Safety and Efficacy Evaluation of Remimazolam for Endoscopic Ultrasound-guided Fine Needle Aspiration/Biopsy
Phase: NA
Conditions: Endoscopic Ultrasonography-guided Fine Needle Aspiration, Sedation Complication, Remimazolam
Sponsor: The Third Xiangya Hospital of Central South University

Safety and Efficacy Evaluation of Remimazolam for Endoscopic 
Ultrasound-guided Fine Needle Aspiration/Biopsy 
Unique protocol ID:EUS-FNA-2022-01 
Date:2022-05-10 
1. Research background and aim 
Endoscopic ultrasound-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, multicenter 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, 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. 
 
2. Study design 
This trial adopted a multicenter, prospective, single-blind, active-drug parallel-controlled 
design. 
3. Blind, concealment and randomization 
Due to the obvious differences between remimazolam and propofol, the anesthesiologists 
will inevitably know the grouping of patients, so this trial adopts a single-blind design. However, 
the drug infusion systems used by the patients are covered with black cloths to prevent the 
recorders, endoscopists and nurses from knowing the patient grouping information.  
Randomization of patients was performed by a dedicated researcher who was not involved 
in the follow-up procedures. The random number table was generated in advance with the help 
of SPSS20.0 software, and it was divided into two groups at 1:1, corresponding to two sedation 
programs. The sedation regimen was determined based on the random number assigned to the 
patient. After the patients completed the follow-up period, the researchers who were 
responsible for the grouping informed them of the grouping status to protect the patients' right 
to know. In emergencies, the researchers and anesthesiologists in charge of the grouping have 
the authority to perform emergency blinding to ensure the quality of medical care. 
4. Research protocol: 
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.  
5. List of adverse events 
Major adverse events: endotracheal intubation, permanent neurologic impairment, or death. 
Other intraoperative adverse events:  
Respiratory system and diaphragm:  

Intraoperative cough or hiccups; 
Respiratory depression: pulse oxygen saturation <90% or breathing <8 breaths/min for 1 
minute or more; apnea: respiratory airflow stopped for more than 15s; 
Circulatory system:  
Hypotension: SBP decreased by more than 20% of the baseline SBP;  
Hypertension: SBP increased by more than 20% of the baseline SBP;  
Tachycardia: HR>100 bpm for 1 minute or more;  
Bradycardia : HR<50bpm for 1 minute or more; 
Psychiatric and nervous system:  
Intraoperative awareness: The modified BRICE questionnaire determines the existence of  
Delayed awakening: unable to open eyes and shake hands 30 minutes after the operation, no 
obvious response to pain stimuli  
Skin: 
 Redness, induration, phlebitis, rash;  
Motor system:  
Body movement, injection pain, involuntary muscle movements (such as rigidity, spasticity, 
clonus, muscle tremors, etc.) 
Postoperative adverse events: 
Postoperative dizziness, headache, drowsiness, vertigo;  
Postoperative weakness chills;  
Postoperative agitation, postoperative cognitive dysfunction, anxiety, confusion, insomnia, 
nervousness, abnormal thinking, abnormal dreams;  
Postoperative sore throat, nausea, vomiting, anorexia;  
Bleeding, pain, infection, organ perforation, adjacent tissue organ damage, puncture needle 
breakage/leftover, etc.