DOI: https://doi.org/10.21203/rs.3.rs-2448390/v1
Background: Although the operation time of hysteroscopy is short, the incidence of postoperative nausea and vomiting (PONV) is high. Research shows that remimazolam besylate combined with remifentanil is safe and effective for anaesthesia during hysteroscopy. Alfentanil is a short-acting opioid drug with low respiratory inhibition, less cough and fast metabolism, thus making it suitable for daily surgical anaesthesia. Remimazolam is a new benzodiazepine drug that can be as effective in preventing PONV as midazolam. When remimazolam is compounded, it has the best compatibility with remifentanil and alfentanil to reduce PONV. The aim of this study was to compare the incidence of PONV between administration of remimazolam-remifentanil and remimazolam-alfentanil during hysteroscopy.
Methods: We conducted a randomized, controlled, double-blind trial. Patients undergoing hysteroscopy were recruited and randomly assigned to either the remimazolam-remifentanil (Group RR) or the remimazolam-alfentanil group (Group RA).
All patients in the two groups were started with an induction dose of remimazolam besylate 0.2 mg/kg and then maintained with a dosage of 1.0 mg/kg/h. After induction with remimazolam besylate, for Group RR, remifentanil was infused using a target-controlled infusion system with a target concentration of 1.5 ng/ml and titrated throughout the procedure.
For Group RA, infusion of alfentanil was started with an initial bolus dose of 20 µg/kg over 30 s and then maintained at an initial rate of 0.16 µg/kg/min. The primary observation outcome was the incidence rate of PONV. The secondary observation outcomes were hypoxemia during the operation and other adverse effects, such as bradycardia, hypotension and body movement.
Results: A total of 204 patients were successfully included in this study. The incidence of PONV in Group RR (2/102, 2.0%) was significantly lower than that in Group RA (12/102, 11.8%) (p<0.05). There were no significant differences in the incidence of other adverse events, such as low SpO2, bradycardia, hypotension and body movement, between the RR and RA groups (p>0.05).
Conclusions: Remimazolam-remifentanil causes less PONV than remimazolam-alfentanil during hysteroscopy.
Trial registration
Clinical trial registration number: ChiCTR2100044177. Full date of the frst registration: 12/03/2021.
Although the operation time of hysteroscopy is short, the incidence of PONV is high. PONV after gynaecological laparoscopy and hysteroscopy is common and represents a significant clinical problem [1]. The use of opioids is one of the major risk factors that can cause PONV [2]. Common anaesthesia methods for hysteroscopic surgery include propofol combined with opioids, propofol combined with dexmedetomidine, paracervical block and local anaesthesia [3–5]. Propofol combined with opioids is still the most commonly used pain control method in hysteroscopy [6]. Research shows that compared with propofol, remimazolam besylate combined with remifentanil is a safer anaesthetic substitute in hysteroscopy [7]. Alfentanil is a short-acting opioid drug with low respiratory inhibition, less cough and fast metabolism, thus making it suitable for daily surgical anaesthesia [8]. Regardless of the specific opioid administered, this class of drugs increases the risk of PONV in a dose-dependent manner, but different combinations of opioids have different effects on PONV [9]. Remimazolam is a new benzodiazepine drug that can be as effective in preventing PONV as midazolam [10, 11].
When remimazolam is compounded, it has the best compatibility with remifentanil and alfentanil for reducing PONV. The aim of this study was to compare the incidence of PONV between administration of remimazolam-remifentanil and remimazolam-alfentanil during hysteroscopy.
This study was approved by the Clinical Research Ethics Committee of Mengcheng County No. 1 People's Hospital (2021MYL21003) and was registered at Chinese Clinical Trial Registry (https://www.chictr.org.cn) on12/03/2021, registration number was ChiCTR2100044177. Informed written consent was obtained from the eligible participants a night in the ward before hysteroscopy at Mengcheng County No. 1 People's Hospital from 15/08/2021 to 20/06/2022.
The inclusion criteria of the patients were 1) age between 18 and 65 years old; 2) American Society of Anaesthesiologists (ASA) physical status I or II; and 3) body mass index (BMI) of 19 to 30 kg/m2. 1) Patients with a history of alcoholism; 2) allergy to general anaesthetic drugs; 3) presence of renal or liver diseases; 4) difficulty with communication, 5) current lactation; and 6) recent respiratory infections were excluded.
Patients were randomly assigned into the remimazolam-remifentanil group (Group RR) and the remimazolam-alfentanil group (Group RA) 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), heart rate (HR), respiratory rate (RR) and SpO2. The SedLine™ monitor (Masimo SedLine®, Masimo Co., US)-derived patient state index (PSI) is used to follow the depth of sedation [12, 13]. All patients inhaled oxygen (2 L/min) through nasal oxygen prongs before anaesthesia induction.
All patients in both Group RR and Group RA were started with an induction dose of remimazolam besylate (Yichang Humanwell Pharmaceutical Co., Ltd., China) 0.2 mg/kg, followed by a maintenance dosage of 1.0 mg/kg/h by continuous IV infusion until the loss of consciousness (LoC) [10, 14]. When the PSI values were ≤ 58 [13], hysteroscopy was started. If the PSI values were > 58, supplemental remimazolam was added at 2.5 mg/dose, with no more than 5 doses administered within 15 minutes, according to the drug instructions of the supplemental drug programme [15].
For Group RR, after remimazolam besylate induction, infusion of remifentanil (Yichang Humanwell Pharmaceutical Co., Ltd.) was started with a TCI pump (Guangxi VERYARK Technology Co., Ltd., China), and the effective effect-site concentration (Ce) (Minto pharmacokinetic model) was 1.5 ng/ml [16]. 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) [17].
For Group RA, after remimazolam besylate induction, infusion of alfentanil (Yichang Humanwell Pharmaceutical Co., Ltd.) was started with an initial bolus dose of 20 µg/kg over 30 s and then maintained at an initial rate of 0.16 µg/kg/min [18]. The infusion rate of opioids was adjusted according to clinical needs: if the heart rate or blood pressure increased by more than 30% compared with the level after induction, 10 µg/kg alfentanil was added, and the infusion rate was increased by 0.16 µg/kg/min. This process was repeated if necessary. If the heart rate and blood pressure remained unchanged for 20 minutes or decreased, the opioid infusion rate of alfentanil was decreased by 0.8 µg/kg/min [19].
The primary outcome of this study was the incidence of postoperative nausea and vomiting (PONV) (definitions in Table 1).
| Adverse events | Definitions | Group RR (N = 102) | Group RA (n = 102) | p value |
|---|---|---|---|---|
| Postoperative nausea and vomiting(PONV) | Appeared while patients stayed in the postanaesthesia care unit (PACU) | 2 (2.0%) | 12 (11.7%) | 0.006 |
| Low SpO2 | Intraoperative SpO2 ≤ 95% | 15 (14.7%) | 22 (21.6%) | 0.203 |
| Bradycardia | Intraoperative HR < 55 bpm | 3 (2.9%) | 3 (2.9%) | 1.000 |
| Hypotension | Intraoperative SBP < 90 mmHg | 8 (7.8%) | 10 (9.8%) | 0.622 |
| Body movement | Visible hand bending or head movement | 30 (29.4%) | 27 (26.5%) | 0.640 |
| Note: Values are presented as n (%); HR-heart rate; SBP-systolic blood pressure | ||||
The incidence of other adverse events was also recorded, such as low SpO2, bradycardia, hypotension, and body movement (definitions in Table 1). These events were treated by injecting ephedrine or atropine intravenously or mask ventilation.
Patient data fluctuations included the mean arterial pressure (MAP) (MAP = (SBP + 2 × DBP)/3), HR, RR, SpO2, and patient state index values at preanaesthesia (T0), 2 minutes post induction (T1), cervical dilatation (T2), the end of the operation (T3), and awakening (T4). The operation time, duration of awakening and postanaesthesia care unit (PACU) length of stay were also recorded.
SPSS statistics 17.0.1 (SPSS Inc., Chicago, Illinois) was used for statistical analysis. For data analysis, the normality test in SPSS statistical software was used to determine whether the data conformed to a normal distribution. Continuous variables with a normal distribution are expressed as the mean ± standard deviation and were analysed by Student’s t test. The Mann‒Whitney U test was used for continuous variables with a nonnormal distribution. Haemodynamic parameters were compared with repeated ANOVA measurements. Categorical variables are expressed as frequencies (percentages) 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 statistically significant.
Because the incidence of PONV caused by different risk factors is different, we assume that the incidence rate of PONV in this study decreased from 20–10% in this study. A sample size of 102 participants in each group was calculated, and the significance level was 0.05 (α = 0.05). Given a 10% attrition rate, the strength was 80% (β = 0.20) [20].
The study population comprised 204 randomly coded patients in Group RR (n = 102) and Group RA (n = 102) (Fig. 1).
The demographic and surgical characteristics of the patients are listed in Table 2. The characteristics of the two groups were similar.
|
Group RR (n = 102) |
Group RA (n = 102) |
p value |
|
|---|---|---|---|
|
Age (years) |
43.3 ± 7.7 |
42.28 ± 8.4 |
0.692 |
|
Height (cm) |
159.2 ± 4.7 |
158.4 ± 4.6 |
0.691 |
|
Weight (kg) |
62.8 ± 7.8 |
61.6 ± 7.0 |
0.256 |
|
BMI (kg/m2) |
24.7 ± 2.8 |
24.5 ± 2.4 |
0.073 |
|
ASA (I/II) (n) |
97/5 |
86/16 |
|
|
Duration of operation (min) |
9.6 ± 4.2 |
8.9 ± 3.7 |
0.241 |
|
Duration of awakening (s) |
200.6 ± 94.6 |
283.5 ± 183.1 |
< 0.001 |
|
PACU length of stay (s) |
354.1 ± 66.8 |
371.8 ± 67.0 |
0.639 |
|
Total remimazolam (mg) |
22.3 ± 4.7 |
21.7 ± 4.5 |
0.722 |
|
Total remifentanil (µg) |
69.1 ± 21.6 |
--- |
|
|
Total alfentanil (ug) |
--- |
894.4 ± 194.2 |
|
| Note: Data indicate the mean ± SD or n; ASA - American Society of Anaesthesiologists; BMI - body mass index; PACU - post anaesthesia care unit. | |||
The operation time was similar in both groups (p = 0.241). The duration of awakening in Group RR (200.6 ± 94.6 s) was significantly shorter than that in Group RA (283.5 ± 183.1 s) (p < 0.001). However, there was no significant difference in the length of stay in the PACU between Group RR (354.1 ± 66.8 s) and Group RA (371.8 ± 67.0 s) (p = 0.639). The total remimazolam dose was not significantly different between the two groups (p = 0.722).
PONV occurred on 2 (2.0%) occasions in group RR and 12 (11.8%) occasions in group RA (p = 0.006) while no severe nausea and vomiting occurred and all self-remission occurred without drug treatment in the two groups (Table 1). There was no significant difference in the incidence of other adverse events, such as low SpO2 (p = 0.203), bradycardia (p = 1.000), hypotension (p = 0.622) and body movement (p = 0.640), between the RR and RA groups.
Compared with T0, the MAP, HR, RR and SpO2 at T1-4 were all reduced in the two groups (all p < 0.05), but all values were within the clinically normal range (Figs. 2–5). The two groups showed less fluctuation and were similar in the MAP, HR, RR and SpO2.
To achieve a more objective depth of conscious sedation than the MOAA/S score, we adopted the method of monitoring PSI values [21]. In our study, all selected patients successfully underwent sedation anaesthesia and hysteroscopy. Neither group needed further medication nor withdrew from this study due to insufficient anaesthesia depth.
During hysteroscopy, the PSI values in both groups were similar and showed sufficient and effective anaesthesia depth (Fig. 6).
Our trial compared the incidence of PONV between remimazolam-remifentanil and remimazolam-alfentanil during hysteroscopy. Based on our data, remimazolam-remifentanil causes less PONV than remimazolam-alfentanil during hysteroscopy.
During the period of this study, we did not observe any serious side effects in the two groups of patients or side effects requiring withdrawal from this study. The incidence of PONV in Group RR (2/102, 2.0%) was significantly lower than that in Group RA (12/102, 11.8%) (p < 0.05). There were no significant differences in the incidence of other adverse events, such as low SpO2, bradycardia, hypotension and body movement, between the RR and RA groups (p > 0.05). The two groups showed less fluctuation and were similar in the MAP, HR, RR and SpO2.
Remimazolam has the advantages of a rapid onset, a short elimination half-life, and a drug metabolism that is independent of liver and kidney function [22]. Remimazolam provides effective procedural sedation with superior success rates and recovery profiles compared to midazolam and can be as effective in preventing PONV as midazolam [10]. In the study by Hari et al., compared to general anaesthesia with desflurane, remimazolam can reduce the incidence of PONV following laparoscopic gynaecological surgery [23].
It has been reported that there are many similarities between alfentanil and remifentanil. In terms of pharmacokinetics, the two drugs were similar in terms of fixed distribution volume, but the central clearance rate of remifentanil was significantly higher (2.9 vs. 0.36 L/min). The terminal half-life of remifentanil was 35.1 minutes, while that of alfentanil was 94.5 minutes, resulting in a faster decrease in blood concentration after infusion discontinuation. In terms of pharmacodynamics, these drugs are similar in terms of the time required to balance the blood and effective site concentrations [24]. This similarity explains the few statistically significant differences between the two groups in this study. The differences in pharmacokinetics and pharmacodynamics between the two drugs can explain most of the results of our study. At the same time, it can be confirmed that remimazolam-alfentanil is safe and effective for anaesthesia during hysteroscopy.
Previous studies comparing remifentanil and alfentanil showed no significant difference in the incidence of PONV [25]. At present, there are few reports of remimazolam combined with remifentanil or alfentanil for anaesthesia. Remimazolam showed high clearance (1.14 L/min), which was close to that of remifentanil [22]. We speculate that remimazolam and remifentanil were cleared synchronously; however, remimazolam and alfentanil cannot be cleared synchronously after drug withdrawal. Through our experimental study, remimazolam-remifentanil caused less PONV than remimazolam-alfentanil during hysteroscopy.
There are some limitations of this study. This was a single-centre investigation, which limited the statistical analysis of the two groups of patients.
Remimazolam-remifentanil causes less PONV than remimazolam-alfentanil during hysteroscopy. Meanwhile, similar to remimazolam-remifentanil used for hysteroscopy, remimazolam-alfentanil is safe and effective for anaesthesia during hysteroscopy. This study was a single-centre study, and multicentre studies are recommended to obtain more relevant conclusions.
Ethics approval and consent to participate
This study was approved by the Clinical Research Ethics Committee of Mengcheng County No. 1 People's Hospital (2021MYL21003) and was registered at Chinese Clinical Trial Registry (https://www.chictr.org.cn) on12/03/2021, registration number was ChiCTR2100044177. Informed written consent was obtained from the eligible participants a night in the ward before hysteroscopy at Mengcheng County No. 1 People's Hospital from 15/08/2021 to 20/06/2022. The study protocol followed the CONSORT guidelines. All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication
Not applicable.
Availability of data and materials
The datasets generated and analysed during the current study are not publicly available due to institutional restrictions but are available from the corresponding author on reasonable request.
Competing interests
All authors declare that they have no conflicts of interest.
Funding
This study was self-financed.
Authors’ contributions
Shuang Li, Xiaoqiang Zhang and Jing Liu designed the study. Shuang Li and Jing Liu recruited patients. Shuang Li performed statistical processing and wrote the manuscript. Xiaoqiang Zhang revised the manuscript. All authors are aware of and responsible for the research data. All authors read and approved the manuscript in its final version.
Acknowledgements
Not applicable.
Author information
Department of Anaesthesiology, Mengcheng County No. 1 People's Hospital, Mengcheng 233500, Anhui Province, P.R. China.