Esketamine-propofol combination for colonoscopy sedation: addressing the limitations of propofol monotherapy

Dear Editor, Colonoscopy is an essential diagnostic and preventive procedure but is often limited by discomfort and the cardiopulmonary adverse effects of deep sedation. Propofol, although widely used for its rapid onset and short recovery profile, lacks intrinsic analgesic activity and can induce dose-dependent hypotension, respiratory depression, and bradycardia, with no available antidote. Efforts to optimize safety have increasingly focused on multimodal regimens combining propofol with low-dose agents that maintain sedation quality while mitigating hemodynamic instability. Esketamine, the S-enantiomer of ketamine, is a potent N-methyl-D-aspartate (NMDA) receptor antagonist with both analgesic and sympathomimetic properties[1]. Unlike propofol, esketamine supports cardiovascular tone and airway reflexes, theoretically counteracting propofol-induced hypotension and respiratory suppression. Across recent randomized clinical trials (RCTs), which were identified through searches of PubMed, Embase, Scopus, China National Knowledge Infrastructure, and Google Scholar, esketamine combined with propofol showed reduction in total propofol consumption and risk of cardiopulmonary adverse events compared to propofol alone. Fu et al demonstrated that esketamine 0.2–0.4 mg/kg significantly decreased the incidence of hypotension from 60 to ≤16%, with stable respiratory parameters across all dosing groups[2]. Similarly, Xiao et al reported a nearly ten-fold reduction in hypotension risk (P < 0.001) and significantly fewer hypoxemic episodes and injection site pain, while maintaining satisfactory sedation quality[3]. Liu et al found that esketamine 0.2 mg/kg improved postoperative cognitive recovery on day 3 (95.2% vs 83.3%), with fewer cardiopulmonary adverse events[4]. In a more recent trial, Sun et al showed that esketamine 0.15 mg/kg nearly halved the incidence of postoperative fatigue (28% vs 44%) and shortened discharge time (25 minutes versus 30 minutes, P = 0.001)[5]. Another study by Li et al found that esketamine (0.5 mg/kg) combined with propofol for painless colonoscopy not only improved hemodynamic stability but also resulted in faster recovery times and more favorable post-procedural moods[6]. These findings suggest that esketamine-propofol co-administration could likely achieve equivalent or superior sedation quality with enhanced hemodynamic safety and faster early recovery. However, the interpretation of this emerging evidence needs caution. All available trials originate from China, with limited sample sizes (ranging from 100 to 252 participants) with predominantly ASA I-II status, which may limit the generalizability of the findings. Routine adoption should await validation through multicenter, well-powered RCTs, ideally including Western, African, and Southeast Asian cohorts. Such studies should further explore optimal dosing, cognitive recovery, cost-effectiveness, satisfaction rates, and long-term outcomes of combination protocols. Practical considerations may also influence whether these findings translate into routine practice. Esketamine’s unit cost and storage requirements (including controlled-substance handling in many jurisdictions) can make it less accessible in colonoscopy units that rely on streamlined, low-cost sedation workflows. Its sympathomimetic profile requires careful safety monitoring for possible transient hypertension or tachycardia, which may not be standard practice in many high-volume colonoscopy units, and regulatory permissions for esketamine outside psychiatric indications vary, meaning many centers may not yet have governance pathways for its procedural use. In conclusion, current data suggest that low-dose esketamine represents a possible adjunct to propofol for colonoscopy sedation, with potential to improve hemodynamic stability and patient recovery without compromising safety. However, methodologic limitations and geographic homogeneity of existing studies preclude universal recommendations. Until confirmatory evidence emerges, esketamine-propofol combination should be considered selectively within clinical-trial or high-acuity procedural contexts where propofol monotherapy poses hemodynamic risks. This letter followed the Transparency in the Reporting of Artificial Intelligence (TITAN) Guidelines 2025[7].