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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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. 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. 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. 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 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 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. 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.

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

Conditions
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Endoscopic Ultrasonography-guided Fine Needle Aspiration, Sedation Complication, Remimazolam

Intervention / Treatment
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* Drug: Remimazolam Injection
* Drug: Propofol Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: ≥18 years old and ≤75 years old BMI: 18kg/m^2<BMI<30kg/m^2; Body weight: 40kg<weight<120kg Patients who intend and qualified to undergo sedated EUS-FNA/FNB. Clearly understand, voluntarily participate in the research, and sign the informed consent form. Exclusion Criteria: Patients who are not suitable for sedated EUS-FNA/FNB for any reason (e.g. cardiovascular disease) Patients have abnormal liver function, AST and/or ALT≥2.5×ULN, TBIL≥1.5×ULN; Patients have abnormal renal function, urea or blood urea nitrogen≥1.5×ULN, serum creatinine≥1.0 ×ULN Those who are allergic to benzodiazepines, opioids, propofol or lidocaine. Patients have contraindications for benzodiazepines, opioids, propofol or lidocaine. Patients have benzodiazepines, opioids, propofol, lidocaine suspected narcotic drug abuse history and pain drug or sedative abuse. 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The experimental group was sedated with remimazolam, and the control group was sedated with propofol;
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remimazolam group<br>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<br>* The experimental group was sedated with remimazolam<br>|
| Active Comparator: Propofol group<br>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<br>* The control group was sedated with propofol<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endoscopic ultrasound-guided fine needle aspiration, Sedation Complication, remimazolam