In this study, we prospectively evaluated the feasibility of TIVA using remimazolam and remifentanil without an NMBA, which has not been fully explored because of limited experience with remimazolam. General anesthesia was successfully induced and maintained, except in one patient who was obese with a BMI of 33.9. In this case, intraoperative movement occurred, and the intraoperative BIS increased to > 60 under the maximal dose of remimazolam and injection of rescue midazolam. Thus, the patient received NMBA with an anesthetic agent substituted with desflurane. Although there was only one dropout case with a high BMI in this study, further research should be conducted on the efficacy and safety of remimazolam anesthesia in obese patients.
During TIVA with remimazolam and remifentanil without NMBA, the maintenance dose of remimazolam was approximately 1.14 mg/kg/h, which did not exceed the recommended dose. However, eight patients were treated with supplementary midazolam when the BIS increased to > 60. Fortunately, intraoperative awareness did not occur in any patient. Notably, BIS monitoring has not to be validated for monitoring the depth of anesthesia with remimazolam. The narcotrend index is also less suitable for monitoring sedation depth with remimazolam, whereas the electroencephalogram β-ratio seems to be suitable for monitoring anesthetic depth by remimazolam [15]. In the present study, we observed the responsiveness scores of both the modified OAA/S and BIS during the induction period. During administration of remimazolam at a rate of 6 mg/kg/h for the induction of anesthesia, approximately 63 s was required to achieve a modified OAA/S scale of 0; however, approximately twice (135 s) as long was required as the BIS dropped to < 60, which is normally recommended for general anesthesia. This result is similar to those of previous studies [16]. Further studies are needed to determine whether BIS can adequately estimate the depth of remimazolam-induced anesthesia.
Remimazolam is known to cause less cardiovascular depression than propofol during general anesthesia [10, 17]. Our study mainly consisted of ASA class I or II patients, and 21.6% of patients experienced hypotension, similar to the previous reports [17]. Although remimazolam is less hypotensive than propofol, it should be noted that the incidence of hypotension is high in vulnerable patients [18]. In our study, bradycardia was not observed alone, which occurred in four (10.8%) patients with hypotension. When remimazolam was used for general anesthesia induction or maintenance, the incidence of bradycardia was reported at 0–6.7% [16, 17]. Bradycardia was also observed at varying frequencies during the procedural sedation (1–11%) [19–21]. However, in early pharmacodynamics study, heart rate reportedly increased by 28 ± 15% during remimazolam infusion [15]. Intraoperative heart rate seems to be affected by the type and amount of opioids administered together; thus, the incidence of bradycardia requires additional research.
In terms of the postoperative recovery profile, the median recovery time from discontinuation of remimazolam to extubation was approximately 7 min without flumazenil, which almost coincides with the CSHT of remimazolam [1]. The relatively constant CSHT of remimazolam allows for no cumulative effect, even after a prolonged continuous infusion [2]. Although the anesthesia times of most patients were < 60 min in our study, no correlation was found between the intraoperative infusion dose of remimazolam and recovery parameters. However, two patients did not awaken 15 min after the discontinuation of remimazolam infusion. Both patients woke up instantly after receiving flumazenil in the operating room and did not fall asleep. Another patient who recovered well from general anesthesia without flumazenil administration in the operating room became drowsy again in the PACU. She was awake after 0.2 mg of flumazenil was administered in the PACU. In these three patients, the amount of drug used did not exceed the usual dose used for the other patients in our study. Considering the nonsignificant correlation between remimazolam dose and recovery time, it is presumed that there may be other causes not yet revealed as the cause of delayed recovery. Flumazenil, a benzodiazepine antagonist, antagonizes the effects of remimazolam. Thus, routine flumazenil injection at the end of surgery may provide a fast and reliable recovery from remimazolam anesthesia. However, Yamamoto et al. recently reported a case in which one patient fell asleep again after remimazolam was reversed with flumazenil [22]. They noted that the effects of remimazolam reappeared when the blood concentration of flumazenil decreased.
As reported previously [1], vascular pain during remimazolam injection did not occur in our patients. In addition, except for three patients, all patients recovered from anesthesia without the use of an antagonist and there was no incidence of immediate PONV in the PACU.
The strength of this study is that it was the first to evaluate whether TIVA in combination with remimazolam and remifentanil can be safely performed in surgery without use of a neuromuscular block. Tracheal intubation and several surgeries were performed under general anesthesia without neuromuscular blockade and the proper doses of various anesthetic agents were evaluated [23–26]. It was confirmed that remimazolam could be safely used as the main anesthetic under these conditions.
This study had several limitations. First, this study was conducted at a single tertiary university hospital and all patients were women who underwent hysteroscopy. Therefore, the generalizability of our findings is unclear. Hence, it is necessary to perform a study on male, old, or obese patients. Second, as the sample size of this single-arm study was not estimated, caution is required when interpreting the results. To validate our findings, non-inferiority or superiority studies between remimazolam and other drugs such as propofol or volatile anesthetic gas are warranted, and anesthetic characteristics, recovery profile, and hemodynamic changes should be compared.