Study to Determine if the Midazolam-Meperidine-Dexmedetomidine is Superior to the Midazolam-Meperidine for Sedation During ERCP
Condition: Undergoing ERCP for Diagnostic or Therapeutic Purposes
Study type: Interventional
Phase: Phase 4

Summary: 
      Endoscopic retrograde cholangiopancreatography (ERCP) takes a longer time and is more complex
      to perform than the other parallel procedures, causing discomfort to patients. It is commonly
      performed under sedation endoscopy. Until recently, the combination administration of
      midazolam and opioid has been widely used as standard therapy due to its superior sedation
      effect compared to the other sedation agents. Midazolam, however, has problems, such as an
      insufficient sedation effect and an intermittent paradoxical response.

      Unlike midazolam, propofol has no antagonist and may cause problems such as respiratory
      depression, and has a narrow therapeutic range for the sedation effect, consequently
      requiring supervision by experienced experts, although it has a better sedation effect than
      midazolam. Due to these disadvantages, propofol is clinically less useful than midazolam.

      Meanwhile, dexmedetomidine, a selective α2 adrenergic agonist, is known to maintain the
      proper level of sedation and has a weak influence on respiratory depression. Recent studies
      have shown positive results with dexmedetomidine in relation with the sedation effect for
      surgery patients under local anesthesia or in intensive care units.

      As such, extensive studies are being conducted on the use of dexmedetomidine in endoscopic
      procedures due to the increased attention to dexmedetomidine. This notwithstanding, the
      clinical usefulness of dexmedetomidine is still debatable. In particular, studies on the use
      of dexmedetomidine for ERCP are very rare.

      Given the recent idea that dexmedetomidine may exert a synergistic effect in combination with
      midazolam, these authors endeavored to prospectively compare and analyze the sedation effect
      and adverse events, including respiratory depression, of the combination therapy of midazolam
      and meperidine, both of which have been widely used in patients undergoing ERCP, and of the
      combination therapy of midazolam, meperidine, and dexmedetomidine.

      The small-scale comparative study on the combination administration of propofol and fentanyl,
      which has a high risk of causing complications, and on the single administration of
      dexmedetomidine is the only study on the sedation effect of dexmedetomidine in the ERCP
      procedure that has yet been conducted; there has been no study that investigated the effect
      of the combination administration of dexmedetomidine and other drugs in the ERCP procedure.
      This study is thus expected to contribute to the development of guidelines on sedation in the
      ERCP procedure.
    

Detailed description: 
      Compared with upper gastrointestinal endoscopy, endoscopic retrograde
      cholangiopancreatography (ERCP) takes a longer time to perform and causes more discomfort to
      patients. In ERCP, benzodiazepine alone or in combination with opioid is commonly used for
      pain control and sedation.

      Of the various benzodiazepine drugs, midazolam, which is water-soluble, has been shown to act
      faster and to be better in terms of anterograde amnesia and its sedation effect than other
      drugs. As midazolam has a suitable antagonist (flumazenil), prompt measures can be taken in
      case of such situations as hypopnea.

      As midazolam was reported to increase the sedation effect and the level of satisfaction of
      patients when used in combination with opioid (meperidine), a combination of midazolam and
      meperidine has been the most widely used regimen so far. The American Society for
      Gastrointestinal Endoscopy recommends a combination of midazolam and meperidine as a standard
      regimen for inducing sedation in upper and lower gastrointestinal endoscopy.

      Several studies reported, however, that midazolam alone or the combination of midazolam and
      meperidine was insufficient for inducing the sedation effect (47-80%). Besides, midazolam has
      the disadvantage of producing a paradoxical response at times, which makes the performance of
      the procedure impossible.

      In many studies, propofol, which is preferred as an alternative to midazolam, was recently
      found to be superior to midazolam in terms of its sedation effect, as it does not cause
      adverse events.

      Because propofol intermittently causes serious respiratory failure and has no antagonist,
      however, clinicians feel burdened with the use of propofol, due to which it is not widely
      used. Moreover, anesthesia specialists as well as experienced assistant staff who had
      received relevant education and training should be available, and all tools needed to
      promptly handle cardiopulmonary complications should be on hand, which lowers the usefulness
      of propofol in clinical practice.

      The sedation effect of dexmedetomidine, however, a selective α2 adrenergic receptor, is
      proportional to its dose, so it allows continuous injection and makes it possible to reduce
      the opioid dose needed for sedation when it is used for sedation. Dexmedetomidine was
      reported to maintain a proper level of sedation, and to influence less the respiratory rate,
      oxygen saturation, and respiratory tract response. Due to these advantages, several recent
      studies reported that dexmedetomidine can be effective for sedation during upper and lower
      gastrointestinal procedures.

      A combination of dexmedetomidine and midazolam was investigated in recent trials with animals
      and in clinical trials, and its synergic effect was shown in several studies.

      In an animal trial using rats, Boehm et al. reported that midazolam increased the
      dose-related analgesic effect of dexmedetomidine when it was used in combination with
      dexmedetomidine. Bol et al. reported that combined administration of dexmedetomidine and
      midazolam increased the sedation effect while reducing adverse cardiovascular events more
      significantly than with a single administration.

      In addition, in a study on rats, Salonen et al. demonstrated the synergic effect of the
      combination of the two drugs and that flumazenil antagonized the combination of the two drugs
      in a dose-dependent manner.

      In one of the representative clinical trials, Bergese et al. compared a combination of
      dexmedetomidine and midazolam with a midazolam-alone regimen in 55 patients who underwent
      awake fibrotic intubation (AFOI).

      Although there was no hemodynamic difference between the two groups, the combination regimen
      had a better sedation effect, resulted in a higher level of satisfaction among the patients,
      and led to fewer adverse events than did the single regimen.

      Besides, in a study on patients who underwent cardiovascular surgery, Dasta et al. reported
      that the use of dexmedetomidine in combination with a standard sedation regimen decreased
      mortality and reduced the period of mechanical ventilation and the cost. Heard et al.
      reported that combined administration of midazolam and dexmedetomidine had a sufficient
      sedation effect on patients who had undergone MRI without adverse events. In the study by
      Heard et al.,however, in which the subjects were children, propofol was used as the control
      drug instead of midazolam.

      So far, no studies have reported the effect of combination administration of dexmedetomidine
      and midazolam in gastrointestinal endoscopy, including in ERCP. Given the synergic effect of
      the two drugs and the usefulness of dexmedetomidine in endoscopy, such studies are urgently
      needed.

      Though the study by Muller et al. was not on the effect of the combined administration, it is
      the only study that investigated the sedation effect of dexmedetomidine in ERCP.

      In the study by Muller et al. on 26 patients who had undergone ERCP (12 of whom received
      dexmedetomidine and 14, propofol), they reported that the effect of sedation and pain control
      was weaker in the dexmedetomidine group than in the propofol group (RR: 2.71/9.42 and NNT:
      1.85/1.42, respectively), and that the hemodynamic instability was high in the
      dexmedetomidine group based on the subjects' mean blood pressure and the heart rate.

      The study by Muller et al. had limitations, however, in that the dose of dexmedetomidine was
      lower than that in other studies and the scale of the study was small. Moreover, although the
      mean blood pressure and the heart rate were lower in the dexmedetomidine group than in the
      propofol group, no clinically significant decrease in the blood pressure and the heart rate
      was observed.

      Moreover, propofol, which was used in the control group, may impose a heavy burden in
      relation to its depressing respiratory effect because of the absence of an antagonist
      (flumazenil), unlike with midazolam, as described previously, which acts faster and requires
      experienced assistant staff; and because the usefulness and frequency of use of propofol in
      clinical practice is low. In addition, as the study by Muller et al. was about single
      dexmedetomidine administration, the comparison of the combined administration of
      dexmedetomidine and midazolam with the single administration of propofol to produce the
      sedation effect could result in different outcomes.

      As such, it is believed that the sedation effect and adverse events from the combined
      administration of dexmedetomidine and midazolam and from single administration of midazolam
      in patients who had undergone ERCP should be studied.

      As described previously, midazolam is considered suitable as a control drug as it is more
      useful than propofol in clinical practice. Moreover, since the combination of dexmedetomidine
      and midazolam has a synergic effect on sedation, the combination is believed to be more
      meaningful than single dexmedetomidine administration.

      In addition, the cardiovascular and respiratory safety of single dexmedetomidine
      administration and the combined administration of dexmedetomidine and midazolam, as reported
      in several previous studies, was shown as satisfactory in this study.

      Whether or not this synergic effect and safety will be seen as well in gastrointestinal
      endoscopy, particularly in ERCP, will be further investigated; and as there is no study yet
      that has investigated the combined administration of dexmedetomidine and midazolam in
      patients undergoing ERCP, this study can be considered meaningful.
    

Intervention name(s): Dexmedetomidine; normal saline
Intervention type(s): Drug; Other
Intervention description(s): dexmedetomidine 1μg/Kg•hr IV continuous infusion, initiated 15 min before the procedure (ERCP) till complete procedure; 0.9% NaCl 1μg/Kg•hr IV continuous infusion, initiated 15 min before the procedure (ERCP) till complete procedure
Other intervention name(s): Precedex® 100μg/1ml vial: DMDTIA; NaCl 0.9% 20ml plastic ample: NSIP
Intervention MeSH terms: Dexmedetomidine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Supportive Care
Keywords: dexmedetomidine; midazolam; ERCP; cholangiopancreatography; sedation; propofol