Low dose esketamine for gastrointestinal endoscopy: a double-blinded, randomized controlled trial

Background: Propofol and remifentanil are frequently used together for painless therapeutic gastrointestinal (GI) endoscopy. However, this combination can result in respiratory and cardiovascular depression. The use of esketamine has the potential to counteract these adverse effects. This study evaluates the efficacy and safety of low-dose esketamine combined with a fixed dose of propofol-remifentanil sedation during painless therapeutic GI endoscopy. Methods: A total of 400 patients undergoing painless therapeutic GI endoscopy were randomly divided into four groups (n = 100 per group). The control group received propofol and remifentanil, while the other three groups received propofol and remifentanil plus 0.05, 0.10 and 0.15 mg/kg/h esketamine. Throughout the procedure, we recorded hemodynamics, pulse oxygen saturation, somatic responses, adverse event management, emergence delirium and perioperative Mini-Mental State Examination (MMSE) scores. Results: Respiratory interventions were significantly higher in the control groupcompared to three esketamine groups (elevated oxygen flow: 15% vs. 2%, 2% and 4%; mandibular support: 10% vs. 1%, 1% and 3%; mask ventilation: 4% vs. 0%, 0% and 0%). Hypotension and bradycardia occurred more frequently in the control group (hypotension: 13% vs. 3%, 1% and 1%; bradycardia: 15% vs. 5%, 3% and 2%). Although there were no significant differences in gagging among the groups, a reduced response to body movement was documented in patients randomized to esketamine when compared to the control group (1% vs. 13%). No significant changes were observed in MMSE scores in any of the groups. Conclusions: The continuous infusion of small-dose esketamine in addition to propofol-remifentanil sedation could provide efficient and safe sedation for painless therapeutic GI endoscopic procedures. Clinical Trial Registration: The study was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2400079866). Date of registration: 15 January 2024.

Esketamine; Propofol-remifentanil; Fixed-dose; Sedation; Gastrointestinal endoscopy

[1] Zhou S, Zhu Z, Dai W, Qi S, Tian W, Zhang Y, et al. National survey on sedation for gastrointestinal endoscopy in 2758 Chinese hospitals. British Journal of Anaesthesia. 2021; 127: 56–64.

[2] Zhong J, Zhang J, Fan Y, Zhu M, Zhao X, Zuo Z, et al. Efficacy and safety of Ciprofol for procedural sedation and anesthesia in non-operating room settings. Journal of Clinical Anesthesia. 2023; 85: 111047.

[3] Wu B, Zhu W, Wang Q, Ren C, Wang L, Xie G. Efficacy and safety of ciprofol-remifentanil versus propofol-remifentanil during fiberoptic bronchoscopy: a prospective, randomized, double-blind, non-inferiority trial. Frontiers in Pharmacology. 2022; 13: 1091579.

[4] Joy PJ, Blanshard HJ. Propofol-remifentanil patient-controlled sedation for endoscopic procedures: a prospective service audit. Canadian Journal of Anesthesia. 2023; 70: 1735–1743.

[5] Wu J, Li N, Zhang J, Tang X, Cao X. Safety and efficacy of remifentanil-propofol combination on “muscle relaxant-free” general anesthesia for therapeutic endoscopic retrograde cholangiopancreatography: a randomized controlled trial. American Journal of Translational Research. 2023; 15: 5292–5303.

[6] De Vico P, Biasucci DG, Aversano L, Polidoro R, Zingaro A, Millarelli FR, et al. Feasibility and safety of deep sedation with propofol and remifentanil in spontaneous breathing during endoscopic retrograde cholangiopancreatography: an observational prospective study. BMC Anesthesiology. 2023; 23: 260.

[7] Feeney A, Papakostas GI. Pharmacotherapy: ketamine and esketamine. Psychiatric Clinics of North America. 2023; 46: 277–290.

[8] Wu J, Gu J, Qiu L, Jin X, Zhou Z. Challenges for esketamine nasal spray in China: use and management. Frontiers in Pharmacology. 2024; 15: 1429435.

[9] Mildh L, Taittonen M, Leino K, Kirvelä O. The effect of low-dose ketamine on fentanyl-induced respiratory depression. Anaesthesia. 1998; 53: 965–970.

[10] Algera MH, Kamp J, van der Schrier R, van Velzen M, Niesters M, Aarts L, et al. Opioid-induced respiratory depression in humans: a review of pharmacokinetic-pharmacodynamic modelling of reversal. British Journal of Anaesthesia. 2019; 122: e168–e179.

[11] Jonkman K, van Rijnsoever E, Olofsen E, Aarts L, Sarton E, van Velzen M, et al. Esketamine counters opioid-induced respiratory depression. British Journal of Anaesthesia. 2018; 120: 1117–1127.

[12] Jansen SC, van Velzen M, Sarton E, Dahan A, Niesters M, van der Schrier R. Acute effects of esketamine on hypoxic ventilatory response, haemodynamics, and brain function in healthy volunteers. British Journal of Anaesthesia. 2024; 134: 557–563.

[13] Dahan A, van der Schrier R, Smith T, Aarts L, van Velzen M, Niesters M. Averting opioid-induced respiratory depression without affecting analgesia. Anesthesiology. 2018; 128: 1027–1037.

[14] Suleiman A, Wongtangman K, Eikermann M, Stucke AG. Neuroanatomical and pharmaco-physiological effects of hypoxia and esketamine on breathing, the sympathetic nerve system, and cortical function. British Journal of Anaesthesia. 2025; 134: 277–280.

[15] Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, et al. Validity and reliability of the observer’s assessment of alertness/sedation scale: study with intravenous midazolam. Journal of Clinical Psychopharmacology. 1990; 10: 244–251.

[16] Bower AL, Ripepi A, Dilger J, Boparai N, Brody FJ, Ponsky JL. Bispectral index monitoring of sedation during endoscopy. Gastrointestinal Endoscopy. 2000; 52: 192–196.

[17] Qadeer MA, Vargo JJ, Patel S, Dumot JA, Lopez AR, Trolli PA, et al. Bispectral index monitoring of conscious sedation with the combination of meperidine and midazolam during endoscopy. Clinical Gastroenterology and Hepatology. 2008; 6: 102–108.

[18] Aldrete JA. The post-anesthesia recovery score revisited. Journal of Clinical Anesthesia. 1995; 7: 89–91.

[19] Kamp J, van Velzen M, Aarts L, Niesters M, Dahan A, Olofsen E. Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers. British Journal of Anaesthesia. 2021; 127: 23–31.

[20] Li Y, Wu ZY, Zheng WC, Wang JX, Yue X, Song RX, et al. Esketamine alleviates postoperative cognitive decline via stimulator of interferon genes/TANK-binding kinase 1 signaling pathway in aged rats. Brain Research Bulletin. 2022; 187: 169–180.

[21] Qiu LL, Pan W, Luo D, Zhang GF, Zhou ZQ, Sun XY, et al. Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice. Journal of Neuroinflammation. 2020; 17: 23.

[22] Yin S, Hong J, Sha T, Chen Z, Guo Y, Li C, et al. Efficacy and tolerability of sufentanil, dexmedetomidine, or ketamine added to propofol-based sedation for gastrointestinal endoscopy in elderly patients: a prospective, randomized, controlled trial. Clinical Therapeutics. 2019; 41: 1864–1877.e0.

[23] Zhan Y, Liang S, Yang Z, Luo Q, Li S, Li J, et al. Efficacy and safety of subanesthetic doses of esketamine combined with propofol in painless gastrointestinal endoscopy: a prospective, double-blind, randomized controlled trial. BMC Gastroenterology. 2022; 22: 391.

[24] Jang SY, Park HG, Jung MK, Cho CM, Park SY, Jeon SW, et al. Bispectral index monitoring as an adjunct to nurse-administered combined sedation during endoscopic retrograde cholangiopancreatography. World Journal of Gastroenterology. 2012; 18: 6284–6289.

[25] Carrara L, Nault M, Morisson L, Godin N, Idrissi M, Fortier A, et al. The impact of bolus versus continuous infusion of intravenous ketamine on bispectral index variations and desflurane administration during major surgery: the KETABIS study. European Journal of Anaesthesiology. 2021; 38: 1168–1179.

[26] Salloum E, Lotte Seibold E, Azimaraghi O, Rudolph MI, Beier J, Schaefer MS, et al. Association of ketamine use during procedural sedation with oxygen desaturation and healthcare utilisation: a multicentre retrospective hospital registry study. British Journal of Anaesthesia. 2024; 132: 779–788.

[27] Absalom AR, Rigby-Jones AE, Rushton AR, Robert Sneyd J. De-mystifying the “Mixifusor”. Paediatric Anaesthesia. 2020; 30: 1292–1298.

[28] Malherbe S, Barker N. Mixing of propofol and remifentanil. Paediatric Anaesthesia. 2021; 31: 504–505.