The 90% Effective Dose (ED90) of Remimazolam Anesthesia Induction in Painless Bidirectional Endoscopy in Children: a Biased Coin up and Down Sequential Trial
Phase: NA
Conditions: Bidirectional Endoscopy
Sponsor: Tongji Hospital

 
Clinical study protocol 
 
________________________________________________________ 
To investigate the 90% effective dose (ED90) induced by 
anesthesia in pediatric painless gastroenteroscopy: an up-and-
down sequential test of biased coins 
Determination of the ED90 (90% Effective Dose) of 
Remimazolam Anesthesia Induction in Pediatric Painless 
Gastrointestinal Endoscopy: A Biased Coin up and Down 
Sequential Trial   
________________________________________________________ 
 
Version 12 
Version date: 2024/01/17 
 
 
 
 
 
 
 
Project leader: Associate Professor Xu Aijun 
Research unit: Department of Anesthesiology, Tongji Hospital, Tongji 
Medical College, Huazhong University of Science and Technology 

 
 
1. Research background 
In recent years, painless digestive endoscopy technology is advancing rapidly in 
our country.According to a national survey1，The volume of digestive endoscopy in our 
country is increasing year by year, and it is expected that by 2030, the number of 
digestive endoscopy under sedation will reach 51 million.Pediatric digestive endoscopy 
tends to have a higher rate of sedation due to low tolerability and adherence in 
childrenGastroenterologists often choose to use painless gastroenteroscopy to assess 
gastrointestinal conditions, and its indications include abdominal pain, vomiting, 
anemia, etc. However, unlike adult painless gastroenteroscopy, children have higher 
sensitivity to endoscopic stimulation and worse tolerance to hypoxia, which leads to a 
significant increase in the probability of adverse events in pediatric patients under 
shallow sedation and deep sedation2,3。 So far, propofol is still the preferred procedural 
sedation drug for clinical application, but its adverse reactions such as hypotension and 
respiratory depression have made researchers urgently seek better alternatives to meet 
higher anesthesia requirements4。 
Remimazolam is a new benzodiazepine drug, which is an ultra-short-acting 
GABAA(γ-aminobutyric acid subtype A) receptor agonists. It not only retains the 
characteristics of benzodiazepines, such as water solubility, antagonism, no injection 
pain, and can be antagonized by flumazenil, but also adds some pharmacological 
characteristics of remifentanil due to the side chain of methyl propionate in the structure, 
such as fast onset, short action time, inactivity of metabolites, and not affected by 
infusion time5–8。Studies have shown that,Remimazolam has the clinical advantages of 
"short", "flat" and "fast", and the patient's recovery time is fast, and the postoperative 
recovery is faster.The incidence of adverse events such as decreased blood pressure and 
respiratory depression during gastroenteroscopy is lower and the safety is higher9。 
The unique pharmacological properties are also suitable for day surgery, precision 
anesthesia, and accelerated recovery surgery(enhanced recovery after surgery, ERAS) 

and other anesthesia concepts, which are suitable for gastroenteroscopy, bronchoscopy 
and anesthesia induction, and can avoid adverse reactions such as hemodynamic 
fluctuations, excessive sedation, and injection pain caused by propofol to a greater 
extent, and the safety is good and better than propofol10,11。 
Domestic and foreign studies on remimazolam mainly focus on sedation effect and 
safety, and there are also studies on the appropriate dose of remimazolam induction 
anesthesia in adults12,13, but there are fewer studies in pediatric anesthesia. In our 
previous study, we found that the treatment rate of remimazolam induction anesthesia 
in pediatric painless gastroenteroscopy was high, and at the same time, the dosage 
required by children of different ages varied, and infants and young children often 
required multiple additional medications to cause unconsciousness, reducing the 
satisfaction of patients and surgeons. shown in a study by George D Politis et al14There 
are indeed differences in the dosage of propofol in induced sedation in children of 
different ages, and at the same time, it has been shown in related studies of 
remimazolam15In adult patients, the effective sedation dose of remimazolam decreases 
with age, so it is meaningful and necessary to explore the dosage of sedation drugs in 
anesthesia induction. 
The safety and efficacy of remimazolam in children of different ages have also 
been confirmed and evaluated by several studies. In preschool children (0-6 years 
old)Remimazolam has been safe and effective for painless gastroscopy16, root canal 
treatment17, tonsillectomy18, fiberoptic bronchoscopic lavage19and other clinical 
operations. These results suggest that remimazolam has the advantage of shortening the 
time to awakening and PACU stay, and reducing the incidence of adverse reactions such 
as respiratory depression, hypotension, and injection pain, and no serious 
remimazolam-related adverse reactions were found.In school-age children (7-12 years 
old)Remimazolam also has a good safety and efficacy18,20It can be successfully used 
for tonsillectomy, supratentorial glioma resection, etc., and the anesthesia process of 
the child is smooth, which better avoids the occurrence of hypotension and propofol 
infusion syndrome, reduces the incidence of postoperative agitation, and improves the 
satisfaction of the child's parents. No other adverse reactions related to remimazolam 

were observed. 
The latest literature shows21, it is not recommended to use the traditional Dixon 
sequential test method to explore the half-effective dose of anesthetic drugs（median 
effective dose,ED50）Then, statistical principles and formulas were used to calculate 
the 90% effective dose （the 90% effective dose,ED90 ）。 In order to avoid 
computational bias, this study intends to explore remimazolam using the bias coin upper 
and 
lower 
sequential 
testAnesthesia-induced 
ED90 
and 
90 
in 
pediatric 
gastroenteroscopy at different ages% confidence interval(confidence interval, CI), to 
provide more clinical reference for the anesthesia induction application of 
remimazolam. 
At the same time, the depth of anesthesia was monitored using the anesthesia depth 
monitor Narcotrend (NT),NT has the advantages of perfect hierarchy, rapid data 
processing, unaffected by electromyographic activity, and high reliability22,23, and its 
technology for using NT in pediatric procedural sedation is also very mature24–26。 
Therefore, NT was chosen to monitor the depth of anesthesia to prevent intraoperative 
inadequacy and to predict and remedy the occurrence of adverse events in time, while 
providing more credible data for the calculation of ED90 in this study. 
 
2. Research purpose 
To explore the ED90 of remimazolam in pediatric gastroenteroscopy in different 
age groups, and to provide a more scientific clinical dose selection basis for the 
anesthesia induction application of remimazolam. 
3. Research design 
This study is a prospective, double-blind, sequential trial. 
1. Patient selection 
It is planned to observe cases of pediatric painless gastroenteroscopy in Tongji 
Hospital from March 2024 to December 2024.  
2. Sample size calculation 
The main observation indicator in this study was the success rate of sedation in 

patients. According to the literature, the offset coin method is used（biased-cion design, 
BCD）Design sequential tests（up-and-down method, UDM）For determination of the 
ED90 of the drug, the recommended sample size is 50-60 cases21。 In this experiment, 
the patients were divided into three groups according to age14：1.Toddler group、
2.Preschool group, 3.School-age groupTherefore, this experiment plans to include 165 
samples, 55 cases in each group. 
3. Inclusion criteria 
（1） Age 1-12 years old 
（2） ASA Class I-II; 
（3） Signed informed consent. 
4. Exclusion Criteria 
（1） Those with developmental delay, or neuropsychiatric diseases; 
（2） Severely malnourished, or severely obese; 
（3） Patients with high risk of stomach satiety and reflux aspiration; 
（4） Those who are allergic to benzodiazepines and opioids; 
（5） Those who have taken sedative, analgesic or antidepressant drugs within 24 
hours; 
（6） Severe sleep apnea; 
（7） Abnormal liver and kidney function; 
（8） Recent participation in other clinical studies. 
5. Midway exit criteria 
（1） Serious adverse events such as major bleeding and intestinal perforation during 
surgery;  
（2） Participant withdraws consent; 
（3） Follow-up shedding.  
6. Rejection criteria 
Enrolled cases that meet any of the following criteria will be excluded and will not be 
analyzed in the next step. 
（1） No use of study drugs; 
（2） No research records; 

For rejection cases, detailed reasons are recorded and CRFs are kept for reference. 
The results of these cases are not further analyzed for treatment effects. 
 
4. Research process 
1. Preoperative evaluation 
Patients will be visited according to clinical routine the day before surgery, 
enrolled patients will be determined according to the inclusion and exclusion criteria, 
and the informed consent form will be signed to record the basic information of the 
patients. 
2.Research methodology 
The research method of this experiment is biased coin sequential analysis (BCD-
UDM).  
3. Research process 
With the exception of the experimental drug remimazolam, all patients received 
standardized care and anesthesia management. All children are required to fast for 8 
hours, abstain from water for 2 hours, and do not use pre-anesthesia medication before 
surgery. Grouping: Children are divided into 3 groups according to age, namely 
1Toddler group: 0-3 years old (<48 MOS), 2Preschool group: 4-6 years old (≥48 and 
<84 MOS), 3School-age group: 7-12 years old (≥84 and <156 MOS). （months, MOS） 
The experimental drug used in this study was remimazolam benzolate for injection, 
and the analgesic drug was remifentanil, and the anesthetic drugs were prepared in 
advance according to the concentration of remimazolam 1mg/ml and remifentanil 
1mcg/ml, and ephedrine, atropine and other drugs were routinely extracted for backup.  
The child entered the children's digestive endoscopy room after opening the 
intravenous infusion in the ward, and the mask inhaled oxygen for 3 L/min. Routine 
monitoring of blood pressure (NIBP), heart rate (HR), blood oxygen saturation (SpO2), 
electrocardiogram (electrocardiogram (ECG), respiratory rate (RR), and perfusion 
index (PI). After lateral decubitus, different doses of remimazolam + remifentanil were 
slowly injected intravenously over 1 minute using a micropump, with a fixed induction 

dose of 0.5 mcg/kg of remifentanil. According to the pre-experiment, the initial dose of 
remimazolam in the toddler group was 0.5 mg/kg, the initial dose was 0.4 mg/kg in the 
preschool group, and the initial dose was 0.3 in the school-age group mg/kg, and the 
dose was 0.02 mg/kg at adjacent intervals. According to the BCD-UDM, the dose of 
remimazolam for the next child is determined based on the response of the previous 
child, the first patient in each group starts with the initial dose, and after the patient is 
administered this dose, the loss of consciousness (negative) within 2 minutes is 
recorded as a failure of sedation, and remimazolam 0.05 mg/kg is added (instruction 
manual requirements: the maximum additional dose at a time does not exceed 2). .5mg, 
the maximum number of additions is 5) + remifentanil 0.1 mcg/kg to keep the child 
quiet and painless. If target sedation is not achieved, 0.5 mg/kg propofol is given as 
rescue sedation. keep the patient quiet and pain-free, and the next patient will be 
increased by one dose; In case of loss of consciousness (positive), the next patient's 
dose of remimazolam remains the same or is reduced by one dose, whether the dose is 
reduced based on a computer-generated list of partial coin experiments. During the 
examination, respiratory depression and blood oxygen saturation decreased, and the jaw 
was supported to assist in respiratory correction; If blood pressure drops significantly 
and heart rate slows down, ephedrine and atropine are given symptomatic treatment to 
maintain circulatory stability.  
After the examination, the child is transferred to the Post-Anesthesia Care Unit 
(PACU) to observe the child's respiratory status to confirm that there is no airway 
obstruction. In the PACU, the child received oxygen via nasal cannula for 2 L/min and 
was monitored by NIBP, HR, and SpO2. If the Postanesthetic Discharge Scoring system 
(PADS) score ≥ 9 points after anesthesia, the transfer from the PACU to the ward is 
confirmed by the attending anesthesiologist.  
4.Blinding 
In this trial, remimazolam was prepared by an independent anesthesia nurse who 
was not involved in further clinical management and research, and anesthesiologists, 
digestive endoscopists and nurses were involved in intraoperative management and 
postoperative outcome assessment, and neither the patient nor their parents were 

informed about the dose of remimazolam. 
5. Observe the indicators 
1) The main observation indicators were the Modified Observer's Assessment of 
Alertness/Sedation Scale (MOAA/S) and the Anesthesia Depth Monitoring Index.  
2) Secondary observation indicators: 
1. 
Incidence of respiratory depression: respiratory rate < 8 times/min or SpO2 < 
90%;  
2. 
Adverse event monitoring: intraoperative blood pressure and heart rate changes: 
record the patient's intraoperative blood pressure, heart rate, and the use of 
related vasoactive drugs; Postoperative adverse reactions: such as hypertension, 
hypotension, tachycardia, gastrointestinal symptoms, postoperative restlessness, 
etc.  
3. 
anesthesia time, induction time, operation time, recovery time, recovery time;  
4. 
the total amount of sedative and analgesic drugs used; 
5. 
Postoperative pain (FLACC Pain Assessment Scale, FLACC pain score): The 
FLACC score was assessed  at different time points in the PACU (0 minutes 
after awakening, 10 minutes after awakening) and within 24 hours after surgery.  
6. 
Postoperative nausea and vomiting (PONV) (BARF score: Buster retching facial 
scale score): PONV was assessed until discharge.  
7. 
24 hours postoperative follow-up: The children and their parents were asked to 
score their sleep quality, daily activities, and parental satisfaction after surgery. 
 
5. Statistical Analysis Plan  
Probit regression analysis was used to calculate the probabilistic regression equation of 
remimazolam in pediatric painless gastroscopy anesthesia induction, and the fit test was 
carried out, and finally the ED90 and 90% CI of remimazolam in pediatric painless 
gastroscopy were calculated according to the equation. SPSS 25.0 statistical software 
was used for data analysis, and the mean ± standard deviation of the continuous data 
was used, and the analysis of variance or paired t-test was used. Count data are 

expressed as percentages and the χ2 test is used. P<0.05 was a statistically significant 
difference.  
 
 
Six. schedule 
1.Improved MOAA/S scoring scale 
fraction 
Reaction description 
5 
Respond quickly to names spoken in a normal tone 
4 
Exhibit a drowsiness response to names spoken in a normal tone 
3 
React only after calling the name aloud and/or repeatedly 
2 
React to slight irritation or shaking 
1 
Responds only after a painful trapezius muscle squeeze 
0 
The trapezius muscle does not respond after squeezing 
 
2. FLACC behavioral rating scale 
content 
Score 
facial 
expression 
No specific expression or smile 
0 
Occasional facial distortion or frowning 
1 
Constant trembling of the chin, constriction of 
the jaw, frowning 
2 
Leg 
activity 
Normal position or relaxed state 
0 
Discomfort, inability to rest, muscle or nerve tension, 
intermittent flexion/stretching of the muscle 
1 
Kicking or straightening the waist, high tension, expanding 
the flexion/extension of the body, shaking 
2 
Position 
Lie quietly and in a normal position, and can move smoothly 0 
Hurried and restless, moving back and forth, nervous, 
hesitant to move 
1 
Curling or spasms, swinging back and forth, shaking the 2 

head from side to side, rubbing a part of the body 
Crying 
Don't cry or make trouble 
0 
Moaning or sobbing, occasionally crying, sighing 
1 
Constantly crying, screaming or sobbing, moaning 
2 
comfortable 
Calm, content, relaxed, not demanding comfort 
0 
Occasional physical contact can dispel doubts and distract 
attention 
1 
Comfort is difficult 
2 
Score 
divide 
 
3. BARF Scoring Table: 
 
fraction 
Reaction description 
10 
Vomiting POV 
6-8 
Severe PON 
2-4 
Mild PON 
0 
not 
 
4. Postoperative sleep quality score table: 
fraction 
Reaction description 
0 
Sleep well 
1 
Waking up at night crying 
2 
Intermittent sleep 
 
5. Daily activity scoring table: 

fraction 
Reaction description 
0 
Normal quality 
1 
Depressed but performing normal daily activities 
2 
Irritability and inability to perform normal activities 
 
6. Parental Satisfaction Score: The score ranges from 0-10, with 10 
indicating the highest level of satisfaction.  
 
7. PADS scoring table: 
standard 
fraction 
Vital signs 
Fluctuations were within 20% of the preoperative 
measurement for both blood pressure and pulse 
2 
Fluctuations in blood pressure and pulse are 
within 20-40% of the preoperative measurement 
1 
Fluctuations occurred when both blood pressure and 
pulse 
were 
outside 
40% 
of 
preoperative 
measurements 
0 
activity 
Steady bearing and gait determination, or return 
to preoperative baseline levels 
2 
Able to determine orientation or steady gait 
1 
Cannot meet any of the first two 
0 
Nausea and vomiting 
Very few 
2 
Moderate 
1 
Severe 
0 
pain 
Very few 
2 

Moderate 
1 
Severe 
0 
Surgical bleeding 
Very few 
2 
Moderate 
1 
Severe 
0 
 
References 
1. Isoldi, S. et al. Gastrointestinal endoscopy in children and adults: How do they 
differ? Dig. Liver Dis. Off. J. Ital. Soc. Gastroenterol. Ital. Assoc. Study Liver 53, 
697–705 (2021). 
2. Jiang, M.-Z. [Development and thoughts of digestive endoscopy in children]. 
Zhongguo Dang Dai Er Ke Za Zhi Chin. J. Contemp. Pediatr. 24, 350–353 (2022). 
3. Zhou, S. et al. National survey on sedation for gastrointestinal endoscopy in 2758 
Chinese hospitals. Br. J. Anaesth. 127, 56–64 (2021). 
4. Zheng, X.-S. et al. ED50 and ED95 of propofol combined with different doses of 
esketamine for children undergoing upper gastrointestinal endoscopy: A prospective 
dose-finding study using up-and-down sequential allocation method. J. Clin. Pharm. 
Ther. 47, 1002–1009 (2022). 
5. Wesolowski, A. M., Zaccagnino, M. P., Malapero, R. J., Kaye, A. D. & Urman, 
R. D. Remimazolam: Pharmacologic Considerations and Clinical Role in 
Anesthesiology. Pharmacotherapy 36, 1021–1027 (2016). 
6. Sneyd, J. R. Remimazolam: new beginnings or just a me-too? Anesth. Analg. 115, 
217–219 (2012). 
7. Schüttler, J. et al. Pharmacokinetics and Pharmacodynamics of Remimazolam 
(CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part I. 
Pharmacokinetics and Clinical Pharmacodynamics. Anesthesiology 132, 636–651 
(2020). 
8. Sneyd, J. R. & Rigby-Jones, A. E. Remimazolam for anaesthesia or sedation. 
Curr. Opin. Anaesthesiol. 33, 506–511 (2020). 
9. Wang, X. et al. Safety and efficacy of remimazolam besylate in patients 
undergoing colonoscopy: A multicentre, single-blind, randomized, controlled, phase 
Ⅲ trial. Front. Pharmacol. 13, 900723 (2022). 
10. Rex, D. K. et al. A phase III study evaluating the efficacy and safety of 
remimazolam (CNS 7056) compared with placebo and midazolam in patients 
undergoing colonoscopy. Gastrointest. Endosc. 88, 427-437.e6 (2018). 
11. Safety and efficacy of remimazolam in high risk colonoscopy: A randomized trial 
- PubMed. https://pubmed.ncbi.nlm.nih.gov/33243567/. 
12. Jeong, H., Kim, H. & Ahn, H. J. An Adequate Infusion Rate of Remimazolam for 
Induction of General Anesthesia in Adult Patients: A Prospective Up-and-Down 

Dose-Finding Study. J. Clin. Med. 12, 1763 (2023). 
13. Liu, M. et al. The Median Effective Dose and Bispectral Index of Remimazolam 
Tosilate for Anesthesia Induction in Elderly Patients: An Up-and-Down Sequential 
Allocation Trial. Clin. Interv. Aging 17, 837–843 (2022). 
14. Politis, G. D. et al. Propofol for pediatric tracheal intubation with deep anesthesia 
during sevoflurane induction: dosing according to elapsed time for two age groups. J. 
Clin. Anesth. 26, 25–35 (2014). 
15. Oh, J. et al. Determination of the 95% effective dose of remimazolam to achieve 
loss of consciousness during anesthesia induction in different age groups. Korean J. 
Anesthesiol. 75, 510–517 (2022). 
16. Shi Cuicui, Sun Jian, & Zhang Yufeng. Application of remimazolam in painless 
gastroscopy in children. Journal of Clinical and Pathology 41, 2918–2922 (2021). 
17. Zhang Tongtong et al. The effect of remimazolam combined with propofol on 
sedation of outpatient root canal treatment in children. Chinese Journal of 
Anesthesiology 42, (2022). 
18. Yang, X. et al. Remimazolam for the Prevention of Emergence Delirium in 
Children Following Tonsillectomy and Adenoidectomy Under Sevoflurane 
Anesthesia: A Randomized Controlled Study. Drug Des. Devel. Ther. 16, 3413–3420 
(2022). 
19. Feasibility and safety study of remimazolam combined with laryngeal mask for 
pediatric fiberoptic bronchoscopic lavage. 
https://d.wanfangdata.com.cn/periodical/ChlQZXJpb2RpY2FsQ0hJTmV3UzIwMjM
wODMxEhpRS0JKQkQyMDIyMjAyMjA3MjMwMDAwODI4MRoIazYxZzlpamg
%3D. 
20. Kamata, K. et al. Successful recording of direct cortical motor-evoked potential 
from a pediatric patient under remimazolam anesthesia: a case report. JA Clin. Rep. 8, 
66 (2022). 
21. Oron, A. P., Souter, M. J. & Flournoy, N. Understanding Research Methods: Up-
and-down Designs for Dose-finding. Anesthesiology 137, 137–150 (2022). 
22. Xia Lingyi, Zhang Qian, Zhuo Ming & Zhong Maolin. Clinical application 
progress of Narcotrend anesthesia depth monitor. Journal of Gannan Medical College 
42, 215–220 (2022). 
23. Shepherd, J. et al. Clinical effectiveness and cost-effectiveness of depth of 
anaesthesia monitoring (E-Entropy, Bispectral Index and Narcotrend): a systematic 
review and economic evaluation. Health Technol. Assess. Winch. Engl. 17, 1–264 
(2013). 
24. ZHONG Jianhong. A clinical controlled study of Narcotrend and BIS on 
monitoring the quality of recovery after pediatric laparoscopic surgery. (Southern 
Medical University, 2014). 
25. Huang Mei. Application of Narcotrend EEG Awareness Depth Monitoring in 
General Anesthesia in Pediatric Day Surgery. Chinese Medical Sciences 10, 227-
229+242 (2020). 
26. de Heer, I. J., Warmenhoven, A. T. & Weber, F. Electroencephalographic density 
spectral array monitoring during propofol sedation in teenagers, using the narcotrend 

electroencephalographic monitor. Minerva Anestesiol. 86, 601–607 (2020).