Midazolam with meperidine and dexmedetomidine vs. midazolam with meperidine for sedation during ERCP: prospective, randomized, double-blinded trial

Background and study aim: The combination of midazolam and opioid has been widely used as a standard sedative regimen for endoscopic retrograde cholangiopancreatography (ERCP). Following recent evidence that dexmedetomidine may exert a synergistic effect in combination with midazolam, this study compared the sedative effect and adverse events of midazolam – meperidine – dexmedetomidine (MMD) and midazolam – meperidine during ERCP.

Patients and methods: A total of 110 patients who were scheduled for ERCP were prospectively enrolled and randomly assigned, in a double-blind manner, to the MMD (n = 53) or midazolam – meperidine (n = 57) groups. Each patient received an intravenous (IV) bolus dose of midazolam and meperidine (0.06 mg/kg and 50 mg, 30 % reduction and 25 mg for patients aged ≥ 65 years, respectively). To this dose, a continuous IV infusion of dexmedetomidine (1 μg/kg/h; MMD group) or the same volume of normal saline (midazolam – meperidine group) was added. The sedation level (Ramsay Sedation Scale [RSS]) as well as hemodynamic and respiratory changes were assessed.

Results: Adequate sedation (RSS ≥ 3) was maintained during ERCP in 75.5 % and 36.8 % of the MMD and midazolam – meperidine group, respectively (P < 0.001). RSS scores were significantly higher in the MMD group (P < 0.001). Intraoperative bispectral index scores were significantly lower in the MMD group (P < 0.001) than in the midazolam – meperidine group. Lower additional (P = 0.001) and total (P = 0.003) doses of midazolam were required in the MMD group. Patients in the MMD group showed lower pain scores (P < 0.001) and higher satisfaction scores (P < 0.001). Desaturation occurred more frequently in the midazolam – meperidine group (11 vs. 1; P = 0.003).

Conclusions: The addition of dexmedetomidine to the midazolam – meperidine regimen provided better sedative efficacy and a superior safety profile during ERCP compared with a midazolam – meperidine regimen.

This trial was registered at ClinicalTrials.gov Identifier (NCT01404689).

^* These authors contributed equally to this work.

• References

• 1 Lichtenstein DR, Jagannath S. Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy et al. Sedation and anesthesia in GI endoscopy. Gastrointest Endosc 2008; 68: 815-826
• 2 Reimann FM, Samson U, Derad I et al. Synergistic sedation with low-dose midazolam and propofol for colonoscopies. Endoscopy 2000; 32: 239-244
• 3 Bell GD. Premedication, preparation, and surveillance. Endoscopy 2000; 32: 92-100
• 4 Garewal D, Powell S, Milan SJ et al. Sedative techniques for endoscopic retrograde cholangiopancreatography. Cochrane Database Syst Rev 2012; CD007274 6
• 5 Honan VJ. Paradoxical reaction to midazolam and control with flumazenil. Gastrointest Endosc 1994; 40: 86-88
• 6 Garewal D, Waikar P. Propofol sedation for ERCP procedures: a dilemna? Observations from an anesthesia perspective. Diagn Ther Endosc 2012; 2012: 639190
• 7 Cohen LB, Delegge MH, Aisenberg J et al. AGA Institute review of endoscopic sedation. Gastroenterology 2007; 133: 675-701
• 8 Cohen LB, Wecsler JS, Gaetano JN et al. Endoscopic sedation in the United States: results from a nationwide survey. Am J Gastroenterol 2006; 101: 967-974
• 9 Riphaus A, Rabofski M, Wehrmann T. Endoscopic sedation and monitoring practice in Germany: results from the first nationwide survey. Z Gastroenterol 2010; 48: 392-397
• 10 Glomsaker T, Soreide K, Hoff G et al. Contemporary use of endoscopic retrograde cholangiopancreatography (ERCP): a Norwegian prospective, multicenter study. Scand J Gastroenterol 2011; 46: 1144-1151
• 11 Triantafillidis JK, Merikas E, Nikolakis D et al. Sedation in gastrointestinal endoscopy: current issues. World J Gastroenterol 2013; 19: 463-481
• 12 Kamibayashi T, Maze M. Clinical uses of alpha2 -adrenergic agonists. Anesthesiology 2000; 93: 1345-1349
• 13 Kunisawa T, Hanada S, Kurosawa A et al. Dexmedetomidine was safely used for sedation during spinal anesthesia in a very elderly patient. J Anesth 2010; 24: 938-941
• 14 Riker RR, Shehabi Y, Bokesch PM et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301: 489-499
• 15 Goksu S, Arik H, Demiryurek S et al. Effects of dexmedetomidine infusion in patients undergoing functional endoscopic sinus surgery under local anaesthesia. Eur J Anaesthesiol 2008; 25: 22-28
• 16 Dere K, Sucullu I, Budak ET et al. A comparison of dexmedetomidine versus midazolam for sedation, pain and hemodynamic control, during colonoscopy under conscious sedation. Eur J Anaesthesiol 2010; 27: 648-652
• 17 Muller S, Borowics SM, Fortis EA et al. Clinical efficacy of dexmedetomidine alone is less than propofol for conscious sedation during ERCP. Gastrointest Endosc 2008; 67: 651-659
• 18 Demiraran Y, Korkut E, Tamer A et al. The comparison of dexmedetomidine and midazolam used for sedation of patients during upper endoscopy: a prospective, randomized study. Can J Gastroenterol 2007; 21: 25-29
• 19 Jalowiecki P, Rudner R, Gonciarz M et al. Sole use of dexmedetomidine has limited utility for conscious sedation during outpatient colonoscopy. Anesthesiology 2005; 103: 269-273
• 20 Bol CJ, Vogelaar JP, Tang JP et al. Quantification of pharmacodynamic interactions between dexmedetomidine and midazolam in the rat. J Pharmacol Exp Therap 2000; 294: 347-355
• 21 Bergese SD, Patrick Bender S, McSweeney TD et al. A comparative study of dexmedetomidine with midazolam and midazolam alone for sedation during elective awake fiberoptic intubation. J Clin Anesthesia 2010; 22: 35-40
• 22 Salonen M, Onaivi ES, Maze M. Dexmedetomidine synergism with midazolam in the elevated plus-maze test in rats. Psychopharmacology 1992; 108: 229-234
• 23 Dasta JF, Jacobi J, Sesti AM et al. Addition of dexmedetomidine to standard sedation regimens after cardiac surgery: an outcomes analysis. Pharmacotherapy 2006; 26: 798-805
• 24 Triggs EJ, Nation RL. Pharmacokinetics in the aged: a review. J Pharmacokinet Biopharm 1975; 3: 387-418
• 25 Ramsay MA, Savege TM, Simpson BR et al. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2: 656-659
• 26 Schutz SM, Abbott RM. Grading ERCPs by degree of difficulty: a new concept to produce more meaningful outcome data. Gastrointest Endosc 2000; 51: 535-539
• 27 Piccirillo JF, Tierney RM, Costas I et al. Prognostic importance of comorbidity in a hospital-based cancer registry. JAMA 2004; 291: 2441-2447
• 28 Glass PS, Bloom M, Kearse L et al. Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology 1997; 86: 836-847
• 29 Aldrete JA. Modifications to the postanesthesia score for use in ambulatory surgery. J Perianesth Nurs 1998; 13: 148-155
• 30 Yüksel O, Parlak E, Koklu S et al. Conscious sedation during endoscopic retrograde cholangiopancreatography: midazolam or midazolam plus meperidine?. Eur J Gastroenterol Hepatol 2007; 19: 1002-1006
• 31 Sokal RR, Rohlf FJ. Biometry. New York: WH Freeman; 1995
• 32 Panzer O, Moitra V, Sladen RN. Pharmacology of sedative-analgesic agents: dexmedetomidine, remifentanil, ketamine, volatile anesthetics, and the role of peripheral Mu antagonists. Anesthesiol Clin 2011; 29: 587-605
• 33 Gerlach AT, Murphy CV, Dasta JF. An updated focused review of dexmedetomidine in adults. Annals Pharmacother 2009; 43: 2064-2074
• 34 Yi SY, Shin JE. Midazolam for patients undergoing upper gastrointestinal endoscopy: a prospective, single-blind and randomized study to determine the appropriate amount and time of initiation of endoscopy. J Gastroenterol Hepatol 2005; 20: 1873-1879
• 35 Jung M, Hofmann C, Kiesslich R et al. Improved sedation in diagnostic and therapeutic ERCP: propofol is an alternative to midazolam. Endoscopy 2000; 32: 233-238
• 36 Wehrmann T, Kokabpick S, Lembcke B et al. Efficacy and safety of intravenous propofol sedation during routine ERCP: a prospective, controlled study. Gastrointest Endosc 1999; 49: 677-683
• 37 Vargo JJ, Zuccaro GJr, Dumot JA et al. Gastroenterologist-administered propofol versus meperidine and midazolam for advanced upper endoscopy: a prospective, randomized trial. Gastroenterology 2002; 123: 8-16
• 38 Bloor BC, Ward DS, Belleville JP et al. Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes. Anesthesiology 1992; 77: 1134-1142
• 39 Kallio A, Scheinin M, Koulu M et al. Effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on hemodynamic control mechanisms. Clin Pharmacol Therap 1989; 46: 33-42
• 40 Gerlach AT, Dasta JF, Steinberg S et al. A new dosing protocol reduces dexmedetomidine-associated hypotension in critically ill surgical patients. J Crit Care 2009; 24: 568-574
• 41 Ickeringill M, Shehabi Y, Adamson H et al. Dexmedetomidine infusion without loading dose in surgical patients requiring mechanical ventilation: haemodynamic effects and efficacy. Anaesth Intensive Care 2004; 32: 741-745
• 42 Hall JE, Uhrich TD, Barney JA et al. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000; 90: 699-705
• 43 Rex DK. Review article: moderate sedation for endoscopy: sedation regimens for non-anaesthesiologists. Aliment Pharmacol Ther 2006; 24: 163-171
• 44 Mazanikov M, Udd M, Kylanpaa L et al. Patient-controlled sedation for ERCP: a randomized double-blind comparison of alfentanil and remifentanil. Endoscopy 2012; 44: 487-492
• 45 Angsuwatcharakon P, Rerknimitr R, Ridtitid W et al. Cocktail sedation containing propofol versus conventional sedation for ERCP: a prospective, randomized controlled study. BMC Anesthesiology 2012; 12: 20