and safety of remimazolam versus midazolam in colonoscopy, Rex et al.⁹ conducted a phase III clinical trial. In this trial, 461 patients were enrolled and randomized into one of three groups: remimazolam (5 initial/2.5 mg top-up dose), placebo, or open-label midazolam (1.75 or 1 initial/1 or 0.5 mg top-up dose). The time to onset of sedation was significantly shorter with remimazolam than with midazolam (4.0 vs. 19.0 min), and less fentanyl was consumed (88.6 vs. 106.9 mcg). Furthermore, remimazolam significantly shortened the recovery time from the end of the procedure to full alert (7.35 vs. 15.84 min) and full conscious (3.2 vs. 6.1 h). Consistent with previous clinical trials, the HVLT-R scores also revealed that the patients’ best recovery of neuropsychiatric function followed remimazolam administration. Regarding safety, there was no significant difference between remimazolam and midazolam in adverse events, although the incidence of hypotension was lower in patients treated with remimazolam.

A non-inferiority study of remimazolam and propofol in gastroscopy¹⁰ and colonoscopy¹¹ was designed by Chen et al. The study included 384 and 388 patients scheduled to undergo gastroscopy and colonoscopy, respectively, and randomly assigned them to receive remimazolam or propofol. The results revealed that the sedation success rate of remimazolam in gastroscopy was 97.34%, and 96.91% in colonoscopy, both of which were non-inferior to that of propofol. In addition, the onset time of sedation with remimazolam was longer than with propofol. Gait disturbances and dizziness were the main adverse events in patients receiving concomitant remimazolam and propofol. However, the incidence of adverse events, bradycardia, and respiratory suppression were significantly lower in the remimazolam-treated population than in the propofol-treated population. A randomized, double-blinded trial evaluated the discharge time of patients administered remimazolam versus propofol for colonoscopy.¹² This trial randomly allocated 132 participants to either the remimazolam or propofol group to achieve adequate sedation (Modified Observer’s Assessment of Alertness/Sedation [MOAA/S] score ≤ 3). The results showed that remimazolam leads to a non-inferior discharge time (24 vs. 21 min), lower occurrence of hypotension (20% vs. 47%) and bradycardia (6% vs. 20%), and higher patient satisfaction scores in ambulatory colonoscopy than propofol.¹² These results indicated that remimazolam has a longer time to onset of sedation than propofol. Still, they confirmed the potential of remimazolam as a valuable medication for gastrointestinal endoscopy with a sedation success rate non-inferior to that of propofol but higher than that of midazolam and with better safety.

American Society of Anesthesiologists (ASA) Class III or IV

A recent study showed that remimazolam was safer than midazolam during colonoscopy in a susceptible patient population.¹³ This study included 79 patients with ASA physical status class III or IV who were randomized to receive remimazolam, and placebo or midazolam. The overall incidence of urgent adverse events was similar between the groups (10.8% vs. 6.7%). Additionally, percutaneous PCO₂ during sedation did not change from the baseline level in any group, and there were no significant differences between remimazolam and midazolam in nadir levels of any vital signs. Remimazolam was also associated with significantly shorter times to onset of sedation (8.0 vs. 18.6 min) and full alertness (11.0 vs. 18.8 min), consistent with the findings in ASA I/II patients.⁹ Thus, remimazolam is considered safe and effective in ASA III or IV patients undergoing colonoscopy. However, considering the declined physical function in fragile patients, we suggest that appropriately reducing the dose of remimazolam in clinical practice.

Elderly Patients

Elderly individuals have comorbidities and decreased organ function, and the incidence of perioperative complications and mortality is significantly higher than those of young adults. A clinical trial was conducted by Liu et al.¹⁴ to investigate the feasibility of remimazolam for colonoscopy in elderly patients. A total of 260 patients were randomly assigned to either remimazolam or etomidate plus propofol. The data revealed that the surgical success rate of the remimazolam group was not inferior to that of the combined group (96.52% vs. 100%). The incidence of fully alert time (3 vs. 4 min), time to discharge (13.92 vs. 14.97 min), and muscle fibrillation and injection pain (3.48% vs. 12.82%) were lower in the remimazolam group.¹⁴ Remimazolam has also been studied in the optimal dose for gastroscopy in the elderly.¹⁵ The cognitive function in patients receiving remimazolam and propofol was assessed comprehensively by the digit symbol substitution test, the number connection test, and the Auditory Verbal Learning Test–Huashan version. The results revealed that cognitive function after administration of 0.1 mg/kg remimazolam was not significantly different from that at the baseline level. Furthermore, remimazolam and propofol did not differ significantly in duration of sedation (8.27 vs. 8.21 min) and recovery time (3.82 vs. 4.33 min). However, remimazolam was associated with a significantly lower incidence of hypotension (3.0% vs. 38.5%). The results suggested that 0.1 mg/kg remimazolam is suitable for sedation in elderly patients undergoing upper gastrointestinal endoscopy, as it demonstrated remarkably stable hemodynamics and acceptable neuropsychiatric functions.

Hepatic or Renal Impairment

Stöhr et al.²¹ conducted a clinical trial to investigate the pharmacokinetics of remimazolam (liver, 0.1 mg/kg; kidney, 1.5 mg) in patients with hepatic and renal insuficiency. The results showed that the clearance of remimazolam was reduced by 38.1% in patients with severe hepatic impairment compared with healthy volunteers, and the recovery time was correspondingly prolonged (healthy 8.0 min; moderate 12.1 min; severe 16.7 min). Furthermore, the clearance of remimazolam in patients with renal impairment was comparable to that in healthy volunteers, but the clearance of its inactive metabolite CNS7054 was consistent with the decreased renal function. Peak plasma concentrations were not associated with the decline in hepatic or renal function. In addition, patients with hepatic and renal dysfunction who receiving remimazolam had a lower overall incidence of adverse events, and there were no severe side effects. A recent clinical study recruited 148 patients with liver cirrhosis (Child-Pugh class A) undergoing gastroscopy to evaluate the efficacy and safety of remimazolam sedation compared with propofol sedation.¹⁶ Patients were divided into two groups to receive either remimazolam or propofol within 30 seconds combined with intravenous sufentanil before sedative medication. The mean time to sedation (MOAA/S score ≤ 1) was longer among patients in the remimazolam group than in the propofol group (88.3 vs. 62.7 s); however, the remimazolam group had a shorter time to recovery (44.7 vs. 64.6 s) and higher satisfaction rate (90.5% vs. 77.0%). Moreover, a lower incidence of respiratory depression (2.7% vs. 17.6%), body movement (8.1% vs. 23.0%), and hypotension (4.1% vs. 14.9%) was noted in the remimazolam group compared with the propofol group. This trial suggested that remimazolam combined with sufentanil adjuvant is better than propofol combined with sufentanil for patients with liver cirrhosis undergoing gastroscopy.¹⁶ The current studies reported that carboxylesterase could be found in the liver, lung, colon, large arteries,²² and adipose tissue²³ at the mRNA and protein levels. Despite its strong extrahepatic metabolic activity, remimazolam is affected to some extent by severe hepatic impairment. According to these specifications, remimazolam can be used regularly in patients who do not require dialysis for renal failure and mild to moderate hepatic impairment. A low-maintenance dose is also recommended for patients with severe hepatic impairment.

Bronchoscopy

A prospective, randomized, double-blind clinical trial examined the effectiveness and safety of remimazolam in bronchoscopy, including 446 patients from 30 medical centers who were administered remimazolam, placebo, or midazolam.¹⁷ The study reported that the sedation success rate of remimazolam was 80.6%, which was significantly higher than that of midazolam (32.9%). Additionally, patients treated with remimazolam had a shorter time to onset of sedation (6.4 vs. 16.3 min) and recovery to full consciousness (6.0 vs. 12.0 min). In addition, HVLT-R scores at 5 minutes after the patients treated with remimazolam were fully alert demonstrated the best recovery of neuropsychiatric function among the groups. There was no significant differences in the incidence of treatment-emergent adverse events and laboratory parameters between remimazolam and midazolam, suggesting that remimazolam is safe for procedural sedation in bronchoscopy. A recent randomized, double-blinded trial recruited 146 patients undergoing bronchoscopy to evaluate the efficacy and safety of remimazolam compared with dexmedetomidine.¹⁸ Sedation (MOAA/S score < 3) was maintained using remimazolam or dexmedetomidine. All the patients were treated with flumazenil at the end of the procedure. The success rate of completing the procedure with remimazolam was non-inferior to that with dexmedetomidine (94.5% vs. 91.8%), and remimazolam had an earlier onset time than dexmedetomidine (13.2 vs. 15.1 min); moreover, the time to becoming fully alert (2.5 vs. 3.6 min) and the time to discharge (18.6 vs. 21.2 min) were significantly shorter in the remimazolam group. Remimazolam provided better time metrics and hemodynamic stability than dexmedetomidine.¹⁸

Hysteroscopy

Zhang et al.¹⁹ revealed that the induction and maintenance doses of remimazolam during hysteroscopy were 0.2 mg/kg and 1.0 mg/kg/h, respectively; the target concentration of remifentanil during the procedure was maintained at 1.5 ng/mL by target-controlled infusion. In another study, Zhang et al.²⁰ revealed that the induction and maintenance doses of remimazolam were 0.25 mg/kg and 0.48–0.6 mg/kg/h, respectively. Both studies included adverse events as the primary outcome and showed significantly lower incidence of adverse events with remimazolam than with propofol. Additionally, the incidence of oxygen saturation, bradycardia, and hypotension was significantly lower in patients receiving remimazolam, indicating lesser impact on patients’ circulatory and respiratory functions. The sedation success rate was 100% in both studies.

Adverse Reactions

Common adverse events associated with remimazolam included hypotension, dizziness, headache, and decreased respiratory rate. Phases I–III studies revealed that the incidence of hypotension was 2.65%–6.45%.^4,8-10 In a Phase III clinical trial, the incidence of respiratory suppression in ASA III/IV patients treated with remimazolam was as high as 19.4%.¹³ No severe consequences occurred, and spontaneous resolution of the symptoms was observed after routine airway management. A recent meta-analysis investigating the efficacy and safety of remimazolam in procedural sedation demonstrated that the sedative efficacy of remimazolam was significantly higher than that of midazolam, but slightly less than that of propofol.²⁴ However, remimazolam was associated with a lower incidence of adverse events (especially respiration and circulation inhibitory effects) than midazolam and propofol.²⁴

Since remimazolam is structurally derived from midazolam, there is a risk of cross-resistance when remimazolam is used in combination with other benzodiazepines.²⁵ In 2021, a patient who had been treated with midazolam under general anesthesia four weeks earlier developed anaphylaxis shortly after receiving an induction dose of remimazolam under general anesthesia.²⁶ Seven similar cases of suspected anaphylaxis after administration of remimazolam were recently published.^27,28 Remimazolam contains dextran 40 as an additive, which is the suspected underlying cause of anaphylaxis.

Processed Electroencephalograms for Assessing the Sedative Level During Anesthesia With Remimazolam

The processed electroencephalogram, bispectral index (BIS) value for assessing appropriate levels of sedation levels during remimazolam anesthesia have been reported to be higher than those of propofol,²⁹ reaching a BIS of over 60 in some cases.³⁰ A recent study also revealed that BIS, patient state index, and spectral edge frequency (SEF) of BIS were relatively higher during remimazolam anesthesia, but the SEF of SedLine or pupillary diameter could be used as a supportive indicator of sedation level confirmation during remimazolam anesthesia.³¹

Summary

Remimazolam is a novel sedative agent with multiple characteristics (fast-acting, short-duration, and non-organ-dependent). It is superior to midazolam and non-inferior to propofol in clinical sedation, with better controllability and lesser impact on the respiratory and cardiovascular systems. Moreover, remimazolam might be effective as a sedative agent in the elderly, obesity, and ASA class III/IV populations. However, the effects of remimazolam in pediatric cases and patients with poor hepatic and renal function needs to be further explored, and the safe use of the antagonist flumazenil requires to be further tested.

Acknowledgments

None.

Conflict of Interest

None.

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References