EMERGING SEDATIVES
In this context, the trial by Luo et al[4] provides valuable evidence that combining etomidate with propofol target-controlled infusion (TCI) preserves hemodynamics without compromising sedation efficacy. The study enrolled 330 patients scheduled for same-day bidirectional endoscopy [American Society of Anesthesiologists (ASA) I-III, body mass index < 28 kg/m2] allocated into three arms: Propofol TCI alone (P group), propofol plus 0.1 mg/kg etomidate (0.1 EP), and propofol plus 0.15 mg/kg etomidate (0.15 EP). The primary endpoint was to verify whether etomidate’s known favorable hemodynamic profile could reduce the incidence of hypotension and thereby improve patient comfort, procedural efficiency, and operator satisfaction. Overall, the study demonstrated the clinical utility of adding 0.15 mg/kg etomidate to propofol TCI. The mean arterial pressure after induction was significantly higher in the 0.15 EP group (88 mmHg) compared with the propofol-only group (78 mmHg). Additionally, the incidence of hypotension fell from 36.4% in propofol controls to 11.8% with etomidate supplementation.
These findings are crucial because large propofol doses, especially in vulnerable populations, can lead to considerable cardiovascular depression. In the 0.15 EP cohort, the mean cumulative dose of propofol was 201.2 mg, significantly lower than the 260.6 mg administered in the control group, thereby decreasing the overall risk of sedation-related hypotension. The etomidate-propofol synergy also accelerated induction times: 1.1 ± 0.3 minutes in 0.15 EP vs 1.9 ± 0.7 minutes in propofol-only, an outcome of practical relevance in high-volume endoscopy units. Furthermore, recovery was expeditious (3.9 ± 1.4 minutes in the 0.15 EP group vs 4.8 ± 2.1 minutes in controls), and no patients required intubation or developed severe hypotension. Patient satisfaction, tied closely to reduced sedation-related interruptions and stable hemodynamics, was significantly higher in the 0.15 EP group. Despite etomidate’s established cardiovascular stability, the risk of myoclonic activity remains a pertinent safety consideration.
Secondary endpoints reinforce the trial’s overarching theme of patient comfort and safety. Respiratory depression, a leading cause of sedation-related morbidity according to both American and European guidelines, was halved when etomidate was added, dropping from 30.9% in propofol-only patients to 10.9% in the higher-dose etomidate group. Severe episodes of hypoventilation likewise declined from 15.5% to 4.5%. Moreover, the single-bolus etomidate used in this study (0.15 mg/kg) did not lead to any clinically significant adrenal suppression, which has historically limited its repeated or prolonged use. Although formal adrenal function tests were not routinely performed, no patient showed overt signs of adrenal compromise during the short observation period, suggesting that low-dose etomidate might be acceptable for one-day endoscopic sedation in low- to moderate-risk (ASA I-III) candidates.
Within the landscape of novel sedation regimens, the etomidate-propofol strategy conforms to current demands for safe, individualized sedation[5,6]. The British Society of Gastroenterology guideline stresses that older adults and patients with substantial cardiopulmonary disease warrant special caution and often benefit from regimens that minimize cardiovascular depression. European Society of Gastrointestinal Endoscopy recommendations similarly advocate patient-specific sedation plans that balance sufficient depth of sedation against cardiopulmonary reserve[3]. These guidelines reflect a global trend toward sedation strategies that cause fewer hemodynamic disruptions, especially amid the growing patient population at elevated cardiovascular risk[7]. The study by Luo et al[4] excluded patients with more severe comorbidities, including obesity over a certain threshold (body mass index ≥ 28 kg/m2) and ASA class IV, leaving unanswered questions about whether the etomidate-propofol combination might also benefit more complex cohorts. Nonetheless, recent evidence, such as that from the EPIC trial, suggests that the etomidate-propofol combination could offer potential benefits in older patients, particularly those classified as ASA IV or with cardiopulmonary compromise[8-11]. Future investigations should refine dosing and monitoring protocols to maximize safety in these populations. However, the data strongly suggest that, at least in typical ASA I-III endoscopy candidates, adding a single bolus of 0.15 mg/kg etomidate can significantly enhance hemodynamic stability, shorten induction time, and reduce total propofol dose, an important trio of outcomes for busy endoscopy units.
Alongside this etomidate-propofol approach, remimazolam, a novel short-acting benzodiazepine, is likewise garnering attention. A growing body of evidence indicate that remimazolam offers a comparable depth of sedation to midazolam or propofol, with reduced risks of hypotension, bradycardia, and respiratory depression, particularly in older or ASA III-IV populations[12-14]. Preliminary randomized trials report that remimazolam ensures faster recovery times compared with midazolam and demonstrates a favorable safety profile for patients at risk of cardiovascular instability[15,16]. Moreover, unlike propofol, remimazolam can be reversed with flumazenil, offering an extra measure of control in cases of unexpected oversedation. Nevertheless, its cost and accessibility remain potential hurdles to broader adoption. The risk of dependence and sedation-related adverse events demands careful monitoring, especially in vulnerable populations[17-20]. Further research, including cost-effectiveness analyses, is therefore essential.
While there are currently few head-to-head comparisons between etomidate-propofol and remimazolam-propofol combinations are not yet abundant, the general trend in sedation research is toward short-acting agents with lower cardiopulmonary impact and allow for rapid emergence from sedation[21]. Although clinical observation remains the most accessible tool for assessing sedation depth, the use of objective measures such as the bispectral index provides more accurate and reproducible monitoring[22]. Its adoption may reduce the risk of over- or under-sedation and should be considered, particularly during longer or more technically demanding interventions.
In the future, it will be crucial to determine whether the etomidate-propofol regimen can be extended to higher-risk populations, including those with obesity, advanced heart failure, or respiratory compromise. At the same time, comparative trials on remimazolam are needed to pinpoint the optimal sedative that maintains hemodynamic stability, reduces respiratory depression, and facilitates rapid discharge. This is underscored by recent findings from Zhang et al[23], who randomized 120 ASA I-II elderly patients (60-75 years) to receive either remimazolam (7 mg) or etomidate (0.1 mg/kg) plus propofol (0.5 mg/kg), both in combination with remifentanil (0.3 μg/kg). Although induction with remimazolam was slightly slower (1.50 minutes vs 1.15 minutes), the stay in the post-anesthesia care unit was shorter (15.17 minutes vs 17.40 minutes), and Mini-Cog scores at discharge were higher. Respiratory events were more common with etomidate-propofol (18.3% vs 5.0%), whereas hiccups occurred more often with remimazolam (13.3% vs 0%). These results underscore that remimazolam is at least as safe and effective as etomidate-propofol for ASA I-II elderly patients, although vigilance for hiccups is essential. Beyond etomidate and remimazolam, ciprofol, a novel propofol analog, has recently gained attention for its rapid onset, reduced injection site pain, and favorable recovery profile[24]. While not addressed in the current discussion, its inclusion in future comparative trials may be valuable to broaden the armamentarium of sedative agents suitable for gastrointestinal endoscopy.
CONCLUSION
As endoscopic interventions become more complex, particularly in advanced contexts such as interventional endoscopic ultrasound, endoscopic retrograde cholangiopancreatography, or endoscopic submucosal dissection, the imperative for stable hemodynamics and reliable sedation depth grows accordingly. Encouraged by the promising findings from Luo et al[4] and Zhang et al[23], future trials should investigate whether the etomidate-propofol regimen may similarly benefit longer or more technically demanding procedures, while also determining if remimazolam could provide equivalent or superior outcomes in these settings. Both approaches align with current objectives of minimizing cardiorespiratory compromise and ensuring an efficient workflow, ultimately enhancing patient comfort, operator performance, and procedural success. Prospective randomized trials comparing both regimens in higher-risk populations, including ASA IV patients, obese individuals, or those with cardiopulmonary compromise, are needed to ascertain the safest and most efficacious sedation strategies for prolonged or complex endoscopic interventions. Emerging delivery modalities such as TCI and patient-controlled sedation offer promising avenues to enhance procedural safety and individualize sedation levels[25,26]. These technologies facilitate precise titration of sedatives, potentially reducing adverse events and improving patient satisfaction. Such studies are critical to determining how best to optimize sedation depth, maintain hemodynamic stability, and uphold patient satisfaction across diverse endoscopic practices.
