Determination of the effective dose of remimazolam combined with sufentanil for inhibiting body movement during surgical abortion: An up-and-down sequential allocation trial

Abstract

Background:

Remimazolam, a recently developed anesthetic characterized by its rapid and ultra-short-acting properties, exhibits pharmacological attributes that make it potentially suitable for painless surgical abortion procedures. The objective of this study was to determine the effective dose of remimazolam when administered in combination with sufentanil, with the intention of inhibiting body movement during surgical abortion. Additionally, a secondary objective was to assess the recovery profile from general anesthesia.

Methods:

The study enrolled a total of 25 healthy women aged 20 to 40, with a body mass index between 18 and 28 kg/m², in their first trimester of pregnancy (up to 12 weeks), and American Society of Anesthesiologists status I and II. Anesthesia induction was initiated by administering sufentanil at a dose of 0.1 μg/kg. The modified Dixon up-and-down method was employed to determine the induction dose of remimazolam for each patient.

Results:

The 50% and 95% effective dose of remimazolam for inhibitory effects of body movement was estimated using centered isotonic regression to be 0.145 mg/kg (95% CI: 0.115, 0.207), and 0.242 mg/kg (95% CI: 0.232, 0.620), respectively. Five out of 25 (20%) experienced hiccups, with 1 patient having persistent hiccups until the end of the surgery. The mean time to first eye-opening was 51.4 ± 20.5 seconds, and the time to obey verbal command was 54.5 ± 20.6 seconds. Upon arrival at the postanesthesia care unit, 95.7% of the patients achieved a Modified Aldrete score ≥ 9.

Conclusions:

The 50% and 95% effective dose of remimazolam for inhibiting body movement during surgical abortion when used in combination with 0.1 μg/kg of sufentanil were 0.145 mg/kg and 0.242 mg/kg, respectively.

1. Introduction

Painless surgical abortion is an outpatient procedure performed under general anesthesia, requiring appropriate anesthetics to ensure the patient’s comfort and safety.^[1] Currently, the most commonly used intravenous anesthesia method for painless abortion involves the combination of propofol and opioids.^[2,3] However, caution must be exercised when using propofol due to its potential for significant hemodynamic and respiratory effects.^[4]

Remimazolam, a novel short-acting intravenous anesthetic, offers several advantages over other benzodiazepines. It exhibits rapid onset, quick metabolism, minimal accumulation, and good safety.^[5–7] Remimazolam can be hydrolyzed and metabolized by nonspecific esterases, independent of liver and kidney function.^[7,8] It induces short sedation, mild circulatory, and respiratory depression, and can be effectively reversed with flumazenil, a benzodiazepine antagonist. These characteristics potentially reduce the risk of excessive sedation and rebound sedation. Remimazolam was approved for general anesthesia in South Korea, China, and Japan, and procedural sedation in China, the United States, and Europe in adults.^[5,9–12]

Yue et al recently presented a study on the utilization of remimazolam in surgical abortion.^[13] However, previous investigations into the optimal dosage of remimazolam, encompassing its administration for sedation during gastroscopy, hysteroscopy, and laryngeal mask insertion without the use of neuromuscular blockade, do not directly align with the specific requirements of surgical abortion. The aim of the present study was to determine the 50% and 95% effective dose (ED50 and ED95) of remimazolam in combination with sufentanil for painless surgical abortion. Additionally, a secondary objective was to assess the recovery profile from general anesthesia.

2. Methods

This clinical study was approved by the Ethics Committee of the Zhenhai District Traditional Chinese Medicine Hospital (YJ-NBZH-KYSB-2023-013), and it has been registered in the clinical trial registration center of China (ChiCTR2300075375). The conduct of this study was in strict adherence to the 2013 Helsinki Declaration.

2.1. Study population

Participants were recruited from Zhenhai District Traditional Chinese Medicine Hospital who were scheduled for surgical abortion from September 6 to October 9, 2023. All patients were provided with comprehensive information about the study and obtained written informed consent.

The inclusion criteria were American Society of Anesthesiologists (ASA) status I and II, aged between 20 and 40 years, body mass index 18 to 28 kg/m², and were in early pregnancy (<12 weeks), confirmed by ultrasound and human chorionic gonadotropin blood test. The exclusion criteria are as follows: (1) cardiopulmonary disease; (2) acute upper respiratory tract infection or recovery period; (3) liver and kidney dysfunction; (4) alcohol abuse; (5) obstructive sleep apnea–hypopnea syndrome; (6) chronic use of tranquillizers/opioids/antidepressants; (7) anesthetic drug allergy.

2.2. Study protocol

All the patients were not administered premedication and were fasting from solids for 8 hours and liquids for 4 hours before the operation. The patients were routinely monitored by a multifunctional monitor for electrocardiogram, noninvasive blood pressure and pulse oxygen saturation. Prior to anesthesia induction, each patient underwent preoxygenation with 100% oxygen for 2 minutes. Anesthesia induction was intravenously initiated by administering sufentanil (Yichang Renfu Pharma Corporation, China) at a dose of 0.1 μg/kg. Subsequently, according to the predetermined dosage, remimazolam tosylate (36 mg, Jiangsu Hengrui Pharma Corporation, China) was administered intravenously over a period of 1 minute. After a waiting period of 150 seconds, another anesthesiologist, who was blinded to the remimazolam dosage, assigned a Modified Observer’s Assessment of Alertness/Sedation score (Table 1). Following a Modified Observer’s Assessment of Alertness/Sedation score of <1, the surgeon proceeded with the placement of the vaginal speculum, indicating the initiation of the surgical procedure. It is important to note that all surgeries were performed by the same surgeon.

Table 1.

Modified observer assessment of alertness/sedation (OAA/S) score.

Score	Response
5	Responds readily to name spoken in normal tone.
4	Lethargic response to name spoken in normal tone.
3	Responds only after name is called loudly or repeatedly.
2	Responds only after mild prodding or shaking.
1	Does not respond to mild prodding or shaking.
0	Does not respond to noxious stimulus.

During the surgical procedure, supplementary doses of IV remimazolam (5 mg) were administered in accordance with the patients’ individual response to achieve optimal sedation. In cases where adequate sedation was not attained, the administration of a rescue drug (propofol) was determined based on the clinical circumstances. In the event that the pulse oxygen saturation drops to 92%, the mandible was lifted or an oxygen mask was utilized for supplemental ventilation. If the average arterial pressure falls below 50 mm Hg, a norepinephrine dose of 50 μg was administered. Throughout the perioperative period, if the heart rate drops below 50 beats per minute, atropine at a dose of 0.5 mg was administered. Upon completion of the surgical procedure, all patients were promptly administered 0.2 mg of flumazenil for the immediate reversal of remimazolam’s effects. Following this, the patient was transferred to the postanesthesia care unit (PACU). If the patient experiences nausea and vomiting, ondansetron was administered as an antiemetic treatment.

The modified Dixon up-and-down method was employed to determine the induction dose of remimazolam for each patient.^[2,14] Based on previous research and our clinical practice, we chose an initial dose of 0.3 mg/kg of remimazolam for this study, with a dose interval of 0.05 mg/kg.^[15,16] A failed result was defined by the observation of bodily movement after the initial dose of remimazolam until cervical dilation.^[17] Conversely, a successful result was determined by the absence of any bodily movement during this period. For successful cases, the subsequent dose administered to the patient is decreased by 0.05 mg/kg. Conversely, for failed cases, the dose is increased by 0.05 mg/kg. This process continues until a total of 7 crossover pairs are reached.

2.3. Measurements

The primary outcome of this study was to determine the effective dose of remimazolam in inhibiting body movement during surgical abortion procedures. Secondary outcomes included the following variables: the time to recovery from general anesthesia evaluated by first eye opening, the time to the first response to verbal instructions, the Modified Aldrete score measured every 5 minutes at the PACU. During the observation period at the PACU, any anesthesia-related adverse events, such as nausea, vomiting, re-sedation, and emergence agitation, were recorded. Re-sedation was defined as a decrease of at least 1 point in the Richmond agitation–sedation scale score, while emergence agitation was defined as a Richmond agitation–sedation scale score of 3 or higher. Additionally, hemodynamic parameters including blood pressure and heart rate were monitored at specific time points: T0: 1 minute prior to induction; T1: 1 minute after induction; T2: during cervical dilation; T3: at the completion of the surgical procedure; T4: 15 minutes post-admission to the PACU.

2.4. Sample size calculation and statistical analysis

To adhere to the statistical requirements of the modified Dixon up-and-down method, at least 7 independent pairs of failure/success are needed, along with a minimum of 7 crossover pairs in the same direction and a total enrollment of 20 or more patients. Therefore, patient enrollment continued until these criteria were met.

For statistical analysis, IBM SPSS Statistics for Windows version 27 (IBM Corp., Armonk, NY) and R statistical software version 3.3.2 (R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org/) were utilized. Continuous data were presented as the mean (standard deviation) or median (quartiles), as appropriate. The Kolmogorov–Smirnov test was employed to assess the normality of the data. For datasets not adhering to a normal distribution, the Mann–Whitney U test was utilized for analysis. Categorical variables were summarized as numbers (%). Repeated measures analysis of variance was performed to compare the changes in hemodynamic variables. Two-sided P-values < .05 were considered statistically significant.

3. Results

A total of 25 patients were enrolled in this study, and their demographic characteristics are summarized in Table 2. The dose–response relationship of remimazolam on the inhibitory effects of body movement during the surgical procedure is depicted in Figure 1. The 50% and 95% effective doses of remimazolam required to inhibit body movement was estimated using centered isotonic regression to be 0.145 mg/kg (95% CI: 0.115, 0.207), and 0.242 mg/kg (95% CI: 0.232, 0.620), respectively (Fig. 2).

Table 2.

The characteristic of patients, surgery, and anesthesia.

Variable	N = 25
Age, year	29.6 ± 4.2
Height, cm	159.1 ± 3.3
Weight, kg	58.4 ± 10.6
BMI, kg/m2	23.1 ± 4.5
ASA PS I/II	20/5
Hypertension, n/total N (%)	2/25 (8%)
Diabetes mellitus, n/total N (%)	1/25 (4%)
Smoking, n/total N (%)	0/25 (0%)
Duration of surgery, s	441.2 ± 230.4
Duration of anesthesia, s	566.0 ± 229.4

Data are expressed as mean ± SD, or number (%).

ASA PS = the American Society of Anesthesiologists physical status, BMI = body mass index.

Figure 1.

The inhibitory effects of the surgical procedure on body movement in 25 consecutive patients. Successful doses are represented by solid circles, while failed doses are denoted by open circles. The horizontal bars indicate the crossover midpoints between failure and success.

Figure 2.

The response rate of remimazolam at each dose was calculated using the Pooled-adjacent violators algorithm (PAVA) through isotonic regression. The black dots in the graph represent the probability of response for each dose of remimazolam.

Two patients who exhibited persistent body movement even after receiving 2 additional doses of remimazolam were administered propofol as a rescue medication. The emergence profiles of these 2 patients were excluded from the analysis.

Among the enrolled patients, 5 out of 25 (20%) experienced hiccups, with 1 patient having persistent hiccups until the end of the surgery (Table 3). One patient (4%) exhibited respiratory depression, characterized by a respiratory rate below 8 breaths/minutes (Table 3). A few patients (2/23, 8.7%) reported postoperative nausea and vomiting, but none of them required antiemetic medication (Table 4). No cases of bradycardia or injection pain were reported. There were no instances of intraoperative recall.

Table 3.

Secondary outcomes.

Variable	N = 25
Injection pain, n/total N (%)	0/25 (0%)
Rescue drug, n/total N (%)	2/25 (8%)
Hypotensive event, n/total N (%)	1/25 (4%)
Bradycardia, n/total N (%)	0/25 (0%)
Respiratory depression, n/total N (%)	1/25 (4%)
Hiccup, n/total N (%)	5/25 (20%)
Patients who needed vasoactive medication, n/total N (%)	0/25 (0%)

Data are expressed as mean ± SD, or number (%).

Table 4.

Emergence profiles.

Variable	N = 23
Time to first eye opening (s)	51.4 ± 20.5
Time to obey verbal command (s)	54.5 ± 20.6
Patients satisfying PACU discharge criteria (Modified Aldrete score ≥ 9)
Upon arrival, n/total N (%)	22/23 (95.7%)
After 15 min, n/total N (%)	23/23 (100%)
After 30 min, n/total N (%)	23/23 (100%)
Emergence-related side effects
Re-sedation, n/total N (%)	0/23 (0%)
Emergence agitation, n/total N (%)	0/23 (0%)
PONV during the PACU stay, n/total N (%)	2/23 (8.7%)
Patients who experienced intraoperative awareness, n/total N (%)	0/23 (0%)

Data are expressed as mean ± SD, or number (%).

PACU = postanesthesia care unit, PONV = postoperative nausea and vomiting.

Although there was a certain degree of blood pressure decrease during induction and intraoperatively (Fig. 3), only 1 patient (4%) experienced hypotension, which did not necessitate the use of vasopressor therapy (Table 3).

Figure 3.

Changes in blood pressure (A and B) and heart rate (C) during study period. Data are expressed as the mean ± SD. T0: 1 minute prior to induction; T1: 1 minute after induction; T2: during cervical dilation; T3: at the completion of the surgical procedure; T4: 15 minutes post-admission to the PACU. *P < .05; **P < .01.

The mean time to first eye opening was 51.4 ± 20.5 seconds, and the time to obey verbal command was 54.5 ± 20.6 seconds (Table 4). Upon arrival at the PACU, 95.7% of the patients achieved a Modified Aldrete score ≥ 9 (Table 4). There were no cases of re-sedation or emergence agitation observed in any of the patients.

4. Discussion

In this study, employing the modified Dixon up-and-down method, we determined the ED50 and ED95 of remimazolam in inhibiting body movement during surgical abortion when administered in combination with 0.1 μg/kg of sufentanil. The calculated ED50 and ED95 values were found to be 0.145 mg/kg (95% CI: 0.115, 0.207), and 0.242 mg/kg (95% CI: 0.232, 0.620).

Anesthesia for surgical abortion requires a rapid onset of action, adequate sedation, analgesia, prompt postoperative recovery, and minimal side effects. The uterus is innervated by both the sympathetic and parasympathetic nervous systems, and the pain caused by abortion is classified as visceral pain. Although various analgesic medications such as ketamine, nalbuphine, and dezocine are available,^[18–20] opioid analgesics remain the most widely used worldwide. Therefore, in this study, sufentanil was chosen as the analgesic agent.

Propofol is the most commonly utilized intravenous anesthetic for painless surgical abortion. Although remimazolam has emerged as a potential substitute for propofol, previous research studies have reported a prolonged recovery time with remimazolam compared to propofol when administered without flumazenil.^[21,22] The clinical efficacy of flumazenil, a benzodiazepine receptor antagonist, has been well-established. Recently, several literatures have examined the clinical significance of incorporating flumazenil in patients undergoing general anesthesia with endotracheal intubation following remimazolam total intravenous anesthesia.^[5,9,10,12] To the best of our knowledge, our study provides the first-ever data on the recovery period following routine administration of flumazenil antagonism during painless surgical abortion.

In our study, we observed that patients who received a combination of remimazolam and flumazenil experienced a remarkably short time to first eye-opening, less than 1 minute, and were able to provide accurate responses to verbal commands almost immediately. These findings suggest a significantly faster emergence compared to previous research results.^[5,9,10,12] However, it is important to note that the recovery-related data in this study were obtained from the use of a single initial dose and subsequent increasing doses of remimazolam. Additionally, the level of anesthesia depth was not monitored, and the administration of additional remimazolam was dependent on the patient’s response to surgical stimuli. As a result, it is possible that patients were in different stages of anesthesia depth when flumazenil was given at the end of the procedure. Therefore, further research is needed to understand the recovery process after short-duration outpatient surgical anesthesia.

In this study, 5 out of 25 participants (20%) experienced hiccups, with a duration of approximately 1 minute. One patient experienced persistent hiccups until awakening. Although the exact mechanism remains elusive, previous studies have consistently reported the occurrence of hiccups following remimazolam administration as an adverse event.^[11,23,24] While the hiccups induced by remimazolam are self-limiting in nature, it is crucial to consider the potential additional risk this side effect may pose for patients susceptible to reflux and aspiration. Furthermore, it is worth investigating whether the different administration methods (infusion and bolus injection) affect the incidence of hiccups.

In previous studies, the continuous infusion of remimazolam has demonstrated a significant reduction in the incidence of adverse events, such as hypotension and bradycardia, when compared to propofol.^[25] This study also evaluated the hemodynamic stability after the injection of remimazolam. Our research findings align with previous studies, indicating that injection of remimazolam does not induce hypotension. However, a recent study reported an increased incidence of hypotension with the utilization of higher doses of remimazolam.^[26] Additionally, none of the patients included in this study experienced bradycardia. The advantage of maintaining hemodynamic stability was confirmed in this study.

This study has several limitations that should be acknowledged. Firstly, the sample size was relatively small and consisted exclusively of young, female patients with American Society of Anesthesiologists status I and II. Consequently, caution should be exercised when generalizing the findings to other patient populations. Secondly, the study employed a classical Dixon up-and-down method with centered isotonic regression using the pooled-adjacent violators algorithm. While this design allowed for estimation of the ED50, a larger sample size and alternative designs such as biased-coin could have provided a more precise estimation of the ED95.^[27] Thirdly, the relationship between remimazolam-induced changes in the level of consciousness and bispectral index remains uncertain.^[27–29] Consequently, the study did not utilize bispectral index values to assess the depth of anesthesia.

5. Conclusions

The study found that the 50% and 95% effective dose of remimazolam for inhibiting body movement during surgical abortion when used in combination with 0.1 μg/kg of sufentanil were 0.145 mg/kg and 0.242 mg/kg, respectively. In the context of flumazenil antagonism, surgical abortion patients achieved a remarkably rapid emergence from anesthesia. However, further investigation is warranted to explore the safety profile and the careful consideration of benefits and risks associated with routine administration of flumazenil antagonism in outpatient surgical patients.

Acknowledgments

We gratefully acknowledge Fanfu Zeng(Center for Disease Control and Prevention of Zhenhai District, Ningbo, Zhejiang, China) for helping us with data statistics in this study.

Author contributions

Conceptualization: Yang Liu, Jinye Gu, Bo Lu.

Data curation: Xiaoyu Li, Bo Lu.

Formal analysis: Xiaoyu Li, Bo Lu.

Investigation: Yang Liu, Jinye Gu, Jianbo Liu, Lei Fu, Xiaoyan Lin, Bona Sun, Bo Lu.

Methodology: Yang Liu, Jinye Gu, Jianbo Liu.

Supervision: Lei Fu.

Validation: Jianbo Liu, Lei Fu.

Writing – original draft: Jinye Gu, Xiaoyu Li, Bo Lu.

Writing – review & editing: Jinye Gu, Xiaoyu Li, Bo Lu.