Midazolam With Meperidine and Dexmedetomidine vs. Midazolam With Meperidine and Propofol for Sedation During ERCP
Condition: Complication
Study type: Interventional
Phase: Phase 4

Summary: 
      This is a single-center, prospective, randomized, double-blinded study of consecutive
      patients referred for ERCP. A recent study suggested that the addition of dexmedetomidine to
      the midazolam-meperidine regimen (MMD)provided better sedative efficacy and a superior safety
      profile during ERCP compared with a midazolam-meperidine regimen. Further study is warranted
      to compare an MMD regimen with propofol-based regimen.

      Randomization is performed by use of a computer-generated random allocations in a ratio of
      1:1 in balanced blocks of 4. A separate sedating nurse, who don't participate in the study,
      is the only person with knowledge of the sedation regimen. This separate nurse repeated the
      injection of propofol and completed questionnaires.
    

Detailed description: 
      Study design This is a single-center, prospective, randomized, double-blinded study of
      consecutive patients referred for ERCP. Randomization is performed by use of a
      computer-generated random allocations in a ratio of 1:1 in balanced blocks of 4. A separate
      sedating nurse, who don't participate in the study, is the only person with knowledge of the
      sedation regimen. This separate nurse repeated the injection of propofol and completed
      questionnaires.

      Inclusion criteria include consecutive patients who are scheduled for ERCP and those are aged
      18-80 years. (ASA class I-III) Exclusion criteria are as follows;

      1) patient age < 18years, 2) pregnancy, 3) American Society of Anesthesiology (ASA) physical
      status class IV, V, 4) history of allergies to drug used, 6) history of complications with
      previous sedation, 5) hypoxemia (baseline SaO2) <90%, 6) hypotension (baseline systolic blood
      pressure <90mmHg), 7) severe bradycardia (heart rate <50/min) and/or brady-dysrhythmias (e.g.
      advanced heart block), 8) impaired ventricular function (left ventricular ejection fraction
      <30%), 9) baseline respiratory rate >25 or <10 breaths/min, and 10) inability to provide
      informed consent. Patients are excluded from the final analysis if the procedure is
      terminated early or abandoned for anatomical reasons (i.e., duodenal obstruction or
      gastrectomy).

      Sedation protocols After randomization patients are allocated to group 1 or 2, and prepared
      for endoscopy.

      All sedatives and analgesics used for the study are administered by trained sedative nurse
      under endoscopist supervision. All participants receive an IV bolus dose of midazolam
      (0.06mg/kg, 50% reduction for patients if age ≥70 or ASA class III-IV; Bukwang Pharm Co.,
      Seoul, Republic of Korea) and meperidine (50mg. 25mg for patients aged ≥70 years; pethidine
      HCL, Hana Pharm Co., Seoul, Republic of Korea). Repeated doses of 10-20 mg propofol are
      titrated to achieve the target level of sedation. Maintenance of sedation is achieved with
      repeated doses of 5 to 20 mg propofol. The total dosage of propofol (including additional
      doses) is limited by lower and upper bounds of 10mg and 100mg, respectively. The target level
      of sedation is moderate sedation based on the ASA levels.

      For the patients allocated to the midazolam-meperidine-dexmedetomidine (MMD) group, both
      midazolam (0.05 mg/kg, 30% reduction for patients if age ≥70 or ASA class III-IV; Bukwang
      Pharm Co., Seoul, Republic of Korea) and meperidine (50mg. 25mg for patients aged ≥70 years;
      pethidine HCL, Hana Pharm Co., Seoul, Republic of Korea) are given intravenously at the
      initiation of sedation. In addition, a continuous IV infusion of dexmedetomidine (1ug/kg/h,
      Precedex; Hospira, Seoul, Republic of Korea) is administered 15 min before the ERCP till
      complete the procedure. Thereafter, repeated doses of 1 to 2 mg midazolam are administered to
      maintain a moderate level of sedation. For the patients allocated to the
      midazolam-meperidine-propofol (BPS) group, both midazolam and meperidine are given at the
      initiation of sedation in the same manner as in the MMD group.

      Thereafter, repeated doses of 10-20 mg propofol are titrated to achieve the target level of
      sedation. Maintenance of sedation is achieved with repeated doses of 5 to 20 mg propofol. The
      total dosage of propofol (including additional doses) is limited by lower and upper bounds of
      10mg and 100mg, respectively. The target level of sedation is moderate sedation based on the
      ASA levels.

      Medications and monitoring Intranasal supplemental oxygen (2L/min) is provided to all
      participants at the initiation of sedation. Heart rate, electrocardiogram, peripheral oxygen
      saturation (SaO2), respiratory rate, and end-tidal carbon dioxide (EtCo2) are constantly
      monitored. Non-invasive blood pressure (NIBP) is automatically measured at 3-minute
      intervals. Sedation level is assessed and recorded every 3 minutes throughout the procedure
      with the Modified Observer's Assessment of Alertness and Sedation (MOAA/S). Patients are
      considered to be oversedated at MOAA/S score 1.

      MOAA/S, Modified Observe's Assessment of Alertness and Sedation: 5-responds readily to name
      spoken in normal tone, 4-lethargic response to name spoken in normal tone, 3-responds only
      after name is called loudly and/or repeatedly, 2-responds only after mild prodding or
      shaking, 1-does not respond to mild prodding or shaking, 0-does not respond to noxious
      stimulus.

      If hypoxemia (SpO2<90%) is observed during sedation in either group, O2 supplementation is
      increased by 2L/min until oxygen saturation is restored. If the SpO2 dropped to < 85% for >30
      sec, despite patient stimulation and interruption of sedatives and jaw thrust maneuver, an
      antagonist to midazolam (flumazenil) could be injected and the procedure is interrupted until
      normalization of oxygen saturation occurred again.

      During recovery, the patient's vital signs (NIBP, SpO2, heart rate), sedation level (Gillham
      scale), and speed of recovery (modified Aldrete score) are recorded at 5-minute intervals
      until discharge from the recovery room.

      Gillham sedation scale; 1-awake and anxious, 2-awake not anxious, 3-speech slurred, 4-eyes
      closed, responds to speech, 5-eye closed, responds to shaking, 6-unresponsive.

      Outcome measurements and definitions The primary endpoint of the study is the rates of
      cardiopulmonary complications and the frequency of interruption of the ERCP procedures
      because of complications included (1) hypoxemia (pulse oximeter oxygen saturation below 90%
      on supplemental oxygen), (2) hypotension (systolic blood pressure below 90 mmHg), (3)
      bradycardia (heart rate below 50 beats/min). Procedure quality is evaluated based on
      therapeutic procedure outcomes, including technical success and total procedure time, and
      procedure-related adverse events. If transient interruptions of the procedure occurred
      because of sedation-related complications, that time is subtracted from the procedure time.

      The endoscopist, blinded to the method of sedation, The secondary endpoints are the ease of
      ERCP performance, speed of recovery, and patient satisfaction with sedation.

      At the end of the procedure, the ease of performance of ERCP is evaluated by the endoscopist
      using structured questionnaires.

      If full recovery is confirmed in the inpatient setting, patient satisfaction with sedation
      and pain intensity during ERCP are assessed by another independent assistant using a 10-cm
      VAS scale (0=no pain/no satisfaction, 10=worst pain/full satisfaction)
    

Intervention name(s): Midazolam®; "Meperidine" (pethidine®); Propofol®; Dexmedetomidine (Precedex®)
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): midazolam (0.05 mg/kg, 30% reduction for patients if age ≥70 or ASA class III-IV; Bukwang Pharm Co., Seoul, Republic of Korea); Meperidine (50mg. 25mg for patients aged ≥70 years; pethidine HCL, Hana Pharm Co., Seoul, Republic of Korea).; Repeated doses of 10-20 mg propofol are titrated to achieve the target level of sedation.; Dexmedetomidine (1μg/kg/h, Precedex; Hospira, Seoul, Republic of Korea) or the same volume of normal saline were administered in the MMD and midazolam-meperidine group
Other intervention name(s): Midazolam; meperidine; Propofol; Dexmedetomidine
Intervention MeSH terms: Midazolam; Meperidine; Dexmedetomidine; Propofol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: ERCP; Sedation; safety