Effective bolus dose of remimazolam for i-gel^® insertion in nonparalyzed patients: a dose-finding study

Figure 1 shows the study flow diagram. Among 30 patients screened for eligibility, three were excluded for not meeting the inclusion criteria. After enrolment, one patient was further excluded because of an error in drug preparation and one patient because of inappropriate screening. The remaining 25 patients completed the study protocol and were included in the final analysis. Patient characteristics of the participants according to failure or success of i-gel insertion on first attempt are presented in Table 1. While no statistically significant differences in baseline characteristics were observed between the “fail” and “success” groups, it was noted that patients in the success group tended to be slightly older and shorter, and included a higher proportion of females.

The sequence of either the success or failure of i-gel insertion at first attempt in the 25 consecutive patients is shown in Fig. 2. Of the 11 patients in which i-gel insertion failed, four patients who received 0.05 mg·kg⁻¹ and one patient who received 0.1 mg·kg⁻¹ failed to reach LOC after 90 sec of remimazolam bolus dose administration. The mean (SD) ED₅₀, estimated from seven crossover pairs using the Dixon’s up-and-down method, was 0.100 (0.027) mg·kg⁻¹ (Table 2). Figure 3 illustrates the PAVA-adjusted probability of successful i-gel insertion for each dose level. The ED₅₀ and ED₉₅ estimates calculated by isotonic regression with PAVA were 0.111 mg·kg⁻¹ (83% CI, 0.096 to 0.131) and 0.182 mg·kg⁻¹ (95% CI, 0.144 to 0.195), respectively (Table 2). We performed a simulation to evaluate the coverage of the CI for ED₉₅ and the results are shown in the ESM eAppendix. Among the 100 simulation trials, the estimated coverage of the 95% CI was 72%.

The trends of MAP, HR, and PSI over time at four time-points are illustrated in Fig. 4. Although both MAP and HR were found to decrease over time and at all time-points compared with baseline, none of the patients in this study required treatment for the correction of hypotension or bradycardia. Similarly, PSI also decreased over time (P < 0.001) and at all time- points compared with baseline (P < 0.001 for all time-points) but the mean (SD) values immediately before and after i-gel insertion remained relatively higher than the recommended range of PSI for general anesthesia at 62 (11) and 52 (14), respectively.

The scores for i-gel insertion conditions were lower in patients with successful i-gel insertion compared with those with failed insertion (P < 0.001). Among the success group, insertion conditions were suboptimal in seven patients who showed either slight swallowing movements, slight head or body movements, or both. Nevertheless, none of the patients in the success group presented with coughing, gagging, or laryngospasm (Table 3). No blood-tinged i-gel devices or oropharyngeal trauma were observed, and none of the patients required endotracheal intubation.

In this study using Dixon’s up-and-down method, we found the estimated mean (SD) ED₅₀ of a remimazolam bolus for successful i-gel insertion when combined with a commonly used Ce of remifentanil in nonparalyzed adults to be 0.100 (0.027) mg·kg⁻¹. Further, the ED₅₀ and ED₉₅ estimated by isotonic regression were 0.111 mg·kg⁻¹ (83% CI, 0.096 to 0.131) and 0.182 mg·kg⁻¹ (95% CI, 0.144 to 0.195), respectively. Coadministration of remimazolam at these specified dosages along with a remifentanil TCI at 3.0 ng·mL⁻¹ not only facilitated i-gel insertion but also ensured hemodynamic stability during anesthesia induction.

The present findings align closely with a recent study by Chae et al.,²⁰ reporting an ED₅₀ of 0.11 mg·kg⁻¹ and ED₉₅ of 0.19 mg·kg⁻¹ for achieving LOC with bolus doses of remimazolam. It is important to note that these doses are most likely insufficient for i-gel insertion when used alone. Nevertheless, when combined with a remifentanil infusion at an Ce of 3.0 ng·mL⁻¹, we observed a synergistic effect that seems to have lowered the required dose of remimazolam.^2,26 The addition of remifentanil during SGA insertion has been shown to reduce the dose requirements of propofol in previous studies. Zaballos et al.¹⁴ reported a reduction of up to 60% in propofol requirements for LMA-Supreme insertion by adding remifentanil at a Ce of 5 ng·mL⁻¹. Similarly, Park et al.²⁷ found that remifentanil halved the 50% effective concentration (EC₅₀) of propofol for LMA insertion in children. Remifentanil infusion is one of the most common methods of analgesic administration during anesthesia induction and maintenance, which makes our study design closely reflective of real-world anesthesia practice.

In our initial experience with remimazolam, we found it challenging to insert an SGA using remimazolam as a standalone anesthetic, either as an infusion or bolus. We therefore opted to incorporate remifentanil along with remimazolam. The target Ce of 3.0 ng·mL⁻¹ for remifentanil was based on a previous report suggesting an EC₅₀ of 3.04 ng·mL⁻¹ for LMA insertion.²⁸ By combining remifentanil TCI to mitigate response to nociceptive stimuli, we found that a relatively low dose of remimazolam was sufficient for facilitating i-gel insertion.

Currently, there are only two studies^2,29 that have investigated the dose of remimazolam for i-gel insertion without the use of NMBAs. Interestingly, both studies reported relatively higher doses of remimazolam compared with our study. In a study that was conducted under similar settings as our present study, the reported mean (SD) ED₅₀ of a remimazolam bolus was 0.280 (0.048) mg·kg⁻¹,² which is more than double that of our findings. This significant difference is noteworthy, especially considering that the target Ce for remifentanil was identical at 3.0 ng·mL⁻¹. The other study investigated the infusion rate of remimazolam for i-gel insertion with the coadministration of fentanyl.²⁹ The authors used 1 µg·kg⁻¹ of fentanyl and attempted to insert the i-gel 2.5 min after the remimazolam infusion and found the ED₅₀ and ED₉₅ to be 8.8 mg·kg·hr⁻¹ and 10.7 mg·kg·hr⁻¹, respectively. While it is challenging to directly compare these results to our study because of the different method of remimazolam administration, a rough conversion of total remimazolam dose from the previous study corresponds to approximately 0.37 mg·kg⁻¹ and 0.45 mg·kg⁻¹ for the ED₅₀ and ED₉₅, respectively, which are notably higher than our findings. One important distinction between our study and the previous two studies lies in the definition of successful i-gel insertion. The two previous studies defined “success” as no resistance to mouth opening (i.e., fully relaxed jaw) and no coughing or body movements. In contrast, we allowed for slightly suboptimal conditions, such as slight swallowing or body movements, as long as the patient remained fully unconscious, the i-gel was properly inserted, and lung ventilation was confirmed. We believe that, in clinical practice, it is realistic to allow for slight movements that do not hinder SGA insertion unless excessive force is required, which may result in oropharyngeal trauma for the patient. If the exact same definitions of “success” for i-gel insertion had been used, our study would have yielded higher bolus doses closer to the results of the previous studies.

Another difference between the previous studies and our study is the time interval from remimazolam administration to i-gel insertion. The previous studies allowed a time interval of 150 sec, whereas we used a shorter interval of 90 sec in our study. The decision to use the 90-sec interval was based on the time to LOC with remimazolam reported in previous studies, which is approximately 50 sec.^2,20 We also considered the time to peak effect of remifentanil, which is reported to be between 1.2 and 1.6 min according to the Minto model.¹⁹ The i-gel has a unique gel-like consistency and structural design that resembles the larynx, resulting in minimal upper airway irritation. Previous reports have shown that the i-gel requires less propofol³⁰ and remifentanil⁴ for successful insertion compared with the LMA. Based on this knowledge, we hypothesized that once the Ce of remifentanil is reached at the state of LOC, the i-gel can be easily inserted without having to wait for more than 90 sec after the bolus dose of remimazolam is fully administered. It should, however, be noted that we found a bolus dose of 0.05 mg·kg⁻¹ remimazolam to be insufficient in achieving LOC within 90 sec, even when coadministered with remifentanil in all four patients that received this dosage. In addition, although our 90-sec time interval was carefully chosen based on previous evidence, it should be kept in mind that this may not always be sufficient for a full effect of remifentanil to be reached because of the limitations of commercialized pharmacokinetic/pharmacodynamic models and the inevitable biological variability between individuals.

The main advantage of a lower dose of remimazolam and a shorter time interval of our study was the improved hemodynamic stability. Compared with our study where none of the patients required treatment for hypotension, the two previous dose-finding studies reported incidences of hypotension of 12%² and 46%,²⁹ respectively. It is always desirable to use the minimally effective dose of hypnotics to avoid unwanted side effects and for cost-effectiveness, and our study shows that a relatively lower bolus dose of remimazolam can facilitate i-gel insertion with greater hemodynamic stability when combined with remifentanil TCI of 3.0 ng·mL⁻¹. These findings may be of more significance in vulnerable patients such as the elderly or those with cardiovascular comorbidities. Further studies investigating different remimazolam bolus doses at variable time intervals and Ce of remifentanil will be able to provide useful information for the application of remimazolam in general anesthesia.

Our study has several limitations. First, the study population consisted mainly of young and healthy adults with BMIs of 30 kg·m⁻² or lower. It is important to recognize that dosage requirements for remimazolam are likely to differ for the elderly^20,31 and individuals who are obese.³² Given that these patient subpopulations constitute a significant proportion of the global population, future studies are warranted to offer practical insights into the application of remimazolam protocols in a wider range of BMI groups. Second, we used TCI for remifentanil administration with a fixed Ce of 3.0 ng·mL⁻¹ throughout the study. This may limit the generalizability of our protocol in clinical settings where TCI is not the preferred method or is unavailable, and our findings do not offer an alternative dosage option for a different Ce. Further research is needed to investigate how various modes of remifentanil administration may impact the required dosage of remimazolam for SGA insertion. Third, our study focused specifically on the i-gel insertion and therefore our results may not be applicable to other commonly used SGAs. Each SGA has its own unique properties, and drug requirements have been reported to be different between different SGAs.^4,30,33 Fourth, although all patients were checked for LOC before attempting to insert the i-gel, we did not record the exact time to LOC. Furthermore, the method we employed to assess LOC in our study (shaking the patient’s shoulders) is subject to issues of objectivity and reproducibility. Incorporating data relevant to LOC that is obtained through objective monitoring methods in future studies would provide further insights into the effects of remifentanil coadministration with remimazolam. Finally, our study was designed with the Dixon’s up-and-down method aimed at targeting ED₅₀, but we estimated extreme percentile ED₉₅. Given that data are primarily collected around ED₅₀ in the up-and-down method, estimates of ED₉₅ may be unreliable, as seen with the estimated coverage of 72%.^34,35 Further research is warranted to estimate higher target percentiles using alternative designs such as a biased coin design,²⁵ developed for targets other than median.

In conclusion, the ED₅₀ of the bolus dose of remimazolam required for i-gel insertion with the coadministration of remifentanil TCI at a Ce of 3.0 ng·mL⁻¹ in nonparalyzed healthy adults was 0.100 (0.027) mg·kg⁻¹. Considering the estimated ED₉₅, which was 0.182 mg·kg⁻¹ (95% CI, 0.144 to 0.195), we suggest using a remimazolam bolus dosage of 0.182 mg·kg⁻¹ in combination with remifentanil when inserting the i-gel without NMBAs. This regimen seems effective and safe in terms of hemodynamic stability in patients undergoing general anesthesia using the i-gel.