Reconsidering Sedation for Endoscopic Retrograde Cholangiopancreatography: The Potential of Remimazolam

Endoscopic retrograde cholangiopancreatography (ERCP) is among the most complex and technically demanding procedures in gastrointestinal endoscopy. Hence, it requires a high level of specialized expertise. Proper sedation is an important factor for ensuring that the procedure is completed safely and successfully. In particular, to decrease the risk of major ERCP-related adverse events such as bleeding, perforation, and pancreatitis, it is essential to achieve a level of sedation that guarantees both operator satisfaction and patient comfort. However, according to a prospective study on sedation in endoscopic practice using traditional sedative agents, deep sedation accompanied by respiratory depression occurs in up to 85% of ERCP cases. Based on this finding, ERCP itself is a significant risk factor for deep sedation [1]. In endoscopic procedures, benzodiazepines, particularly midazolam, are widely used as hypnotic sedatives in routine clinical settings. However, according to the current Japanese guidelines on sedation in endoscopic practice [2], no specific benzodiazepine agent has been definitely established as suitable for therapeutic endoscopic interventions, including ERCP. Moreover, no such agent is currently covered by the national health insurance system in Japan. In ERCP, midazolam alone or in combination with analgesics such as pethidine hydrochloride has traditionally been used. Recently, propofol-based sedation has become increasingly common due to its favorable recovery profile. A previous meta-analysis examined nine randomized controlled trials (RCTs) comparing propofol with traditional sedative agents for sedation in therapeutic endoscopic procedures including ERCP. Results showed that propofol had a significantly shorter recovery time than traditional sedative agents, although there were no significant differences in the incidence of hypoxemia or hypotension between the two types of drugs [3]. However, unlike benzodiazepines, propofol has no specific reversal agent; therefore, particular caution is required regarding its dose-dependent risk of cardiovascular and respiratory depression. In contrast to western countries, where anesthesiologists typically manage sedation for ERCP, endoscopists in Japan often assume this role. Therefore, they must have adequate training in airway management to ensure patient safety. At our institution, propofol-based sedation has been used for ERCP for over a decade. Further, only endoscopists who have been formally certified by the hospital to perform sedation, after receiving training directly from anesthesiologists, which includes endotracheal intubation techniques, are permitted to administer propofol. Moreover, bispectral index (BIS) monitoring is routinely utilized to maintain a constant and optimal depth of sedation [4]. Accordingly, the limited availability of sedative agents for ERCP, none of which are covered by insurance in Japan, and some ongoing safety concerns are challenges that remain unresolved and must be addressed. More recently, remimazolam has emerged as a novel hypnotic sedative agent for the induction and maintenance of general anesthesia, and it was first approved for clinical use in Japan in 2020 [5]. Remimazolam is a short-acting benzodiazepine that exerts its sedative effects by acting on the γ-aminobutyric acid-type A receptors [5]. Some of its pharmacological characteristics are similar to those of midazolam, including decreased risk of cardiovascular suppression, negligible injection pain, and reversibility with flumazenil. The most notable feature of remimazolam is its fast systemic clearance and short half-life. Compared with midazolam, remimazolam exhibits approximately threefold faster clearance (70.3 vs. 23.0 L/h) and a significantly shorter terminal half-life (0.75 vs. 2.89 h) [6]. In addition, remimazolam is metabolized independently of the cytochrome P450 system, resulting in a lower potential for drug–drug interactions [5]. In the field of general anesthesia, meta-analyses comparing remimazolam with propofol have been published, and accumulating evidence indicates that remimazolam is superior in reducing the risk of hypoxemia, bradycardia, and injection pain [7, 8]. The efficacy and safety of remimazolam for sedation during therapeutic endoscopic practice including ERCP have not yet been established, as only a limited number of studies have been reported to date. In the current issue of Digestive Endoscopy, Kim et al. [9] have reported a systematic review and meta-analysis comparing the use of remimazolam versus propofol for sedation in ERCP. This study included 965 participants from five RCTs—four conducted in China and one in South Korea—and evaluated the efficacy and safety of remimazolam compared with conventional propofol-based sedation during ERCP. In addition to conventional meta-analysis, a trial sequential analysis (TSA) was performed to control for type I error due to the small number of trials that were included. A conventional meta-analysis showed that remimazolam-based sedation was superior to propofol-based sedation in terms of reducing the incidence of hypoxia, hypotension, and bradycardia, with all outcomes rated as high certainty according to the GRADE system [9]. The required information size was not reached for any of the three events in TSA; however, the cumulative Z-curve crossed the TSA monitoring boundaries, indicating that remimazolam had a favorable safety profile despite the limited sample size [9]. The superiority of remimazolam over propofol in terms of safety profile in this study can be a game changer in sedation during ERCP. However, caution is required in interpreting the results of this meta-analysis, as several critical questions should still be addressed. First, among the five RCTs included in this meta-analysis, there was significant variability in the induction, maintenance, and rescue doses of remimazolam and a difference in propofol dosing across studies [9]. Further, various opioids, such as remifentanil, alfentanil, and butorphanol, were co-administered alongside remimazolam or propofol. Therefore, agents other than benzodiazepines might have influenced the outcomes. Subgroup analyses controlling for benzodiazepine dosage and concomitant opioid use are not currently feasible due to the limited data available. Nevertheless, future studies should be performed to validate these findings in larger, more homogeneous populations with standardized sedation protocols. Second, there have been concerns related to body movement, which was evaluated as one of the procedure condition variables. During ERCP, body movement can interfere with delicate endoscopic maneuvers, particularly during biliary cannulation or endoscopic sphincterotomy. The current meta-analysis found no significant difference in the completion rate of ERCP procedures. Nonetheless, the increased incidence of body movement associated with remimazolam may negatively impact endoscopist satisfaction [9]. Although deep sedation should be avoided from a safety perspective, excessive body movement under light sedation can compromise the successful and safe completion of ERCP procedures. Therefore, it is essential to cautiously balance the depth of sedation to optimize both safety and procedural conditions. Adjusting sedation depth using BIS monitoring may be a useful strategy. However, BIS was originally developed to assess sedation depth with propofol, not benzodiazepines, and its applicability to remimazolam-based sedation may be limited. Third, benzodiazepines can induce delirium. Although the current meta-analysis found no significant difference in the incidence of delirium between the remimazolam and propofol groups, subgroup analyses focusing specifically on elderly patients were not conducted. In the context of general anesthesia, a meta-analysis of 11 RCTs reported no significant difference in the incidence of postoperative delirium between remimazolam and propofol in elderly patients [7]. However, considering the increasing number of ERCP procedures being performed in extremely elderly individuals, a cautious and individualized approach remains essential. Although remimazolam is characterized by its short half-life and rapid offset, the occurrence of re-sedation after reversal with flumazenil has been reported [8]. Hence, it should be used with caution in clinical settings. Finally, the current meta-analysis did not perform a cost-effectiveness comparison. To establish the use of remimazolam as a routine sedative agent for ERCP in daily clinical practice, economic evaluations should be performed. Future large-scale studies must be conducted to assess its cost-effectiveness compared with conventional sedative agents. In conclusion, although there are still several unresolved issues, this meta-analysis first compared the efficacy and safety of the novel sedative remimazolam with conventional propofol during ERCP. It offers novel insights that may prompt a reconsideration of sedation strategies in ERCP practice. Timely enough, in June 2025, the use of remimazolam (Anerem; Mundipharma K.K., Tokyo, Japan) in endoscopic procedures received insurance approval in Japan, based on the results of a domestic phase III clinical trial [10]. Therefore, to date, remimazolam is the first and only benzodiazepine that is covered by insurance for endoscopic practice in Japan. While the Japanese phase III trial only included a few ERCP procedures, the encouraging findings of this meta-analysis on remimazolam warrant further confirmation via future large-scale studies, both in Japan and other countries globally, to reinforce their reproducibility and ensure their generalizability across broader clinical settings. Kosuke Minaga: drafting of the manuscript. Akane Hara and Masatoshi Kudo: critical revision of the manuscript. All authors have read and agreed to the submitted version of the manuscript. The authors would like to thank Enago (www.enago.jp) for the English language review. Author Kosuke Minaga is an Associate Editor of Digestive Endoscopy. The other authors declare no conflicts of interest for this article. This article is linked to https://doi.org/10.1111/den.15078.