Gastrointestinal and pulmonary endoscopy has undergone a significant transformation since they were introduced decades ago.1 Significant improvement in technology has made endoscopy the first-line method for screening, diagnosis, and treatment of many gastrointestinal conditions and the numbers performed annually are increasing worldwide from year to year.1 In the majority of cases, moderate to deep sedation is required to enable the easy performance of the procedure and to provide comfort for the patient.2 Because most patients are ambulatory and the nature of the work in the endoscopy suite requires a rapid turnover of cases, short-acting sedative agents are preferred. Propofol currently seems to be the gold standard, especially because it has a rapid onset and offset.3 However, propofol sedation is associated with injection pain, hypotension, bradycardia, hypoxia, apnoea, reduced swallowing capability, and fatigue.4,5 Any drug with a similar sedative profile or with a faster onset/offset than propofol which additionally is devoid of side effects would create a significant improvement in clinical sedation in the endoscopy suite.
Remimazolam is a sedative benzodiazepine drug that binds selectively to GABAA receptors in the brain.6 Due to an ester linkage it is easily hydrolysed, producing inactive metabolites. Thus, a rapid offset can be achieved. Therefore, it also shows great potential as a sedative agent in the endoscopy suite.6 Several phase II and phase III trials have evaluated remimazolam in endoscopy patients and compared it to midazolam, indicating the superiority of remimazolam.7–11 Chen et al. compared remimazolam to propofol in a multicenter trial during colonoscopy and concluded that remimazolam was noninferior to propofol for sedation efficacy and was superior to propofol for the profile of side-effects.12,13
In the current issue of the European Journal of Anaesthesiology, two additional clinical trials evaluated the use of remimazolam during colonoscopy and compared it to a propofol-based sedation strategy.13,14 Both trials specifically focused on the recovery profile and discharge from the hospital. Yao et al. performed a prospective, randomised, noninferiority trial in 132 patients who underwent ambulatory colonoscopy.13 The primary outcome variable was discharge time after colonoscopy using a validated postanesthetic discharge scoring system scale. The difference in discharge time to define noninferiority was set before the start of the study to be less than 5 min. Secondary outcomes included induction and emergence times, the extent of recovery upon arrival in the postanesthesia care unit, fatigue, the satisfaction of both patient and endoscopist, and the occurrence of adverse events. A difference of 2 min in discharge times was identified, demonstrating noninferiority of remimazolam. No differences in most secondary sedation outcomes were identified except for higher patient satisfaction with remimazolam. Injection pain, hypotension, and bradycardia were more frequently observed with propofol. Guo et al. evaluated the postoperative quality of recovery scale on day 3 after the colonoscopy as the primary outcome variable in almost 250 patients.14 Again, no difference in recovery was noted and these authors also concluded that remimazolam was noninferior in terms of recovery profile compared with propofol. Pain on injection, respiratory depression, and hypotension were observed more frequently in the propofol-treated patient group.
These two studies are important because they demonstrate both the feasibility and safety of remimazolam in this specific groups of patients and procedures. Indeed, remimazolam is effective in producing sedation of similar quality to that of propofol while safety seems to be increased. However, many limitations must be mentioned and several unanswered questions remain. Notably, remimazolam was given in fixed doses and to relatively young and healthy patients. Additionally, lipophilic opioids were co-administered in the study by Yao et al.13 Therefore, further research must address the dose-response relationship of remimazolam as well as appropriately characterise interactions and synergisms when opioids are co-administered with remimazolam. Many patients undergoing endoscopy are old and frail and additional studies in a frail, elderly population are therefore essential. Similarly, studies on paediatric patients are limited. Finally, most new drugs are relatively expensive and require careful cost-benefit evaluation and analysis to see if the perceived benefits identified in the present body of evidence are sufficient to compensate for the undoubtedly increased cost. Even though remimazolam appears to be a safe medication at first glance, there is a long way to go until it has been delivered to the millions of people who have already had propofol. During the evaluation of remimazolam other additional adverse effects may arise along the way. In 2021, a patient who had previously received midazolam in association with general anaesthesia 4 weeks earlier experienced anaphylaxis shortly after receiving an induction dose of remimazolam for general anaesthesia15 and very recently, seven similar cases of suspected anaphylaxis after remimazolam administration have been published.16,17 Remimazolam contains dextran 40 as an additive, and this has been suspected as the underlying cause for the anaphylaxis.
To conclude, as an anaesthetic community we are excited to see research into new, rapidly acting, fast offset drugs. We do need these drugs, especially in ambulatory care. However, it is not certain that remimazolam is the holy grail of endoscopic sedation. During the production of this editorial, two further cases of suspected remimazolam anaphylaxis have been published.18
Acknowledgements relating to this article
Assistance with article: none.
Financial support and sponsorship: none.
Conflicts of interest: TH was an advisor for Paion AG Germany.
Comment from the Editor: this article was checked and accepted by the Editors, but was not sent for external peer-review.
1. Ponsky JL, Strong AT. A history of flexible gastrointestinal endoscopy. Surg Clin North Am
2. Eberl S, Koers L, van Hooft F de, et al. The effectiveness of a low-dose esketamine versus an alfentanil adjunct to propofol sedation during endoscopic retrograde cholangiopancreatography: a randomized controlled multicentre trial. Eur J Anaesthesiol
3. Mason KP, Raymond S, Sullivan CA, et al. The synergistic effect of dexmedetomidine on propofol for paediatric sedation: a randomized trial. Eur J Anaesthesiol
4. Hanamoto H, Togawa E, Yokoe C, Niwa H. Swallowing ability and intra-oral water-retaining ability during moderate propofol sedation in healthy human volunteers: a prospective observational study. Eur J Anaesthesiol
5. Conway A, Collins P, Chang K, et al. High flow nasal oxygen during procedural sedation for cardiac implantable electronic device procedures: a randomized controlled trial. Eur J Anaesthesiol
6. Lee A, Shirley M. Remimazolam: a review in procedural sedation. Drugs
7. Pastis NJ, Yarmus LB, Schippers F, et al. Safety and efficacy of remimazolam compared with placebo and midazolam for moder- ate sedation during bronchoscopy. Chest
8. Rex DK, Bhandari R, Desta T, et al. A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. Gastrointest Endosc
2018; 88:427437. e6.
9. Rex DK, Bhandari R, Lorch DG, et al. Safety and efficacy of remimazolam in high-risk colonoscopy: a randomized trial. Dig Liver Dis
10. Pambianco DJ, Borkett KM, Riff DS, et al. A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy. Gastrointest Endosc
11. Borkett KM, Riff DS, Schwartz HI, et al. A phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy. Anesth Analg
12. Chen S, Wang J, Xu X, et al. The efficacy and safety of remimazolam tosylate versus propofol in patients undergoing colonoscopy: a multicenter, randomized, positive-controlled, phase III clinical trial. Am J Transl Res
13. Yao Y, Guan J, Liu L, et al. Discharge readiness after remimazolam versus propofol for colonoscopy: a randomized, double-blind trial. Eur J Anaesthesiol
14. Guo L, Liu T, Zhang Y, Qi D. Effect of remimazolam versus propofol sedation on the quality of recovery after colonoscopy: a randomized, controlled, noninferiority trial. Eur J Anaesthesiol
15. Tsurumi K, Hiramoto Y, Nagumo K, et al. Remimazolam anaphylaxis during anesthesia induction. J Anesth
16. Uchida S, Takekawa D, Kitayama M, Hirota K. Two cases of circulatory collapse due to suspected remimazolam anaphylaxis. JA Clin Rep
17. Kim KM, Lee H, Bang JY, et al. Anaphylaxis following remimazolam administration during induction of anaesthesia. Br J Anesth
2022; S0007-0912(22)00435-4. doi: 10.1016/j.bja.2022.07.047.
18. Uchida S, Takekawa D, Kitayama M, Hirota K. Two cases of circulatory collapse due to suspected remimazolam anaphylaxis. JA Clinical Reports