Comparison of the anesthetic effects of remimazolam tosilate and remimazolam besylate in daytime hysteroscopic surgery

Abstract

Objective

The purpose of this study is to observe whether there is a difference in the anesthetic effect of remimazolam tosilate and remimazolam besylate in daytime hysteroscopic surgery, so as to provide reference for clinical application.

Methods

Fifty patients, aged 18–65 years, ASA I-II, scheduled for hysteroscopy under total intravenous anesthesia were selected. The patients were randomly divided into two groups (n = 25): remimazolam tosilate group (group T) and remimazolam besylate group ( group R). The main observation index was the induction dose of remimazolam; secondary observation indicators were sleep time, anesthesia maintenance time, recovery time, induction maintenance dose of alfentanil, maintenance dose of remimazolam, and incidence of adverse events during anesthesia ( hypertension, hypotension, bradycardia, tachycardia).

Results

There was no significant difference in anesthesia induction dose, recovery time, sleep time, anesthesia maintenance time, and incidence of adverse events during anesthesia ( body movement, cough, hypertension, hypotension, bradycardia, tachycardia) between the two groups (P > 0.05).

Conclusion

There was no significant difference in the anesthetic effect of remimazolam tosilate and remimazolam besylate in daytime hysteroscopic surgery.

Clinical trial Registration

Chinese Clinical Trial Registry, ChiCTR2400081688.

Introduction

Daytime hysteroscopic surgery has the characteristics of fast turnover efficiency, high patient satisfaction, low medical expenses, and low nosocomial infection rate. More and more hospitals have begun to carry out daytime hysteroscopic surgery. Hysteroscopic surgery has the characteristics of small trauma, short operation time, and fast recovery of patients after operation, etc. In the expert consensus on anesthesia management for hysteroscopic diagnosis and treatment in China, short-acting sedative and analgesic drugs, such as remimazolam, are recommended for anesthesia of gynecological hysteroscopic surgery. Remimazolam is a new type of ultra-short-acting benzodiazepines. Its mechanism is to enhance the activity of GABAA receptor by specifically acting on GABAA receptor, selectively promoting extracellular chloride ions into the cell, resulting in increased resting potential of the cell membrane and hyperpolarization, decreased excitability, thereby inhibiting neuronal electrical activity and producing sedative effect [1]. According to the different acid, Remimazolam for injection has two dosage forms: remimazolam besylate and remimazolam tosilate. At present, there is no relevant study to compare the anesthetic effects of these two dosage forms. The purpose of this study is to observe whether there are differences in the anesthetic effects of remimazolam besylate and remimazolam tosilate in daytime hysteroscopic surgery, so as to provide reference for clinical application.

Information and methods

Patient inclusion criteria

This study was approved by the Ethics Committee of Weifang People’s Hospital (KYLL20231126-1) and registered at the Chinese Clinical Trials Registry (ID: ChiCTR2400081688; Date:08/03/2024). Written informed consent was obtained from all patients before enrollment. The principles of Declaration of Helsinki were followed for this study. This manuscript adheres to the applicable CONSORT guidelines.

Fifty ASA I ~ II patients scheduled for elective day hysteroscopy under total intravenous anesthesia were selected. Exclusion criteria: patients with pregnancy, lactation, history of chronic pain, history of sedatives and analgesics, and allergy to any research drug. Exclusion criteria: patients with abnormal hearing; patients with blood pressure more than 180 / 110 after admission; there are patients who are allergic to drugs such as remimazolam and addicted to sedative drugs and alcohol; patients with cognitive impairment and low compliance; patients lost to follow-up after surgery, etc. According to the random number table method, they were divided into two groups: remimazolam tosilate group (group T) and remimazolam besylate group (group R), with 25 patients in each group.

The study drugs were prepared by an anesthesiology nurse, who had been given a detailed description of the programme and was aware of the patient’s distribution. Before the operation, the anesthesia nurse diluted the remimazolam besylate or remimazolam tosilate to 1 mg/ml and placed it in a sterile sealed bag. Anesthesiologists who did not know the specific types of drugs were given anesthesia by anesthesiologists when anesthesia was performed. Surgeons and patients were also unaware of the drugs administered. Data collection was performed by another independent anesthesiologist who was unaware of the group assignment.

Methods of anaesthesia

The patients were routinely fasted and fasting, and no preoperative medication was given. After entering the room, the forearm vein channel of the upper limb was opened and the rapid infusion was performed. The ECG, SPO2, NIBP and BIS were monitored and the basic values were recorded. Before anesthesia induction, flurbiprofen 50 mg and dexamethasone 5 mg were intravenously injected. The two groups of patients were treated with the same anesthesia method, but the patients in each group were treated with different dosage forms of remimazolam. Anesthesia induction: Remimazolam 6mg / kg / h pump to sleep, and then given mivacurium chloride 0.2mg / kg and alfentanil 20ug / kg slow injection, 3min after the insertion of laryngeal mask. Anesthesia was maintained with intravenous infusion of remifentanil 1 mg / kg / h and alfentanil 40 ug / kg / h. The BIS value was maintained between 50 and 60, and mivacurium 0.1 mg / kg was injected intermittently when necessary. Ventilator-assisted breathing was performed during the operation. The parameters were set as follows: tidal volume 6-8ml / kg, respiratory rate 10–12 times / min, respiratory ratio 1: 2, and end-tidal CO2 maintained at 35–45 mmHg. After the operation, the drug was discontinued, and the tracheal tube was removed after fully awake and sent to PACU for observation for 2 h. When the Aldrete score was greater than 9 points, they were sent back to the ward.

Observe the metrics

The main observation index was the induction dose of remifentanil anesthesia; secondary observation indicators were sleep time, anesthesia maintenance time, recovery time, induction maintenance dose of alfentanil, maintenance dose of remimazolam, and incidence of adverse events during anesthesia (hypertension, hypotension, bradycardia, tachycardia).

Statistical analysis

Statistical methods SPSS25.0 software was used for statistical analysis, and the data were tested for normality and homogeneity of variance. The measurement data of normal distribution were expressed as mean ± standard deviation, independent sample T test was used for comparison between groups, and the median (interquartile distance) [M (Q1 ~ Q3)] was used for continuous variables of non-normal distribution, and rank sum test was used for comparison between groups. Counting data were expressed as a percentage, and the chi-square test was used for comparison between groups. P < 0.05 was considered statistically significant.

Results

A total of 50 patients were included in this study, with 25 patients in each group. One patient in the remimazolam tosilate group chose to withdraw during the study, so 24 patients were included in the remimazolam tosilate group Fig. 1.

Fig. 1

Study flowchart

Comparison of general data between the two groups, there was no significant difference in age, weight, body mass index (BMI), ASA classification, anesthesia time, induction dose and maintenance dose of alfentanil between the two groups (P > 0.05), as shown in Table 1.

Table 1 Comparison of general information between the two groups

There was no significant difference in the induction and maintenance dose of remimazolam, sleep time and wake time between the two groups (P > 0.05), as shown in Table 2.

Table 2 Comparison of time to sleep, time to awaken, and dose of remimazolam between the two groups

There were no significant differences in intraoperative adverse reactions between the two groups (P > 0.05) Table 3.

Table 3 Comparison of adverse reactions between the two groups

Discussion

In January 2020, ramimazolam was first approved as a general anesthesia drug in Japan [2]; in March 2021, remimazolam was approved for induction and maintenance of general anesthesia in China. Remimazolam is a benzodiazepine drug, and its chemical structure adds a carboxylate side chain to the original benzodiazepine structure [3]. Therefore, the liver drug enzyme metabolism of midazolam was changed to the tissue esterase metabolism [4]. Remimazolam has the dual characteristics of midazolam and remifentanil [5]. It is an analogue of midazolam, and combined with the pharmacokinetic characteristics of remifentanil, it is rapidly converted into a carboxylic acid compound-zolam propionic acid by non-specific esterase. The affinity of zolam propionic acid to GABA receptor is only 1 / 400 of that of remifentanil, and it has almost no pharmacological activity. Therefore, the recovery time of patients is shorter than that of midazolam and long-term infusion is not easy to accumulate. Its drug clearance rate is three times that of midazolam [4]. Midazolam is mainly metabolized by P450 3A4 enzyme. Different genes between patients can lead to pharmacokinetic differences, and the metabolites of midazolam are active and easy to accumulate in the body. In addition, since remimazolam is not dependent on organ elimination, it can be safely used in patients with liver or kidney damage. However, it does not have the analgesic effect of opioids and often needs to be used in combination with other opioid analgesics. Therefore, in this study, remimazolam combined with analgesic alfentanil was used to induce and maintain general anesthesia. Alfentanil is a new type of short-acting opioids. The onset time is 30 s, and the effect can reach a peak at 1.4 min. The duration of action is about 1 / 3 (10 ~ 15 min) of fentanyl, and the analgesic potency is 15 times that of morphine, which is in line with the characteristics of daytime surgery anesthesia needs. A number of studies have shown that [6, 7], compared with remifentanil, alfentanil has a significantly lower respiratory inhibition effect and can better maintain hemodynamic stability.

Remimazolam was first developed by Paion AG in Germany. Due to the instability of the free base of remimazolam, Paion AG developed the benzene sulfonate compound of remimazolam, while Hengrui developed the toluene sulfonate compound of remimazolam. Hengrui manufacturers claim that toluene sulfonate has lower toxicity and higher clinical safety, but there is no study to compare the efficacy and safety of the two formulations. Therefore, this study used different dosage forms of remimazolam combined with alfentanil for hysteroscopic surgery to observe the efficacy and safety of different dosage forms of remimazolam. Both remifentanil and alfentanil have the clinical advantages of rapid onset, short action time, small impact on respiration and circulation, and high quality of postoperative recovery. They can be used as the preferred combination of anesthetic drugs for daytime surgery. Zhao et al. [8] used remifentanil and propofol combined with alfentanil for sedation anesthesia in patients undergoing third molar extraction. Compared with propofol group, the onset time and recovery time of remifentanil combined with alfentanil group were faster, and the incidence of adverse reactions such as hypotension and injection pain was lower.

In this study, we compared the perioperative dose and the incidence of related adverse reactions of two different dosage forms of remimazolam. The study showed that there was no significant difference in the efficacy and safety of the two dosage forms of remimazolam, which could be effectively used for general anesthesia. This may be due to the fact that the difference between besylate acid and tosilate acid is relatively small and has minimal effect on the physicochemical properties of the drug and hence the effect on the efficacy of the drug is also minimal. Also no previously reported allergic reactions were observed in the present study. Previous studies have shown that both remimazolam tosilate and remimazolam besylate can be effectively used for induction and maintenance of general anesthesia [9,10,11,12]. One of the single-center, prospective studies compared the efficacy and safety of remimazolam and propofol for hysteroscopy [9]. It was found that the perioperative adverse reactions of remimazolam tosilate were less than those of propofol, which could be safely and effectively used for hysteroscopy. In addition, Zhang et al. [10] also studied the safety and efficacy of remimazolam besylate and propofol in hysteroscopy, and reached similar conclusions. These two studies are similar to the results of this study, which further confirms that there is no significant difference in efficacy and safety between remimazolam tosilate and remimazolam besylate. In the phase I study of remimazolam besylate [4], the population pharmacokinetic and pharmacodynamic models of remimazolam besylate and midazolam were in good agreement with the observed data. The simulation based on these models showed that the sedative effect of remimazolam was very rapid, and the maximum effect was achieved within 3 min of the start of treatment. Remimazolam besylate has the characteristics of rapid onset, rapid recovery and good tolerance. This is basically consistent with the results of phase I clinical study of remimazolam tosylate [13]. There was no significant difference in pharmacodynamics and pharmacokinetics between the two formulations of remimazolam. For the study of other adverse reactions of remimazolam, all case reports of anaphylactic reactions to remimazolam have occurred with remimazolam besylate, and no anaphylactic reactions to remimazolam tosilate have been reported, and future pharmacologic studies of anaphylactic reactions to remimazolam could be of greater clinical benefit.

Disadvantages

This study is a small-sample, single-center study, and no obvious adverse reactions occurred during the study, so a large-sample, multi-center study is needed.

Conclusions

There was no significant difference in the anesthetic effect of remimazolam tosilate and remimazolam besylate in daytime hysteroscopic surgery.