Since its introduction almost 40 years ago, propofol has been adopted worldwide as the intravenous anesthetic of choice, with alternatives such as ketamine and etomidate limited to unusual indications. However, propofol has several common adverse effects, including pain on injection and hypotension. While rare, infection (from contamination of the infusate) and propofol infusion syndrome are possible lethal complications of propofol infusions.

Despite a clearance that exceeds hepatic blood flow, propofol can accumulate during long infusions. The offset kinetics do not come close to those of remifentanil, whose ester hydrolysis enables elimination of more than half of the drug in the blood within a few minutes after terminating an infusion of any duration. Lastly, there is no reversal for propofol. A drug that reversed propofol might be useful for patients who awaken slowly after an exceptionally long infusion, or to manage a severe propofol-induced hypotensive episode refractory to hemodynamic intervention.

These limitations have inspired continuous research into a superior alternative ever since the introduction of propofol (Curr Opin Anaesthesiol 2020;33:499-505; Drug Des Devel Ther 2022;16:3431-44; J Clin Med 2023;12:7316).

The primary contender as a superior hypnotic is remimazolam (Byfavo®), a benzodiazepine developed by PAION AG and granted clinical approval in 2020 (Drugs 2020;80:625-33). Unusually well-named, remimazolam combines the pharmacokinetics of remifentanil with the pharmacodynamics of midazolam. Indeed, the name “remimazolam” conveys nearly everything the practitioner needs to know about the drug.

  1. Like midazolam, it will not sting on injection.
  2. Like midazolam, it can be reversed by flumazenil.
  3. Like midazolam, it will cause only modest hypotension, if any.
  4. Like remifentanil, it is a “soft drug” that rapidly splits into metabolites through ester hydrolysis.
  5. Like remifentanil, it will not accumulate during long infusions, delaying recovery (Anesth Analg 2012;115:284-96).
  6. It cannot cause propofol infusion syndrome because it is not propofol (A similar syndrome has not been reported for benzodiazepines).

Anesthesiologists know that midazolam is perfectly capable of causing profound respiratory depression, particularly with opioids. There is no reason to expect remimazolam to be any different.

Remimazolam derives from midazolam and is a class 1.1 new drug (Drug Des Devel Ther 2022;16:3431-44). Its pharmacological action mirrors that of midazolam, influencing gamma-aminobutyric acid (GABA) receptors and inhibiting cellular excitation in the midbrain’s reticular formation (Anesth Pain Med (Seoul) 2022;17:1-11; Ther Clin Risk Manag 2022;18:95-100). This short-acting GABA receptor agonist boasts high organ-independent clearance, lack of accumulation during prolonged infusions, and minimal injection pain (Drug Des Devel Ther 2022;16:3431-44). This confirms some of the anticipated benefits. As expected, remimazolam is readily reversible with flumazenil (J Clin Med 2023;12:7316). This might prove helpful in settings of unexpected toxicity, but the rapid elimination through ester hydrolysis precludes considering this a significant advantage.

Remimazolam is approved for procedural sedation and general anesthesia. As noted in a previous review in the ASA Monitor, it might prove to be particularly useful during brief, invasive procedures lasting 30 minutes or more, where the rapid offset might offer appreciable benefits over propofol (ASA Monitor 2020; 84: 1,12). Clinical studies involving thousands of patients have demonstrated favorable efficacy and safety profile in procedures such as colonoscopy and bronchoscopy (Anesth Pain Med (Seoul) 2022;17:1-11; ASA Monitor 2020;84:1:12).

Numerous studies have documented that remimazolam is a reasonable hypnotic for use during general anesthesia (Minerva Anestesiol 2023;89:553564.). These studies suggest that remimazolam generally causes less hypotension than propofol. Remimazolam also appears to be associated with less hypotension than propofol when combined with remifentanil for total intravenous anesthesia (Eur J Anaesthesiol 2024;41:208-16).

Remimazolam has been studied in elderly patients to assess whether age affects the pharmacokinetics, as well as to determine whether remimazolam might mitigate postoperative delirium and adverse cognitive effects (Drug Des Devel Ther 2022;16:3431-44). These studies included looking at challenging procedures, such as aortic valve replacement (Pharmacol Res Perspect 2021;9:e00851). The studies demonstrate that remimazolam retains the rapid esterase metabolism observed in younger patients. They also suggest that remimazolam causes considerably less hypotension than propofol. A recent review concludes that remimazolam is the preferred anesthetic for older patients (Heliyon 2024;10:e25399).

The pharmacokinetics of remimazolam (like remifentanil) appear unaffected by either renal or hepatic impairment (Br J Anaesth 2021;127:415-23). As a result, no dose adjustment is required in these patients.

Like remifentanil before it, there are modest effects of age, BMI, and some covariates in remimazolam pharmacokinetics (Drug Des Devel Ther 2022;16:3957-74). Continuing the analogy to remifentanil, the “one dose fits all” approach to remimazolam is probably a poor choice. Doses of remimazolam should be lowered in compromised patients. The literature is still working out how much adjustment is required (Drug Des Devel Ther 2022;16:3957-74).

Further exploration into remimazolam’s application in target-controlled infusion (TCI) reveals intriguing pharmacological nuances. A study employing a three-period crossover design stratified by age and sex demonstrated that these are important covariates to incorporate in remimazolam TCI (Anesthesiology 2024;140:207-19). Unexpectedly, the authors also demonstrated acute tolerance during remimazolam administration, which was elicited with a step-up/step-down paradigm of target concentrations (Anesthesiology 2024;140:207-19). Tolerance to benzodiazepines is well documented, of course. However, it is an unwelcome surprise that remimazolam can induce acute tolerance. This may be of no consequence, similar to the acute opioid tolerance demonstrated for remifentanil, which has almost no clinical consequence (Am J Ther 2015;22:e62-74). However, it could also present a clinical challenge in very long cases, offsetting the pharmacokinetic advantages of remimazolam over propofol.

“Remimazolam has been successfully studied for the induction and maintenance of procedural sedation and general anaesthesia due to its fast onset, short and predictable duration of sedative action, short recovery time, rare accumulation after long-term infusion, and less serious side effects as compared with those of other currently used benzodiazepines.”

As with all anesthetics, intravenous remimazolam must be administered by individuals trained to administer general anesthesia. Remimazolam can be expected to cause modest hypotension and hypoventilation (Drug Des Devel Ther 2022;16:3431-44). It appears that these cardiorespiratory effects are generally mild, at least when remimazolam is used for sedation (Drug Des Devel Ther 2022;16:3957-74). There have also been reported instances of anaphylactic shock (Ther Clin Risk Manag 2022;18:95-100).

Perhaps the most concerning complication is that patients who receive flumazenil at the end of a remimazolam anesthetic can undergo “re-sedation” if the effects of remimazolam outlast the flumazenil antagonism. This would appear to be an entirely avoidable complication. Quoting from a recent review of remimazolam, “reversal by flumazenil should be reserved for and used carefully in patients with delayed emergence” (Eur J Anaesthesiol 2023;40:841-53).

Like midazolam, remimazolam appears to have limited abuse liability. In a study among healthy recreational drug users aged 18-55, intravenous remimazolam had lower overall liking scores than equipotent intravenous scores for midazolam (Clin Pharmacol 2020;60:1189-97). The study participants also reported that they would be less willing to take remimazolam again, although this difference did not reach statistical significance.

To gain additional insights into the use of remimazolam, the ASA Monitor connected with Michel M.R.F. Struys, MD, PhD, FRCA. Dr. Struys is Professor and Chair, Department of Anesthesiology, University of Groningen-University Medical Center Groningen, and Professor, Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium.

ASA Monitor: In the context of general anesthesia, how does the integration of remimazolam prompt a reevaluation of benzodiazepines, and what challenges and opportunities does it bring to clinical practice?

Dr. Struys: Remimazolam offers similar effects and side effects as other benzodiazepines. Remimazolam has been successfully studied for the induction and maintenance of procedural sedation and general anaesthesia due to its fast onset, short and predictable duration of sedative action, short recovery time, rare accumulation after long-term infusion, and less serious side effects as compared with those of other currently used benzodiazepines. (Dr. Struys notes that answers to this question use modified text from an article authored by him and his colleagues.) (J Clin Med 2022; 11: 3493)

There are several studies that have shown that remimazolam is well tolerated and effective for procedural sedation. Remimazolam causes some increase in heart rate and some decrease in blood pressure at the start of the infusion, albeit less than propofol. Onset of sedation is rapid compared to midazolam, even though it is less potent. In studies, single boluses combined with top-up doses provide sufficient sedation levels for a colonoscopy without the need for mechanical ventilation. It has been shown that less fentanyl was needed during colonoscopy and that patients recovered faster and were ready for discharge earlier than with midazolam. They furthermore reported a lower incidence of hypotension, but a similar frequency of hypoxia compared to midazolam. Several studies have shown that remimazolam, in contrast to propofol, does not induce pain during infusion, which would be beneficial in pediatric practice. One of the more important favorable characteristics of remimazolam is that, unlike other current anesthetic agents, its effects can be antagonized with flumazenil.

Remimazolam is found to be non-inferior to propofol for general anesthesia in ASA II and III patients with respect to safety and efficacy. However, it appears to induce loss of consciousness more slowly than propofol.

More studies are required to gain more information about safety and dosing in children. Additionally, some reports on anaphylaxis with remimazolam have been published. Two other important caveats associated with remimazolam use are the fact that remimazolam precipitates when mixed with Ringer’s acetate or Ringer’s lactate solutions. Therefore, co-administration with other intravenous fluids is needed. Additionally, there are some publications showing detailed information on the incidence of the occurrence of delirium, despite the potential benefit of the fast offset of action. These topics still need further research.

ASA Monitor: What implications does acute tolerance development have on remimazolam’s safety and efficacy, and how should clinicians adjust dosing strategies? Further research is needed to refine dosing, especially in diverse patient populations. What areas of research should be prioritized to address acute tolerance complexities in remimazolam administration?

“It would be very interesting to study remimazolam during ICU sedation knowing the limitation for the use of propofol in the ICU and the known risk of longer recovery times when using continuous administration of midazolam.”

Dr. Struys: Our publication is a first report on the development of acute tolerance of remimazolam. Our findings are based on population-based pharmacokinetic-dynamic modelling. Our findings need to be investigated further using receptor pharmacology approaches to better understand the possible underlying mechanisms of this phenomenon. Until then, it’s difficult to have a definitive answer on the impact. Observing our data, tolerance looks like being less relevant in lower-level dosing schemes during sedation and shorter anesthesia cases. It might be more relevant when using remimazolam during longer procedures and during ICU sedation. Some preliminary studies found some tolerance to remimazolam after 24 hours of drug administration at the ICU. At this moment, remimazolam is not approved for ICU sedation and further information is required, although some countries (e.g., Belgium) allowed compassionate use during the COVID pandemic period (due to shortage of other drugs for ICU sedation).

It would be very interesting to study remimazolam during ICU sedation knowing the limitation for the use of propofol in the ICU and the known risk of longer recovery times when using continuous administration of midazolam.

ASA Monitor: What specific pharmacovigilance measures are being employed to continually monitor and assess the real-world abuse patterns and adverse effects associated with remimazolam?

Dr. Struys: Remimazolam is a benzodiazepine. As remimazolam is an ultra-short-acting drug, the risk of abuse is less compared to longer-acting benzodiazepines. A recent study concluded that the abuse potential of remimazolam is comparable to or lower than that of midazolam, a drug known to have a low potential for intravenous abuse (J Clin Pharmacol 2020;60:1189-97).