Comparison of remimazolam tosylate and propofol in patients undergoing general anesthesia using a laryngeal mask airway without muscle relaxants

1. Introduction

The Laryngeal mask airway (LMA) is a widely used supraglottic airway device in general anesthesia, eliminating the need for vocal cord visualization and reducing airway stimulation, making muscle relaxants unnecessary for LMA anesthesia [1]. This approach minimizes the risk of anaphylaxis and residual effects associated with muscle relaxants, particularly in short-duration surgeries [2].

Propofol is a commonly used intravenous anesthetic with rapid onset and offset, frequently employed for anesthesia induction and tracheal intubation. Propofol can also reduce muscle power during deep anesthesia [3], leading to its use in combination with opioids for LMA insertion during anesthesia induction without muscle relaxants [1]. However, propofol is known to cause issues such as hypotension and injection pain, which can be concerning for anesthesiologists.

Remimazolam, a newer benzodiazepine, offers rapid onset and metabolism. Prior studies have suggested that remimazolam anesthesia is associated with fewer adverse events, including hypotension, bradycardia and injection pain, compared to propofol [4, 5]. Recently, several studies showed that remimazolam could be used with opioids for LMA anesthesia without muscle relaxants [6, 7]. Nevertheless, there is limited evidence comparing remimazolam and propofol for LMA anesthesia without muscle relaxants. Thus, we performed this study to provide a comparative analysis of remimazolam and propofol for LMA anesthesia in short-duration surgeries.

2. Methods

2.3 Interventions

Patients underwent a preoperative fasting period of at least 8 hours for solids and 2 hours for liquids. Upon arrival in the operating room, they were monitored with an electrocardiogram and underwent noninvasive blood pressure, pulse oximetry (SpO₂) and bispectral index (BIS, Covidien LLC, USA). A peripheral intravenous line was established, and a compound sodium chloride solution was administered at a rate of 4 to 6 mL/min. Preoxygenation was performed using a face mask with an oxygen flow of 5 L/min. Intravenous sufentanil 0.2 µg/kg (01A06051, Yichang Humanwell Pharmaceutical Co, Ltd, Yichang, Hubei, China) was administered over 10 seconds, with patients instructed to breathe before losing consciousness. Prior to LMA insertion (GMA, Tianjin MEDAN Medical Corp., China, Fig. 1), lubrication with lidocaine cream was applied, and LMA size selection was based on patient weight (size 3 for 30 to 50 kg, size 4 for 50 to 90 kg). Three minutes after sufentanil administration, sedatives were manually administered within 30 seconds according to randomization. Group P received propofol 2 mg/kg (2005130, AstraZeneca, Caponago, Italy), while group R received remimazolam tosylate 0.3 mg/kg (200419AK, HengRui Medicine, Lianyungang, Jiangsu, China), diluted to 1 mg/mL with normal saline. All drugs were administered via a T-connector, with the infusion tube extending 35 cm from the T-connector to the cannulation site on the patient’s hand. If patients exhibited reduced breathing during anesthesia induction, manual ventilation was provided. LMA insertion was initiated when BIS ≤60. The LMA was inserted by one of two experienced anesthesiologists without assistance, and the insertion condition was graded by the same anesthesiologist according to the criteria listed in Table 1 [7]. If the BIS was still greater than 60 after 1.5 minutes of the sedative bolus, or if patients resisted insertion of the LMA, propofol 0.5 mg/kg or remimazolam 0.05 mg/kg was added at 1-minute intervals. Considering the relationship between remimazolam sedation and BIS was still unclear [8], the LMA could be inserted after two additional boluses of remimazolam if the patient was unresponsive to verbal contact or jaw thrust. After the successful insertion of the LMA, the patients were mechanically ventilated. Ventilation parameters were set as follows: tidal volume 6 to 8 mL/kg, respiratory rate 10 to 15 breaths/min, fresh gas flow 2 L/min, inspired oxygen fraction 40% to 60%, and positive end-expiratory pressure 5 cmH₂O, maintaining end-tidal carbon dioxide pressure at 35 to 45 mmHg. Anesthesia was maintained with propofol at 4 to 10 mg/kg/h in group P and with remimazolam at 0.5 to 2 mg/kg/h in group R, respectively. The sedative infusion rate was adjusted to maintain BIS between 40 and 60. Mean arterial pressure (MAP) changes were kept within 20% of baseline. Additional intraoperative sufentanil 0.1 to 0.2 µg/kg could be administered if analgesia was inadequate, at the discretion of the anesthesiologist. Dopamine 2 mg was administered if SAP fell below 80 mmHg, and atropine 0.5 mg was given for heart rates (HR) under 45 bpm. Ondansetron 8 mg was intravenously administered before the surgery concluded. The sedative infusion ceased upon completion of the final suture. After regaining consciousness and respiration, the LMA was removed, and patients were transferred to the post-anesthesia care unit (PACU).

Fig. 1.GMA laryngeal mask airway.

Table 1.The criteria of LMA insertion condition.

Criteria items	Score
	1	2	3
Mouth opening	Full	Partial	Nil
Swallowing	Nil	Slight	Gross
Coughing	Nil	Slight	Gross
Head or body motion	Nil	Slight	Gross
Laryngospasm	Nil	Mild	Severe
Ease of LMA insertion	Easy	Difficult	Impossible
LMA: Laryngeal mask airway.

3. Results

This study recruited 120 participants, 4 patients did not meet the inclusion criteria and 21 patients dropped out after randomization, leaving 95 participants to complete the study, with 48 assigned to group P and 47 to group R (Fig. 2). Patient characteristics showed no significant differences between the two groups (Table 2). As detailed in Table 3, the overall incidence of hypotension in group R was insignificantly lower than in group P (36.2% vs. 47.9%, p = 0.246). Furthermore, the occurrences of hypertension, bradycardia, and tachycardia did not significantly differ between the two groups (p > 0.05). In group P, three patients (6.3%) reported injection pain, whereas none did in group R (p = 0.242). Shivering was reported by only one patient in each group during anesthesia recovery. Notably, none of the patients experienced hypoxemia or intraoperative awareness. However, it is worth highlighting that hiccups occurred in 7 patients (14.9%) in group R during anesthesia, whereas only 1 patient (2.1%) in group P experienced hiccups during anesthesia (p = 0.031). Furthermore, 5 patients (71.4%) experienced hiccups during or after remimazolam injection (Table 4).

Fig. 2.Flow diagram of the study.

Table 5 displays the first attempt LMA insertion success rate and LMA insertion score, revealing no significant differences between the two groups (p > 0.1). However, due to the 0.3 mg/kg bolus of remimazolam leading to a higher incidence of BIS >60, a significantly greater proportion of patients required rescue sedation in group R compared to group P (38.3% vs. 12.5%, p = 0.004). Furthermore, despite the increased need for rescue sedation, group R maintained significantly higher BIS values at T2, T3 and T4 during anesthesia induction compared to group P (p < 0.001, Fig. 3). Similarly, the HR in group R was significantly higher than that in group P at T2, T3, T4 and T5 (p = 0.023, Fig. 4A). Conversely, the changes in SAP, DAP and MAP during anesthesia induction did not exhibit significant differences between the two groups (p > 0.1, Fig. 4B–D). Furthermore, despite no significant disparity in operating time (p = 0.961, Table 5), LMA removal time was significantly prolonged in group R compared to group P (12 min vs. 8 min, p = 0.001, Table 5).

Fig. 3.BIS changes during anesthesia induction and LMA insertion. Data are mean with standard deviation. *p < 0.05 compared to group P at the same time points. BIS: bispectral index.

Fig. 4.Blood pressure and HR changes during anesthesia induction and LMA insertion and 2 min after LMA removal. Data are mean with standard deviation. *p < 0.05 compared to group P at the same time points. T0: immediately before sufentanil administration, T1: 3 min after sufentanil administration, T2: immediately before the first attempt of LMA insertion, T3: immediately after successful LMA insertion, T4: 2 min after LMA insertion, T5: 4 min after LMA insertion, T6: 2 min after LMA removal. HR: heart rates; SAP: systolic arterial pressure; DAP: diastolic arterial pressure; MAP: mean arterial pressure.

4. Discussion

Previous studies have shown that the main advantage of remimazolam over propofol is that it has less of an effect on blood pressure [4, 5, 9]. However, in this study, we found a slightly but insignificantly lower incidence of hypotension with remimazolam compared with propofol in LMA anesthesia without muscle relaxants. We hypothesize this lack of statistical significance to the relatively small sample size and the use of a relatively higher dose of remimazolam in the context of LMA anesthesia during surgeries without muscle relaxants. Furthermore, our findings also indicated that remimazolam administration was associated with a higher occurrence of hiccups following anesthesia induction, and the time required for LMA removal was longer after remimazolam anesthesia compared to anesthesia using propofol.

The dose of remimazolam administered to patients can impact their blood pressure, and in our study, the initial induction dose of remimazolam was 0.3 mg/kg. In a study by Dai et al. [10], where sufentanil and cisatracurium were used for anesthesia induction and tracheal intubation, the incidence of hypotension induced by remimazolam bolus doses of 0.2, 0.3 and 0.4 mg/kg were found to be 13%, 24% and 34%, respectively. In our study, we observed an incidence of hypotension during anesthesia induction with remimazolam 0.3 mg/kg to be 25.5%, which aligns with previous findings. However, Dai et al. [10] also reported that the MAP during anesthesia induction with 0.3 mg/kg remimazolam was significantly higher than with propofol. Similarly, in a study by Tang et al. [7], using remifentanil and sufentanil in combination with remimazolam at a total induction dose of 0.3 mg/kg, they found that it provided similar LMA insertion conditions without muscle relaxants compared to propofol. Furthermore, the SAP immediately following LMA insertion was slightly but significantly lower with remimazolam than with propofol (n = 36). In contrast, despite the larger sample size in our study (n = 48 and n = 47), we did not observe significant differences in blood pressure between the two groups. We believe that the higher incidence of rescue sedation required to achieve the target BIS value during anesthesia induction and LMA insertion in group R compared to group P (38.3% vs. 12.5%) may have contributed to the lack of significance in blood pressure values.

In this study, despite the higher incidence of rescue sedation, the BIS value during the induction of anesthesia was still significantly higher in group R compared to group P. The relationship between the depth of remimazolam anesthesia and BIS remains unclear [8], prompting the decision to proceed with LMA insertion when patients were unresponsive to verbal contact or jaw thrust even after rescue sedation. However, it is important to note that remimazolam anesthesia offered a more stable HR compared to propofol anesthesia, which may be attributed to less vagal stimulation and a shallower depth of anesthesia achieved with remimazolam as opposed to propofol.

Furthermore, only three patients experienced injection pain during propofol injection, resulting in an incidence of 6.3%, which was notably lower than previously reported rates (up to 80.5%) [5]. We attribute this lower incidence to the analgesic effect of sufentanil administered prior to propofol injection. Although the operative time was similar between the two groups, LMA removal took longer under remimazolam anesthesia compared to propofol anesthesia, consistent with findings from prior studies [4, 5]. Remimazolam sedation can be rapidly reversed by flumazenil within 2 minutes [4], allowing for rapid recovery from remimazolam anesthesia. However, Oh et al. [11] reported that when a large dose of remimazolam was administered intraoperatively, there might be a rebound increase in remimazolam concentration after flumazenil reversal, potentially leading to re-sedation in patients.

Notably, the incidence of hiccups in group R was 14.9%, which was significantly higher than in group P. Interestingly, two patients in group R experienced hiccups for more than 10 minutes, although the hiccups were typically self-limiting. Hiccups can be triggered by stimulation of the vagus nerve or phrenic nerve, with the vagus nerve innervating the pharynx and upper esophagus. Previous studies have indicated that LMA insertion can stimulate the hypopharynx and induce hiccups, with reported incidences ranging from 3% to 11% [12, 13]. However, in our study, only one patient experienced hiccups after LMA insertion, while five patients experienced hiccups during or after the bolus administration of remimazolam. Therefore, it is plausible that a rapid bolus of remimazolam as part of the induction dose may contribute to hiccups. It is worth noting that remimazolam-induced hiccups have been rarely reported in previous studies. Chen et al. [14] mentioned that hiccups occurred “frequently” in patients receiving intravenous remimazolam at a dose of 0.4 mg/kg over 1 minute, followed by an infusion at 1.5 mg/kg/h. This bolus dose of 0.4 mg/kg was higher than the generally recommended dose of 0.1 to 0.2 mg/kg over 1 minute [4, 5]. However, their study did not provide detailed information about the hiccups. Another study by Dai et al. [10] reported that remimazolam administered at a dose of 0.4 mg/kg over 1 minute successfully and safely induced anesthesia, but hiccups were not mentioned. We contacted the authors through correspondence, and they confirmed that few patients experienced hiccups [15].

The exact mechanism behind remimazolam-induced hiccups remains unclear, and the duration of hiccups appears unpredictable. We believe that the primary risk factor contributing to the high incidence of remimazolam-induced hiccups in our study was the rapid administration of 0.3 mg/kg of remimazolam within 30 seconds, resulting in a transient spike in plasma remimazolam concentration. A similar observation was made by Tang et al. [7], who reported that 11.1% (4 out of 36) of patients experienced hiccups during the induction of anesthesia and LMA insertion without muscle relaxants when administered 0.3 mg/kg of remimazolam. However, their study involved administering the total remimazolam dose in two boluses, and they did not specify the timing of the hiccups. Interestingly, Oh et al. [16] conducted a research to find the effective dose of remimazolam co‑administered with remifentanil to facilitate LMA insertion without muscle relaxant, the authors administered remimazolam (0.15 mg/kg to 0.45 mg/kg) over few seconds and 2 out of 25 patients had hiccups. In contrast, Choi et al. [17] infused remimazolam at a dose of 12 mg/kg/h (0.2 mg/kg/min) for anesthesia induction and LMA insertion with remifentanil, no hiccups were reported in their study.

Notably, midazolam, a commonly used benzodiazepine for anesthesia, has also been reported to induce hiccups. For instance, Marhofer et al. [18] reported that the incidence of rectal midazolam-induced hiccups in children ranged from 22% to 26%, and these hiccups were effectively terminated by intranasal ethyl chloride spray. Liu et al. [19] documented that during gastrointestinal endoscopy and colonoscopy procedures, hiccups occurred more frequently in patients who received sedation compared to those without sedation. Moreover, hiccups were more common in patients who received a higher dose (2 mg) of midazolam than in those who received 1 mg. The authors suggested that midazolam might affect diaphragm contractility, leading to hiccups. Additionally, there have been reports of midazolam-induced hiccups being successfully treated with flumazenil [20]. Consequently, it is conceivable that the gamma-aminobutyric acid (GABA) receptor may play a role in benzodiazepine-induced hiccups. However, it is worth noting that there have been cases of hiccups treated with midazolam as well [21, 22]. Given the findings of this study, clinicians should exercise caution regarding this adverse effect of remimazolam and avoid rapid bolus administration, especially in cases of remimazolam anesthesia without muscle relaxants.

5. Limitations

This study has several limitations that should be acknowledged. First, the sample size was relatively small, which might explain the lack of significant differences in the incidence of hypotension between remimazolam and propofol-based LMA anesthesia without muscle relaxants. Second, we did not follow certain recommended remimazolam infusion rates, such as 12 mg/kg/h for anesthesia induction. Therefore, the study does not provide insights into potential differences between bolus injection and continuous infusion of remimazolam for anesthesia induction and LMA insertion without muscle relaxants. Third, we used a sufentanil induction dose of 0.2 µg/kg, and it could be possible that different hemodynamic changes could occur with higher sufentanil doses, potentially leading to different outcomes in propofol and remimazolam anesthesia for LMA insertion without muscle relaxants. Further research with larger sample sizes and different dosing regimens is needed to better understand these aspects.

6. Conclusions

Our study did not reveal a statistically significant difference in the incidence of hypotension during LMA anesthesia without muscle relaxants when comparing the use of remimazolam to propofol, possibly due to the limited sample size. Considering the risk of remimazolam-induced hiccups associated with rapid bolus administration, a larger-scale study with similar conditions might not be feasible. Furthermore, we observed higher BIS values during the induction of anesthesia with remimazolam compared to propofol, but remimazolam provided more stable heart rates, with slightly longer recovery times compared to propofol. Additional research with larger sample sizes and optimized dosing protocols is needed to gain a more comprehensive understanding of the comparative effects of these two agents in LMA anesthesia without muscle relaxants.

Availability of data and materials

The data presented in this study are available on reasonable request from the corresponding author.

Author contributions

QH, YZ and GYK—designed the research study, analyzed the data. QH, YZ, WYC, KL, TH, BBP and YZL—performed the research. QH and YZ—wrote the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The research protocol was approved by the Ethics Committee of Hunan Provincial People’s Hospital (Approval No. 2020-31) and was registered with the Chinese Clinical Trial Registry (ChiCTR 2000037276). All patients have signed informed consent for the study.

Acknowledgment

Not applicable.

Funding

Health Commission of Hunan Province (202104111828); Beijing Medical Award Foundation (H2020-28, H2021-24).

Conflict of interest

The authors declare no conflict of interest.