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Background: Therapeutic gastrointestinal endoscopy, including endoscopic retrograde cholangiopancreatography and endoscopic submucosal dissection, requires effective sedation strategies to ensure procedural success and patient safety. However, optimal pharmacological regimens remain unclear, particularly for prolonged procedures. Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) for randomised controlled trials comparing pharmacological sedation strategies in patients undergoing therapeutic gastrointestinal endoscopy. Outcomes included procedural interference events, hypoxia, hypotension, bradycardia, recovery time, induction time, satisfaction, and postoperative nausea and vomiting. Risk of bias was assessed using the Cochrane RoB 2.0 tool, and certainty of evidence was rated using GRADE framework. A frequentist random-effects network meta-analysis was conducted, along with cluster ranking of co-primary outcomes to evaluate benefit-risk trade-offs. Results: Sixty randomised controlled trials involving 7,071 patients and 32 pharmacological regimens were included. Compared with propofol-opioid, which remained the reference standard, no regimen significantly reduced procedural interference events. Ketamine-propofol demonstrated consistent advantages across hypoxia (relative risk RR 0.12, 95% confidence interval CI 0.03 to 0.59, P = 0.009; moderate certainty), hypotension (RR 0.28, 95% CI 0.09 to 0.83, P = 0.021; low certainty), and bradycardia (RR 0.11, 95% CI 0.01 to 0.86, P = 0.035; moderate certainty). Cluster rank analyses identified ketamine-propofol and lidocaine-midazolam-propofol as the highest-ranking regimens in both efficacy and safety domains. Meta-regression revealed no significant effect modifiers. Conclusion: While propofol-opioid remains the standard reference, alternative sedation strategies such as ketamine-propofol and lidocaine-midazolam-propofol offer favourable profiles for therapeutic gastrointestinal endoscopy. These findings support individualised regimen selection based on patient and procedural needs. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251018215.
Jiang et al. (Tue,) studied this question.