Ethics and Registration
This study was approved by the Clinical Research Ethics Committee of Mengcheng County No. 1 People's Hospital (2020MYL20003) and registered at https://www.chictr.org.cn (15/09/2020, ChiCTR-2000038252). The study protocol followed the CONSORT guidelines. The study protocol was performed in the relevant guidelines. Written informed consent was obtained from patients undergoing elective hysteroscopy at Mengcheng County No. 1 People's Hospital from 15/09/2020 to 20/12/2020.
Patient Inclusion and Exclusion Criteria
The inclusion criteria of the patients were age between 18 and 65 years old, American Society of Anesthesiologists (ASA) physical status I or II and body mass index (BMI) of 19 to 30 kg/m2. Patients with history of alcoholism or allergy to general anaesthetic drugs, renal or liver diseases, communication difficulties, lactation or recent respiratory infections were excluded.
Patients were randomly assigned into the remimazolam group (Group R) and the propofol group (Group P) by computer generated randomization.
All patients fasted routinely before surgery. On arrival in the operating room, the Bene View N15 monitor (Mindray Biomedical Electronics Co., Shenzhen, China) was connected to monitor the electrocardiogram (ECG), noninvasive blood pressure (NIBP) including systolic blood pressure (SBP) and diastolic blood pressure (DBP), SpO2, and heart rate (HR). All patients inhaled oxygen (2 L/min) through a Venturi oxygen mask, and all patients received an intravenous (IV) COX-2 inhibiter, flurbiprofen axetil 50 mg (Wuhan Docan Pharmaceutical Co., Ltd., China) for analgesic preconditioning before the start of hysteroscopy.
Grouping and Intervention
All patients in Group R were started at an induction dose of 0.2 mg/kg remimazolam besylate (Yichang Humanwell Pharmaceutical Co., Ltd., China) and a maintenance dosage of 1 mg/kg/h by continuous IV infusion until the loss of consciousness (LoC). The dose was based on a randomized phase IIb/III trial conducted by Japanese researchers in 2019 showed that the induction dose of remimazolam (0.2 mg/kg) was no less effective than propofol (2.0–2.5 mg/kg) when used as a general anaesthesia sedative. When the Modified Observer's Alertness/Sedation (MOAA/S) score was ≤2, hysteroscopy was started. According to the MOAA/S score, supplemental remimazolam was added at 2.5 mg/dose, with no more than 5 doses administered within 15 min, according to the drug instructions of the supplemental drug program.
All patients in Group P were started at 1.5–2.0 mg/kg propofol (Fresenius Kabi AG, Austria). When the MOAA/S score was ≤2, hysteroscopy was started. Then, the infusion rate of propofol was maintained with a dosage of 3.0 mg/kg/h. According to the MOAA/S score, the injection speed of propofol was adjusted to 3.0–6.0 mg/kg/h.
After remimazolam besylate or propofol induction, infusion of remifentanil (Yichang Humanwell Pharmaceutical Co., Ltd.) in both the groups was started with TCI pump (Guangxi VERYARK Technology Co., Ltd., China), and the effective effect-site concentration (Ce) (Minto pharmacokinetic model) was 1.5 ng/ml. Remifentanil was increased by 0.5 ng/ml when analgesia was insufficient (facial grimace, movement, SBP > 140 mmHg, heart rate (HR) > 100 beats/min (bpm) or sudden increase of more than 30 bpm over baseline) and was decreased by 0.5 ng/ml with signs of excessive analgesia (respiratory depression, hypotension, or bradycardia).
Primary Outcome. The primary outcome of this study was the incidence of various adverse events, such as injection pain, low SpO2, bradycardia and hypotension (definitions in Table 1). These events were treated by injecting ephedrine or atropine intravenously, or mask ventilating.
Secondary Outcomes. The incidence of body movement and postoperative dizziness (definitions in Table 2) were recorded. Patient data fluctuations included the mean arterial pressure (MAP) (MAP = (SBP + 2 × DBP)/3), HR, SpO2, and MOAA/S score at pre-anaesthesia (T0), 2 min post induction (T1), cervical dilatation (T2), the end of the operation (T3), and awakening (T4). The duration of awakening and postanaesthesia care unit (PACU) length of stay were recorded.
We searched relevant literature regarding remimazolam and found that MOAA/S scores were used as the evaluation method of anaesthetic depth in most of the studies. The guiding significance of using the bispectral index (BIS) to study remimazolam was not clear; therefore, we had no confidence in using BIS and chose the MOAA/S score instead.
Sample Size and Statistical Analysis
In the pilot study on the combined use of propofol and remifentanil in hysteroscopy, the incidence of various intraoperative adverse events was 30%. This result of our small sample pre-experiment indicated a clinically significant reduction in the incidence of adverse events to 5% by the use of remimazolam. A sample size of 41 participants in each group was calculated, and the significance level was 0.05 (a = 0.05). Given a 10% attrition rate, the strength was 80% (b = 0.20).
Statistical analysis was performed using SPSS Statistics 17.0.1 (SPSS Inc., Chicago, IL). Normality test in SPSS statistics software was used for data analysis to determine whether the data were in accordance with a normal distribution. Normally distributed continuous variables are presented as the mean ± standard deviation and were analysed using Student's t test. The Mann-Whitney U test was used for non-normally distributed continuous variables. Hemodynamic parameters were compared by repeated measures ANOVA. Categorical variables are expressed as a frequency (percentage) and were analysed using the Pearson chi-square test. The Wilcoxon Signed-Rank test was used to compare continuous variables. A p value < 0.05 was considered to indicate statistical significance.
BMC Anesthesiol. 2021;21(156) © 2021 BioMed Central, Ltd.