Safety and Efficacy Evaluation of Remimazolam for Endoscopic Ultrasound-guided Fine Needle Aspiration/Biopsy

This study aims to compare the safety and efficacy of remimazolam and propofol in EUS-FNA/FNB sedation. This study is a prospective, single-blind study. We plan to enroll 264 patients undergoing EUS-FNA and divide them into two groups. The experimental group was sedated with remimazolam, and the control group was sedated with propofol; safety and efficacy parameters such as intraoperative blood pressure, finger pulse oxygen, heart rate and sedation success rate would be compared. We hypothesized that patients in the experimental group would be superior in terms of safety parameters; the two would be equal in terms of sedation success.

Study Overview

• Status: Recruiting
• Conditions: Sedation Complication; Remimazolam; Endoscopic Ultrasonography-guided Fine Needle Aspiration
• Intervention / Treatment: Drug: Remimazolam Injection; Drug: Propofol Injection

Detailed Description

Endoscopic ultrasonography-guided fine needle aspiration/biopsy (EUS-FNA/FNB) is an important basis for the diagnosis of lesions in the upper gastrointestinal tract and adjacent organs, and plays an important role in the diagnosis of gastrointestinal tumors. Sedation is the key to a successful EUS-FNA/FNB procedure. However, intraoperative sedation in EUS-FNA/FNB is difficult and challenging. First, EUS-FNA/FNB requires a relatively long operation time and is prone to sedation-related adverse events, such as cardiovascular and cerebrovascular accidents. Second, EUS-FNA/FNB requires weakened gastrointestinal motility, thus deeper sedation is required during the operation; thirdly, the ultrasound probe used in EUS-FNA/FNB surgery is thicker than that of ordinary gastroscopes, which requires better cooperation from the patient. Therefore, the rational use of anesthesia drugs during surgery is required to ensure safety.

In current clinical studies, propofol is mostly used for anesthesia in patients undergoing EUS-FNA/FNB. In recent years, the defects of propofol for EUS sedation have gradually emerged, and its respiratory and circulatory inhibition effects have gradually caused researchers to worry. At present, propofol is still a commonly used EUS sedative drug, but with the improvement of people's requirements for sedation quality, its safety gradually cannot meet the demand. Therefore, it is the general trend to explore new EUS-FNA intraoperative sedation schemes.

Remimazolam is one of the new alternative drugs. Remimazolam is a new type of short-acting sedative-hypnotic drug, which has little inhibition on the respiratory system, less impact on hemodynamics, rapid onset of action, short half-life, rapid recovery, and no accumulation after long-term infusion. Thus, remimazolam is an effective drug for induction and maintenance of general anesthesia.

This study aims to compare the safety and efficacy of remimazolam and propofol in EUS-FNA/FNB sedation. This study is a prospective, single-blind interventional study. We plan to enroll 264 patients undergoing EUS-FNA and divide them into two groups. The experimental group was sedated with remimazolam, and the control group was sedated with propofol; safety and efficacy parameters such as intraoperative blood pressure, finger pulse oxygen, heart rate and sedation success rate would be compared. We hypothesized that patients in the experimental group would be superior in terms of safety parameters; the two would be equal in terms of sedation success.

This study is divided into the following steps:

1. Informed consent and participant recruitment First of all, inform the patients of the source, purpose, significance, and possible benefits and risks of participating in this study, so that patients can decide whether to participate after they have a full understanding. Patients who participated voluntarily signed the informed consent form. Eligible patients (n=264) would be selected according to the inclusion and exclusion criteria.
2. Information collection and participant screening Collect participant information, including name, gender, age, hospital number, enrollment date, education background, occupation, smoking status, drinking status, ASA classification, height, weight, lesion location, comorbidities (if any), medical history, physical examination results, laboratory examination results and imaging findings. Among them, physical examination results include general condition, upper limb skin, head, chest, abdomen, and necessary neurological examination results; laboratory results include blood routine, liver function, renal function, blood biochemistry, and coagulation routine. Imaging examinations are abdominal CT and other examination results that can reflect the location and size of the lesions.
3. Randomization With the help of the random number table pre-generated by SPSS20.0 software, participants would be divided into two groups (1:1). The sedation regimen is determined according to the random number obtained by the patient's lottery. The randomization process was completed by the designated study designer. Neither the patients nor the endoscopist knew the grouping status.
4. EUS-FNA/FNB information collection and preoperative preparation Collect operation information, including probe type, operation type, operator qualifications, operation indications, anesthesiologist qualifications, etc.

The patient fasted for at least 6 hours before the operation. Before the operation, the patient took 5ml of 2% lidocaine for topical anesthesia. Inhale oxygen for the patient (4L/min). The patient was placed in the left lateral decubitus position, connected to an ECG monitor, and venous access was established through the vein of the hand. The outpatient operating room is equipped with emergency facilities and equipment (emergency medicines, simple breathing balloons and masks, endotracheal intubation equipment and anesthesia machines).

5. Sedation induction and maintenance

1. Sedation protocol

   Remimazolam group:

   Background oxycodone injection: Slowly inject oxycodone(0.05mg/kg) intravenously. Three minutes (± 1min) after the end of oxycodone injection, begin sedation induction as follows.

   Sedation induction before EUS-FNA/FNB: the initial dose of remimazolam is 0.15-0.2 mg/kg, and the intravenous injection time is about 1 minute. If the subject's MOAA/S score is 1 point or below after the initial dose, EUS-FNA/FNB can be started; if the degree of sedation is insufficient, additional remimazolam(0.05 mg/kg each time) is allowed. The injection time of additional remimazolam is not less than 15 seconds, and the time interval between each additional administration is ≥ 2 minutes.

   Maintenance of sedation: In order to maintain the MOAA/S≤1, the investigator can decide to add remimazolam 0.05mg/kg each time, and the intravenous injection time should not be less than 15 seconds, with an additional administration interval of ≥ 2 minutes.

   Propofol group:

   Background oxycodone injection: Slowly inject oxycodone(0.05mg/kg) intravenously. Three minutes (± 1min) after the end of oxycodone injection , begin sedation induction as follows.

   Sedation induction before EUS-FNA/FNB: the initial dose of propofol is 1.5-2.0 mg/kg, and the intravenous injection time is about 1 minute. If the subject's MOAA/S score is 1 point or below after the initial dose, EUS-FNA/FNB can be started; if the degree of sedation is insufficient, additional propofol(0.5 mg/kg each time) is allowed. The injection time of additional propofol is not less than 15 seconds, and the time interval between each additional administration is ≥ 2 minutes.

   Maintenance of sedation: In order to maintain the MOAA/S≤1, the investigator can decide to add propofol 0.5mg/kg each time, and the intravenous injection time should not be less than 15 seconds, with an additional administration interval of ≥ 2 minutes

2. Judgment of sedation failure After the sedation inducement, if more than 5 additional doses are injected in any 15-minute time period, it is considered as a sedation failure. The anesthesiologist should use other sedative rescue measures (such as propofol, etc.) to maintain. After the additional bolus of the sedative, if the participant is still unable to cooperate due to physical movement or other reasons, but the interval between the next additional bolus does not reach 2 minutes, the anesthesiologist can decide to give the subject other sedative rescue measures (such as propofol, etc.) .In this case, failed sedation should be judged due to the use of sedative rescue measures.
3. Treatment protocol for adverse events The most likely adverse events in the study were respiratory depression, hypotension, and bradycardia. The corresponding treatment process is as follows: when the pulse oxygen saturation drops below 90% and does not recover spontaneously, the anesthesiologist will perform a 30-second chin lift operation; if blood oxygen saturation still cannot recover, increase the oxygen flow to 6L/min and the anesthesiologist compress the chest for assisted breathing; after 1 minute of observation, if there is still no recovery, a oxygen mask should be used; if it still cannot recover, perform mechanical ventilation or tracheal intubation. Hypotension was corrected with ephedrine (5 mg/time, intravenously) and bradycardia with atropine (0.5 mg/time, intravenously).

6. EUS-FNA/FNB operation and postoperative recovery EUS-FNA/FNB should perform according to routine procedures. After EUS-FNA/FNB procedure, patients were monitored in the postoperative recovery room until the modified Alderte score was 9 or greater before patients were allowed to leave. Patients will fill out the Modified Brice Questionnaire before departure.

7. Follow-up of patients 1-3 days after operation The patients were followed up 1-3 days after EUS/FNA-FNB to investigate the occurrence of adverse events and re-measure the changes of vital signs.

8. Data recording The patient's heart rate, systolic blood pressure, diastolic blood pressure, pulse oxygen saturation and MOAA/S score would be recorded every three minutes. Record the occurrence of adverse events, specific adverse event types, treatment methods and duration. 3) Record the total dosage of propofol or remimazolam after the operation.

• Study Type: Interventional
• Enrollment (Anticipated): 264
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xiaoyan Wang, Doctor; Phone Number: +8673188618011; Email: 912877437@qq.com
• Study Contact Backup: Name: Ning Fang, Doctor; Phone Number: +8618160992303; Email: golempowers@csu.edu.cn

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410013
      • Recruiting
      • The Third Xiangya Hospital of Central South University
      • Contact: Xiaoyan Wang, Doctor; Phone Number: +8673188618011; Email: 912877437@qq.com
      • Contact: Ning Fang, Doctor; Phone Number: +8618160992303; Email: golempowers@csu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age: ≥18 years old and ≤75 years old
2. BMI: 18kg/m^2<BMI<30kg/m^2;
3. Body weight: 40kg<weight<120kg
4. Patients who intend and qualified to undergo sedated EUS-FNA/FNB.
5. Clearly understand, voluntarily participate in the research, and sign the informed consent form.

Exclusion Criteria:

1. Patients who are not suitable for sedated EUS-FNA/FNB for any reason (e.g. cardiovascular disease)
2. Patients have abnormal liver function, AST and/or ALT≥2.5×ULN, TBIL≥1.5×ULN;
3. Patients have abnormal renal function, urea or blood urea nitrogen≥1.5×ULN, serum creatinine≥1.0 ×ULN
4. Those who are allergic to benzodiazepines, opioids, propofol or lidocaine.
5. Patients have contraindications for benzodiazepines, opioids, propofol or lidocaine.
6. Patients have benzodiazepines, opioids, propofol, lidocaine suspected narcotic drug abuse history and pain drug or sedative abuse.
7. Patients have history of drug use and/or alcoholism within 2 years before the start of the period. Alcoholism means drinking more than 2 units of alcohol on average per day (1 unit = 360 mL of beer or 45 mL of liquor with an alcohol content of 40% or 150 mL of wine)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Remimazolam group; Background oxycodone injection: Slowly inject oxycodone(0.05mg/kg) intravenously. Three minutes (± 1min) after the end of oxycodone injection , begin sedation induction as follows.; Sedation induction before EUS-FNA/FNB: the initial dose of remimazolam is 0.15-0.2 mg/kg, and the intravenous injection time is about 1 minute. If the subject's MOAA/S score is 1 point or below after the initial dose, EUS-FNA/FNB can be started; if the degree of sedation is insufficient, additional remimazolam(0.05 mg/kg each time) is allowed. The injection time of additional remimazolam is not less than 15 seconds, and the time interval between each additional administration is ≥ 2 minutes.; Maintenance of sedation: In order to maintain the MOAA/S≤1, the investigator can decide to add remimazolam 0.05mg/kg each time, and the intravenous injection time should not be less than 15 seconds, with an additional administration interval of ≥ 2 minutes.	Drug: Remimazolam Injection; The experimental group was sedated with remimazolam
ACTIVE_COMPARATOR: Propofol group; Background oxycodone injection: Slowly inject oxycodone(0.05mg/kg) intravenously. Three minutes (± 1min) after the end of oxycodone injection , begin sedation induction as follows.; Sedation induction before EUS-FNA/FNB: the initial dose of propofol is 1.5-2.0 mg/kg, and the intravenous injection time is about 1 minute. If the subject's MOAA/S score is 1 point or below after the initial dose, EUS-FNA/FNB can be started; if the degree of sedation is insufficient, additional propofol(0.5 mg/kg each time) is allowed. The injection time of additional propofol is not less than 15 seconds, and the time interval between each additional administration is ≥ 2 minutes.; Maintenance of sedation: In order to maintain the MOAA/S≤1, the investigator can decide to add propofol 0.5mg/kg each time, and the intravenous injection time should not be less than 15 seconds, with an additional administration interval of ≥ 2 minutes.	Drug: Propofol Injection; The control group was sedated with propofol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiopulmonary adverse event incidence	The occurrence of any one of the following reactions was recorded as "Cardiopulmonary Adverse Event", and the cardiopulmonary adverse event incidence was defined as the proportion of the subjects with cardiopulmonary adverse events in each group. Cardiopulmonary adverse events were defined as: any of the following conditions occurred during the operation: 1. respiratory depression: oxygen saturation <90%, or breathing <8 times/min; 2. apnea: respiratory airflow stopped for more than 15s; 3. hypotension: systolic blood pressure decrease greater than 20% of baseline systolic blood pressure; 4. hypertension: systolic blood pressure increase greater than 20% of baseline systolic blood pressure; 5. tachycardia: heart rate>100bpm for 1 minute or more; 6. bradycardia: HR<50, lasting 1 minute or more	The whole EUS-FNA/FNB procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse event incidence	The respective incidence of each adverse event that occurred during the EUS-FNA/FNB procedure, such as the incidence of cough or body movement.	The whole EUS-FNA/FNB procedure
Sedation success rate:	Sedation success was defined as: completion of the entire procedure; no sedative rescue medication administered; ≤5 additional doses in any 15-minute period from the end of the initial dose of the trial drug. The sedation success rate was defined as the proportion of subjects in the group who were successfully sedated.	The whole EUS-FNA/FNB procedure

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dosage of sedations	The total dosage of remimazolam or propofol and the dosage per kilogram of body weight.	The whole EUS-FNA/FNB procedure

Collaborators and Investigators

• Sponsor: The Third Xiangya Hospital of Central South University

Publications and helpful links

General Publications

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• 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.
• Behrens A, Kreuzmayr A, Manner H, Koop H, Lorenz A, Schaefer C, Plauth M, Jetschmann JU, von Tirpitz C, Ewald M, Sackmann M, Renner W, Kruger M, Schwab D, Hoffmann W, Engelke O, Pech O, Kullmann F, Pampuch S, Lenfers B, Weickert U, Schilling D, Boehm S, Beckebaum S, Cicinnati V, Erckenbrecht JF, Dumoulin FL, Benz C, Rabenstein T, Haltern G, Balsliemke M, de Mas C, Kleber G, Pehl C, Vogt C, Kiesslich R, Fischbach W, Koop I, Kuehne J, Breidert M, Sass NL, May A, Friedrich C, Veitt R, Porschen R, Ellrichmann M, Arlt A, Schmitt W, Dollhopf M, Schmidbaur W, Dignass A, Schmitz V, Labenz J, Kaiser G, Krannich A, Barteska N, Ell C. Acute sedation-associated complications in GI endoscopy (ProSed 2 Study): results from the prospective multicentre electronic registry of sedation-associated complications. Gut. 2019 Mar;68(3):445-452. doi: 10.1136/gutjnl-2015-311037. Epub 2018 Jan 3.
• Pagano N, Arosio M, Romeo F, Rando G, Del Conte G, Carlino A, Strangio G, Vitetta E, Malesci A, Repici A. Balanced Propofol Sedation in Patients Undergoing EUS-FNA: A Pilot Study to Assess Feasibility and Safety. Diagn Ther Endosc. 2011;2011:542159. doi: 10.1155/2011/542159. Epub 2011 Jul 12.
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• Heuss LT, Schnieper P, Drewe J, Pflimlin E, Beglinger C. Risk stratification and safe administration of propofol by registered nurses supervised by the gastroenterologist: a prospective observational study of more than 2000 cases. Gastrointest Endosc. 2003 May;57(6):664-71. doi: 10.1067/mge.2003.191.
• Dewitt J, McGreevy K, Sherman S, Imperiale TF. Nurse-administered propofol sedation compared with midazolam and meperidine for EUS: a prospective, randomized trial. Gastrointest Endosc. 2008 Sep;68(3):499-509. doi: 10.1016/j.gie.2008.02.092. Epub 2008 Jun 17.
• Trummel JM, Surgenor SD, Cravero JP, Gordon SR, Blike GT. Comparison of differing sedation practice for upper endoscopic ultrasound using expert observational analysis of the procedural sedation. J Patient Saf. 2009 Sep;5(3):153-9. doi: 10.1097/PTS.0b013e3181b53f80.
• Amornyotin S, Leelakusolvong S, Chalayonnawin W, Kongphlay S. Age-dependent safety analysis of propofol-based deep sedation for ERCP and EUS procedures at an endoscopy training center in a developing country. Clin Exp Gastroenterol. 2012;5:123-8. doi: 10.2147/CEG.S31275. Epub 2012 Jul 9.
• Yusoff IF, Raymond G, Sahai AV. Endoscopist administered propofol for upper-GI EUS is safe and effective: a prospective study in 500 patients. Gastrointest Endosc. 2004 Sep;60(3):356-60. doi: 10.1016/s0016-5107(04)01711-0.
• Ye L, Xiao X, Zhu L. The Comparison of Etomidate and Propofol Anesthesia in Patients Undergoing Gastrointestinal Endoscopy: A Systematic Review and Meta-Analysis. Surg Laparosc Endosc Percutan Tech. 2017 Feb;27(1):1-7. doi: 10.1097/SLE.0000000000000373.
• Wang F, Zhou Q, Shen M, Quan J, Chen J, Shi J, Zou X. Efficacy and safety of remimazolam in procedural sedation and analgesia: A protocol for systematic review and meta analysis. Medicine (Baltimore). 2020 Jul 2;99(27):e20765. doi: 10.1097/MD.0000000000020765.
• Borkett KM, Riff DS, Schwartz HI, Winkle PJ, Pambianco DJ, Lees JP, Wilhelm-Ogunbiyi K. A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy. Anesth Analg. 2015 Apr;120(4):771-80. doi: 10.1213/ANE.0000000000000548.
• Pambianco DJ, Borkett KM, Riff DS, Winkle PJ, Schwartz HI, Melson TI, Wilhelm-Ogunbiyi K. A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy. Gastrointest Endosc. 2016 May;83(5):984-92. doi: 10.1016/j.gie.2015.08.062. Epub 2015 Sep 9.
• Uzman S, Gurbulak B, Gurbulak EK, Donmez T, Hut A, Yildirim D. A comparison of propofol and midazolam/meperidine sedation in upper gastrointestinal endoscopy. Wideochir Inne Tech Maloinwazyjne. 2016;11(3):178-185. doi: 10.5114/wiitm.2016.61521. Epub 2016 Jul 29.
• Kashiwagi K, Hosoe N, Takahashi K, Nishino H, Miyachi H, Kudo SE, Martin JF, Ogata H. Prospective, randomized, placebo-controlled trial evaluating the efficacy and safety of propofol sedation by anesthesiologists and gastroenterologist-led teams using computer-assisted personalized sedation during upper and lower gastrointestinal endoscopy. Dig Endosc. 2016 Sep;28(6):657-64. doi: 10.1111/den.12678. Epub 2016 Jun 29.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2021
• Primary Completion (ANTICIPATED): December 31, 2022
• Study Completion (ANTICIPATED): December 31, 2022

Study Registration Dates

• First Submitted: June 23, 2022
• First Submitted That Met QC Criteria: June 23, 2022
• First Posted (ACTUAL): June 29, 2022

Study Record Updates

• Last Update Posted (ACTUAL): June 29, 2022
• Last Update Submitted That Met QC Criteria: June 23, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: remimazolam; Endoscopic ultrasound-guided fine needle aspiration; Sedation Complication
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Hypnotics and Sedatives; Propofol
• Other Study ID Numbers: EUS-FNA-2022-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Some data underlying this trial cannot be shared publicly due to protection of participant's privacy.

Drug and device information, study documents

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