2.1. Ethics and informed consent
This study was approved by the Ethics Committee of The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital (KJ2021001). The study obtained written informed consent was obtained from all participants. The study was registered in the Chinese Clinical Trial Registry (ChiCTR2100049683).
2.2. Participants and Study design
This was a randomized, double-blind, single-center, parallel-controlled clinical trial. A total of 106 patients who were scheduled for painless gastroscopy at The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital were enrolled in this study from March 2021 to August 2021. After 6 refused to participate, 100 eligible participants were included in the final analysis. They were randomly divided into the control group (Con group) and the remazolam group(Rem group), with 50 patients per group (Fig. 1). Inclusion criteria: Patients aged between 18 to 65 years old were scheduled for painless gastroscopy, with American Society of Anesthesiologists grade Ⅰ or Ⅱ. Exclusion criteria:
(1) Patients with concomitant acute phase respiratory infections;
(2) Patients with obstructive sleep apnea syndrome (OSAS);
(3) Patients with a history of hypersensitivity to benzodiazepines and related narcotic drugs;
(4) Patients with a history of intoxication with alcohol or taking analgesic and sedative medications for a long time;
(5) Patients with major upper gastrointestinal (GI) bleeding within 48 h;
(6) Women who are pregnant or breastfeeding;
(7) Patients with psychiatric disorders;
(8) Those with airways considered difficult were also excluded, such as cervical spine fixation, limited mouth opening, etc. Termination criteria:
(1) The patient had severe choking on examination that could not be continued;
(2) The patient required further gastroscopic treatment during the examination;
(3) The patient had severe respiratory circulatory depression on examination, which required intubation.
On the day of surgery, the enrolled patients were randomly divided into Rem group or Con group by a single investigator who was involved only in randomization, using the random number table method. A random sequence without stratification was generated by a computer and sealed with consecutively numbered envelopes to conceal the random assignment. Before the operation, an independent anesthesiologist not involved in the study was responsible for preparing remazolam or saline placebo opened the envelope to show the allocation of treatment, and then used the same 50 ml syringe to extract the drug. Either 0.9% isotonic saline (Con group) or remazolam (Rem group) was diluted in 0.9% isotonic saline to a final volume of 36ml (final concentrations: remazolam 1mg/mL). We pumped the drug into the patient in a blind manner. Patients, surgeons, researchers, and statisticians were not aware of the blind assignment until the final statistical analysis was completed.
2.3. Anesthetic protocol
The patient fasted for 8 hours and was unable to drink for 2 hours. Monitoring was performed throughout the operation. After entering the operating room, 3-lead electrocardiography, blood pressure and pulse oxygen saturation were monitored. Oxygen was delivered by a face mask. Intravenous channels were established and lactate Ringer's solution was infused at 5mL/kg/h. All patients underwent bolus sufentanil 0.05ug/kg after venous access was established. In Rem group, Remazolam 3mg and propofol 0.75~2.5mg/kg were infused intravenously one minute after bolus sufentanil. In Con group, patients were infused with the same dose of normal saline and propofol in the same way. Gastroscopy was performed when the Ramsay Sedation score was > 5 and the eyelash reflex was absent. During examination, additional propofol 0.5 mg/kg would be added immediately if the patient experienced somatization or choking that affected the gastroscopy.
2.4 Outcome measures
2.4.1 Main measures
Vital signs like SBP, DBP, HR and SPO2 of patients were recorded at six different time points: before anesthesia (baseline, T0), after the bolus was finished (T1), at the time of gastroscope placement (T2), 3 min after the beginning of the examination (T3), when the patient was awake (T4), and at the time of discharge from the PACU (T5).
2.4.2 Secondary outcomes
(1)Patients' general conditions: gender, age, height, weight and body mass index (BMI)
(2)Dosage of propofol and additional times of propofol
(3)Adverse reactions
Adverse reactions, such as hypertension (SBP ≥ 140mmHg and/or DBP ≥ 90mmHg), hypotension (SBP < 90mmHg and/or DBP < 60mmHg), bradycardia (HR < 60 times/ minutes), tachycardia (HR >100 times/minutes), hypoxemia (SPO2 < 90%) and arrhythmia were recorded during the perioperative period. Besides, the occurrence of nausea, vomiting and dizziness after surgery was also recorded.
(4)Duration of gastroscopy (min), awakening time (min) (the time after the operator completely withdraws from gastroscope until the patient can open his/her eyes), dwell time in the anesthesia recovery room (min) (the time after the operator completely withdraws from gastroscope until Chung's score ≥ 9 points)
2.8. Statistical analysis
According to the pre-experimental results, the sample size calculation was based on the peak SBP at T1 as the primary outcome. Set α=0.05 and power=0.8 was used to determine the study. According to the formula estimate the effective sample size N ≈ 42 for each group. Invasive clinical trials often need to recruit more subjects to prevent patients from falling out during follow-up. Based on experience, it is assumed that 20% of the trials are lost to follow-up, so each group of samples is adjusted up to N*=N÷(1-0.2) ≈ 53.
Data analysis was achieved by using SPSS for Windows version 26.0. Normally distributed measurement data were expressed as mean ± standard deviation(x̄ ± s). Continuous variables that were normally distributed were analyzed using an independent t-test, while non-normally distributed variables were analyzed using the Mann–Whitney U test for comparison between the groups. Repeated measures analysis of variance will be used for intra-group comparisons. The χ2 test will be used for the comparison of count data. P<0.05, indicating that the difference is statistically significant.