Efficacy and Safety Profile of Remimazolam-alfentanil Combination for ERCP Sedation

A Randomized, Controlled Trial to Compare the Efficacy and Safety Profile of a Remimazolam-alfentanil Combination With a Propofol-alfentanil Combination for ERCP

Moderate to deep levels of sedation and analgesia are required for ERCP. Propofol-based sedation is simple, easy to use, and effective, but is not without cardiovascular and respiratory adverse effects. The combination of remimazolam and alfentanil has shown promising results for sedation in other similar scenarios. The aim of this study was to compare the efficacy and safety of a standard propofol-alfentanil regimen with a remimazolam-alfentanil combination.

Study Overview

• Status: Recruiting
• Conditions: Anesthesia
• Intervention / Treatment: Drug: remimazolam-alfentanil combination; Drug: propofol-alfentanil combination

Detailed Description

What is already known about this topic is that propofol-based sedation techniques are effective for ERCP procedures but are not without cardiovascular and respiratory adverse effects.

1. Title:A randomized, controlled trial to compare the efficacy and safety profile of a remimazolam-alfentanil combination with a propofol-alfentanil combination for ERCP.
2. Research center: Single center.
3. The Design of the study: Randomized, double-blind, controlled study.
4. The population of the study: Age is between 18 and 85 years; ASA I-III levels; Patients undergone elective ERCP surgery, non-intubation patients;
5. Sample size: Based on Akhondzadeh R et al. research, propofol based sedation resulted in 43% patients present oxygen desaturation, and assuming a 15% reduction in hypoxic events in remimazolam group. From this, we have estimated that oxygen desaturation rate will be 43% in the propofol group and 28 % in the remimazolam group. We have estimated that, with a sample size of 207 patients, the study will have 80% power to detect a significant difference using the log-rank test. We have estimated that the rate of dropout or withdrawal will be approximately 20%, and thus we plan to enroll 259 patients each group

6. Interventions: Group remimazolam-alfentanil combination received 10 µg/kg alfentanil and 0.3mg/kg remimazolam over 30 seconds, followed by an infusion of remimazolam at 0.2 to 1 mg/kg/hr and alfentanil at 0 to 1ug/kg/min. In case of the sudden patient movement, and difficulty in maneuvering the endoscope, remimazolam 0.1mg/kg was used in the form of bolus, as rescue drugs, and alfentanil 5ug/kg when additional analgesia is needed.

   Group propofol-alfentanil combination received 10 µg/kg alfentanil and 1.5 to 2 mg/kg propofol over 30 seconds followed by an infusion of propofol at 2 to 6mg/kg/hr and alfentanil at 0 to 1ug/kg/min. In case of the sudden patient movement, and difficulty in maneuvering the endoscope,propofol 0.5mg/kg was used in the form of bolus, as rescue drugs, and alfentanil 5ug/kg when additional analgesia is needed.

7. Outcome： Primary outcome： The occurrence of hypoxia, defined by any event of SpO2 (oxygen saturation measured by pulse oximetry) < 90% of any duration.

   Secondary outcome： Number of events of hypoxia, defined as desaturation < 90%. The mean number of events during the procedure will be compared between the two groups.

   Lowest recorded SpO2 during the procedure. Requirement of minor airway manoeuvres: jaw lift/jaw thrust, nasopharyngeal airway insertion.

   Requirement of major airway manoeuvres: bag mask ventilation, endotracheal intubation.

   Total alfentanyl dose. The mean values (the doses in micrograms) during the procedure will be compared between the two groups.

   Requirement of antispasmodic agent. Proportion of patients requiring this medication will be compared between the two groups.

   Endoscope re-insertion rate. Rescued sedation: drugs dose. Total duration of procedure. Duration under sedation/anaesthesia. Successful completion of the procedure: Yes/No. Proportion of patients fulfilling this criterion will be compared between the two groups.

   Sensation of abdominal bloating: Y/N. Proportion of patients experiencing this adverse event will be compared between the two groups.

   Patients' satisfaction score on leaving recovery: 5 points numerical rating scale: Very satisfied (5), somewhat satisfied (4), neither satisfied nor dissatisfied (3), somewhat dissatisfied (2), very dissatisfied (1). Proportion of patients at a particular threshold will be compared between the two groups.

   The endoscopist assessed the ease of performing at the end of the procedure as I-satisfactory, II-difficult or III-impossible.

   QOR-15. Recovery time :The time to recovery based on Modified Aldrete score was noted every 5 minutes, starting from the time of endoscope removal . A score of 9 was considered as recovery and the patient was discharged to the ward.The estimated duration of the study:2-3 years.

   If the procure is expected more than 1 hour, the arterial blood gas (ABG) will be detected before and after the ERCP, and the serum Aβ1-40 will be also determined by the commercial kits.

8. Adverse events:

   Incidence of hypertention, hypotension，tachycardia , bradycardia，nausea，vomiting, POD, Sensation of abdominal bloating, The dosage of urapidil, ephedrine, atropine and esmolol during the observation period

9. Safety consideration: ECG, HR, MAP, respiratory rate was monitored.
10. Statistical analysis Mean and standard deviation values will be estimated for continuous outcomes while frequency and percentage will be computed for binary outcomes. 95% confidence intervals around the point estimate will be calculated where appropriate for the primary and secondary outcomes. Descriptive statistics will be used to present the results. P < 0.05 will be considered significant. Analyses will be intention-to-treat from randomisation. All randomised cases will be included in the analyses, regardless of missing data. As the data capture is only limited to a few hours after the intervention and the investigators are directly involved in the conduct of the study, we anticipate very few missing data. A subgroup analyses will be attempted (if feasible)

• Study Type: Interventional
• Enrollment (Anticipated): 1000
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300100
      • Recruiting
      • Tianjin Nankai Hospital
      • Contact: Jianbo Yu, MD; Phone Number: 86-022-27435008; Email: nkyyll@126.com
      • Contact: Phone Number: 86-022-27435008; Email: nkyyll@126.com
    • Tianjin, Tianjin, China
      • Recruiting
      • Tianjin Nankai Hospital
      • Contact: Jianbo Yu, MD,PhD; Phone Number: 022-27435873; Email: yujianbo11@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 81 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age is between 18 and 85 years
• ASA I-III levels;
• Patients undergone elective ERCP surgery, non-intubation patients;

Exclusion Criteria:

• Chronic pain with long-term use of analgesics, psychotropic substances (including opioids, NSAIDs, sedatives, antidepressants), alcohol abusers, with known drug allergy;
• BMI<18 or BMI>30;
• Abnormal renal function ;
• Previous abnormal surgical anesthesia recovery history;
• Hypertension or systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg when the patient admission to the operating room
• Sedatives, analgesics and antipruritic drugs were used 24 hours before operation;
• Expected difficult intubation ;
• Opioids allergy history;
• Take monoamine oxidase inhibitor or antidepressant within 15 days;
• Pregnant or parturient women;
• Involved in other drug trials within three months;
• Patients who can not communicate well with the researcher

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: remimazolam-alfentanil combination; Group remimazolam-alfentanil combination received 10 µg/kg alfentanil and 0.3mg/kg remimazolam over 30 seconds, followed by an infusion of remimazolam at 0.2 to 1 mg/kg/hr and alfentanil at 0 to 1ug/kg/min. In case of the sudden patient movement, and difficulty in maneuvering the endoscope, remimazolam 0.1mg/kg was used in the form of bolus, as rescue drugs, and alfentanil 5ug/kg when additional analgesia is needed	Drug: remimazolam-alfentanil combination; Group remimazolam-alfentanil combination received 10 µg/kg alfentanil and 0.3mg/kg remimazolam over 30 seconds, followed by an infusion of remimazolam at 0.2 to 1 mg/kg/hr and alfentanil at 0 to 1ug/kg/min. In case of the sudden patient movement, and difficulty in maneuvering the endoscope, remimazolam 0.1mg/kg was used in the form of bolus, as rescue drugs, and alfentanil 5ug/kg when additional analgesia is needed; Other Names: RA Combination
Active Comparator: propofol-alfentanil combination; Group propofol-alfentanil combination received 10 µg/kg alfentanil and 1.5 to 2mg/kg propofol over 30 seconds followed by an infusion of propofol at 2 to 6 mg/kg/hr and alfentanil at 0 to 1ug/kg/min. In case of the sudden patient movement, and difficulty in maneuvering the endoscope, propofol 0.5 mg/kg was used in the form of bolus, as rescue drugs, and alfentanil 5ug/kg when additional analgesia is needed	Drug: propofol-alfentanil combination; Group propofol-alfentanil combination received 10 µg/kg alfentanil and 1 mg/kg propofol over 30 seconds followed by an infusion of propofol at 2 to 6 mg/kg/hr. In case of the sudden patient movement, and difficulty in maneuvering the endoscope, propofol 0.5 mg/kg was used in the form of bolus, as rescue drugs，and alfentanil 5ug/kg when additional analgesia is needed; Other Names: PA combination

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of hypoxia	defined by any event of SpO2 (oxygen saturation measured by pulse oximetry) < 90% of any duration.	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of events of hypoxia, defined as desaturation < 90%.	The mean number of events during the procedure will be compared between the two groups	1 day
Lowest recorded SpO2 during the procedure	the lowest SpO2 during the procedure	1 day
the number of requirement for minor airway manoeuvres	such as jaw lift/jaw thrust, nasopharyngeal airway insertion.	1 day
the number of requirement for major airway manoeuvres	such as bag mask ventilation, endotracheal intubation.	1 day
Total alfentanyl dose	The mean values during the procedure will be compared between the two groups	1 day
Requirement of antispasmodic agent	Proportion of patients requiring this medication will be compared between the two groups	1 day
Endoscope re-insertion rate	Endoscope reinsertion	1 day
Rescued sedation:	drugs dose	1 day
Total duration of procedure	the duration of ERCP	1 day
Duration under sedation/anaesthesia	Total anesthesia duration	1day
Successful completion of the procedure	Yes/No. Proportion of patients fulfilling this criterion will be compared between the two groups	1 day
Sensation of abdominal bloating	Y/N. Proportion of patients experiencing this adverse event will be compared between the two groups	1-3 days
Patients' satisfaction score on leaving recovery	5 points numerical rating scale: Very satisfied (5), somewhat satisfied (4), neither satisfied nor dissatisfied (3), somewhat dissatisfied (2), very dissatisfied (1). Proportion of patients at a particular threshold will be compared between the two groups	1-3 days
The endoscopist assessed the ease of performing at the end of the procedure as I-satisfactory, II-difficult or III-impossible	The endoscopist assessed the ease of performing at the end of the procedure as I-satisfactory, II-difficult or III-impossible	1 days
quality of recovery score-15	The quality of recovery score (QOR)-15 questionnaire	1-3 days
Recovery time	The time to recovery based on Modified Aldrete score was noted every 5 minutes, starting from the time of endoscope removal 9. A score of 9 was considered as recovery and the patient was discharged to the ward.	1 day

Collaborators and Investigators

• Sponsor: Tianjin Nankai Hospital
• Investigators: Principal Investigator: Jianbo Yu, MD, Tianjin Nankai Hospital

Publications and helpful links

General Publications

• Pastis NJ, Yarmus LB, Schippers F, Ostroff R, Chen A, Akulian J, Wahidi M, Shojaee S, Tanner NT, Callahan SP, Feldman G, Lorch DG Jr, Ndukwu I, Pritchett MA, Silvestri GA; PAION Investigators. Safety and Efficacy of Remimazolam Compared With Placebo and Midazolam for Moderate Sedation During Bronchoscopy. Chest. 2019 Jan;155(1):137-146. doi: 10.1016/j.chest.2018.09.015. Epub 2018 Oct 4.
• Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg. 2012 Aug;115(2):274-83. doi: 10.1213/ANE.0b013e31823f0c28. Epub 2011 Dec 20.
• Akhondzadeh R, Ghomeishi A, Nesioonpour S, Nourizade S. A comparison between the effects of propofol-fentanyl with propofol-ketamine for sedation in patients undergoing endoscopic retrograde cholangiopancreatography outside the operating room. Biomed J. 2016 Apr;39(2):145-9. doi: 10.1016/j.bj.2015.11.002. Epub 2016 Jun 21.
• Mazanikov M, Udd M, Kylanpaa L, Mustonen H, Lindstrom O, Farkkila M, Halttunen J, Poyhia R. A randomized comparison of target-controlled propofol infusion and patient-controlled sedation during ERCP. Endoscopy. 2013 Nov;45(11):915-9. doi: 10.1055/s-0033-1344712. Epub 2013 Oct 8.
• Eberl S, Koers L, van Hooft J, de Jong E, Hermanides J, Hollmann MW, Preckel B. The effectiveness of a low-dose esketamine versus an alfentanil adjunct to propofol sedation during endoscopic retrograde cholangiopancreatography: A randomised controlled multicentre trial. Eur J Anaesthesiol. 2020 May;37(5):394-401. doi: 10.1097/EJA.0000000000001134.
• Rex DK, Bhandari R, Desta T, DeMicco MP, Schaeffer C, Etzkorn K, Barish CF, Pruitt R, Cash BD, Quirk D, Tiongco F, Sullivan S, Bernstein D. A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2018 Sep;88(3):427-437.e6. doi: 10.1016/j.gie.2018.04.2351. Epub 2018 Apr 30.
• Goyal R, Hasnain S, Mittal S, Shreevastava S. A randomized, controlled trial to compare the efficacy and safety profile of a dexmedetomidine-ketamine combination with a propofol-fentanyl combination for ERCP. Gastrointest Endosc. 2016 May;83(5):928-33. doi: 10.1016/j.gie.2015.08.077. Epub 2015 Sep 11.
• Thiruvenkatarajan V, Dharmalingam A, Arenas G, Wahba M, Steiner R, Kadam VR, Tran A, Currie J, Van Wijk R, Quail A, Ludbrook G. High-flow nasal cannula versus standard oxygen therapy assisting sedation during endoscopic retrograde cholangiopancreatography in high risk cases (OTHER): study protocol of a randomised multicentric trial. Trials. 2020 May 29;21(1):444. doi: 10.1186/s13063-020-04378-z.
• Eberl S, Koers L, van Hooft JE, de Jong E, Schneider T, Hollmann MW, Preckel B. Sedation with propofol during ERCP: is the combination with esketamine more effective and safer than with alfentanil? Study protocol for a randomized controlled trial. Trials. 2017 Oct 11;18(1):472. doi: 10.1186/s13063-017-2197-8.

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2020
• Primary Completion (Anticipated): October 1, 2022
• Study Completion (Anticipated): October 1, 2023

Study Registration Dates

• First Submitted: December 1, 2020
• First Submitted That Met QC Criteria: December 1, 2020
• First Posted (Actual): December 8, 2020

Study Record Updates

• Last Update Posted (Actual): December 20, 2021
• Last Update Submitted That Met QC Criteria: December 4, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: ERCP; Propofol; Alfentanil; Remimazolam
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Propofol; Alfentanil
• Other Study ID Numbers: NKYY_YXKT_IRB_2020_063_01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No