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Abstract

Remimazolam is an ultra-short-acting benzodiazepine anesthetic agent. Because of pharmacodynamic interactions in the sedation effect between benzodiazepines and propofol, the combination of remimazolam and propofol may allow for a dose reduction of each agent while providing effective sedation for general anesthesia. We experienced three cases in which general anesthesia was induced with remimazolam and maintained with relatively small doses of remimazolam and propofol target-controlled infusion. In all cases, electroencephalogram changes associated with sedation induced by remimazolam were carefully observed during anesthesia induction before administration of propofol. The time required for recovery from anesthesia was 8–13 min. This is the first report in which remimazolam and propofol were concomitantly used for general anesthesia based on the concept of pharmacodynamic interaction. This anesthetic combination may be beneficial in reducing doses of each anesthetic and avoiding delayed recovery from anesthesia, although further study is needed to confirm this.

Keywords

remimazolam propofol concomitant use patient state index

Introduction

In 2020, remimazolam, an ultra-short-acting benzodiazepine anesthetic agent, was launched in Japan. Immediately after that, the use of remimazolam was restricted due to a series of shipment adjustments associated with quality control. In addition, remimazolam and propofol were also in short supply due to the COVID-19 pandemic. Thus, we need to reduce the consumption of these anesthetics.

Modern general anesthesia is predominantly a balanced anesthesia approach using sedatives, analgesics, and muscle relaxants to achieve each of the three components of sedation, analgesia, and immobilization, respectively. When considering the sedative effects of anesthesia maintenance, inhaled anesthetics, propofol, or benzodiazepines such as midazolam are often used alone. However, combinations of multiple sedatives may be used to achieve sedation. For example, the combination of propofol and sevoflurane has been shown to exhibit additive interactions in loss of consciousness (LOC) and bispectral index.^1,2 This combination of anesthetic techniques is used clinically as a feasible alternative to propofol-based total intravenous anesthesia.^3,4 Such an approach utilizing drug interaction reduces both the amount of each drug used and their side effects, compared to single drug use.

Also, due to pharmacodynamic interactions in the sedation effect between benzodiazepines and propofol,^5
–8 the combination of remimazolam and propofol may allow for a dose reduction of each agent while providing adequate sedation for general anesthesia maintenance.

In this case series, we report three cases in which anesthesia was induced with remimazolam and maintained with remimazolam and propofol while referring to patient state index (PSI) and raw electroencephalogram (EEG) obtained with a processed EEG monitor (SedLine® system, Masimo Corporation; Irvine, CA, USA). Written informed consent for publication was obtained from all patients.

Case presentations

Case 1

The patient was a 40-year-old man (height 176 cm, weight 81 kg) undergoing skin graft surgery following ring finger amputation. He had no history of medication. After performing a brachial plexus block, general anesthesia was induced with remimazolam 12 mg/kg/h (Figure 1). The patient lost responsiveness to repeated verbal stimuli (i.e., Modified Observer’s Assessment of Alertness and Sedation [MOAA/S]⁹ of <3), and his PSI value decreased from 95 to 39. After confirming MOAA/S <3 and spindle wave EEG (Figure 2), the remimazolam dose was lowered to 1 mg/kg/h, and remifentanil 0.14 µg/kg/min, fentanyl 100 µg, and rocuronium 50 mg were administered. After tracheal intubation, remifentanil was reduced to 0.04 µg/kg/min. The remimazolam dose was then gradually reduced to 0.3 mg/kg/h while confirming that an arousal tendency was not observed on EEG. After that, the remimazolam dose was fixed, and propofol target-controlled infusion (TCI) (1 µg/mL) was started. The remifentanil dose and propofol target concentration were titrated according to the surgical stimulus and PSI values, respectively. The effect-site concentrations of remimazolam (RzCe) and propofol (PCe) during maintenance were stabilized at approximately 0.38 µg/mL (Masui model¹⁰) and 1 µg/mL (Diprifusor system¹¹), respectively. PSI remained at around 30 during surgery. Surgical procedures were completed in 56 min. The patient spontaneously recovered consciousness and was extubated 8 min after the end of remimazolam and propofol administration. No postoperative nausea and vomiting (PONV), postoperative delirium (POD), or intraoperative awareness and recall (IAR) was reported. The patient was discharged from hospital without any complications 2 days postoperatively.

Figure 1

Time courses of remimazolam effect-site concentration (RzCe, black curve), propofol effect-site concentration (PCe, grey curve), remifentanil effect-site concentration (RfCe, dotted curve), systolic blood pressure (▼), diastolic blood pressure (▲), heart rate (•), and patient state index (—) in Case 1. Fentanyl 100 µg was administered at time 2 min. To calculate RzCe, we converted the fentanyl effect-site concentrations simulated using the Shafer model¹² toremifentanil equivalents¹³ using a remifentanil:fentanyl equivalency ratio of 1:1.

Figure 2.

Raw electroencephalograms before anesthesia induction, after loss of responsiveness, during anesthesia maintenance, and after recovery of responsiveness (Case 2).

Case 2

The patient was a 67-year-old man (height 167 cm, weight 72 kg) undergoing robot-assisted total prostatectomy for prostate cancer. He had a history of controlled hypertension. General anesthesia was induced with remimazolam 12 mg/kg/h (Figure 3) and his PSI value decreased from 95 to 42. After confirming MOAA/S <3 and spindle wave EEG, the remimazolam dose was lowered to 1 mg/kg/h, and remifentanil 0.12 µg/kg/min, fentanyl 100 µg, and rocuronium 50 mg were administered. After tracheal intubation, remifentanil was reduced to 0.05 µg/kg/min. Then, the remimazolam dose was gradually reduced to 0.3 mg/kg/h while confirming that an arousal tendency was not observed on EEG. After that, the remimazolam dose was fixed, and propofol TCI (1 µg/mL) was started. The remifentanil dose and propofol target concentration were titrated according to the surgical stimulus and PSI values, respectively. The RzCe and PCe during maintenance stabilized at approximately 0.34 and 1 µg/mL, respectively. PSI remained at 25–30 during surgery. Surgical procedures were completed in 277 min. The patient spontaneously recovered consciousness and was extubated 13 min after the end of remimazolam and propofol administration. No PONV, POD, or IAR was reported. The patient was discharged from hospital without any complications 10 days postoperatively.

Figure 3.

Time courses of remimazolam effect-site concentration (RzCe, black curve), propofol effect-site concentration (PCe, gray curve), remifentanil effect-site concentration (RfCe, dotted curve), systolic blood pressure (▼), diastolic blood pressure (▲), heart rate (•), and patient state index (━) in Case 2. Remimazolam dose was reduced from 1 to 0.5 mg/kg/h at 13 min, 0.5 to 0.4 mg/kg/h at 17 min, and 0.4 to 0.3 mg/kg/h at 21 min; not all of which are shown in the dosing history on the upper part of this graph. Fentanyl 100 µg was administered at times 2 min and 215 min. To calculate RzCe, we converted the fentanyl effect-site concentrations simulated using the Shafer model¹² to remifentanil equivalents¹³ using a remifentanil:fentanyl equivalency ratio of 1:1.

Case 3

The patient was an 82-year-old woman (height 131 cm, weight 40 kg) undergoing molar extraction. She had a history of angina, which was treated by a coronary stent graft. General anesthesia was induced with remimazolam 12 mg/kg/h (Figure 4), and her PSI value decreased from 91 to 50. After confirming MOAA/S <3 and spindle wave EEG, the remimazolam dose was lowered to 1 mg/kg/h, and remifentanil 0.21 µg/kg/min, fentanyl 100 µg, and rocuronium 25 mg were administered. After tracheal intubation, remifentanil was reduced to 0.04 µg/kg/min. Then, the remimazolam dose was gradually reduced to 0.3 mg/kg/h while confirming that an arousal tendency was not observed on EEG. After that, the remimazolam dose was fixed, and propofol TCI (1 µg/mL) was started. The remifentanil dose was titrated according to the surgical stimulus. The RzCe and PCe during maintenance stabilized at approximately 0.29 and 1 µg/mL, respectively. PSI remained at 25–50 most of the time during surgery. Surgical procedures were completed in 70 min. The patient spontaneously recovered consciousness and was extubated 11 min after the end of remimazolam and propofol administration. Repeated bolus doses of ephedrine and phenylephrine were required (12 and 0.6 mg in total, respectively) to maintain blood pressure. No PONV, POD, or IAR was reported. The patient was discharged from hospital without any complications 3 days postoperatively.

Figure 4.

Time courses of remimazolam effect-site concentration (RzCe, black curve), propofol effect-site concentration (PCe, gray curve), remifentanil effect-site concentration (RfCe, dotted curve), systolic blood pressure (▼), diastolic blood pressure (▲), heart rate (•), and patient state index (━) in Case 3. Fentanyl 100 µg was administered for 3 min. To calculate RzCe, we converted the fentanyl effect-site concentrations simulated using the Shafer model¹² to remifentanil equivalents¹³ using a remifentanil:fentanyl equivalency ratio of 1:1.

Discussion

Remimazolam 50 mg (1 V) is generally diluted with 50 mL NS and administered using a syringe pump. Since the default maintenance dose is 1 mg/kg/h, the consumption of remimazolam tends to be generally high. Because the use of remimazolam was restricted as mentioned in the background section, we considered anesthesia methods with reduced maintenance doses of remimazolam and with propofol as an additional sedative, based on a multimodal anesthesia approach,¹⁴ in which multiple anesthetics are used to maintain anesthesia. Many human studies on the combination of midazolam, typical benzodiazepine anesthetic, and propofol have shown synergistic effects.^5
–8

During general anesthesia, maintaining adequate sedation depth is critical to prevent IAR. It has been reported that some patients are resistant to the standard dose of remimazolam; thus, monitoring is required to confirm that the patient has been adequately sedated.^15
–17 Regarding processed EEG monitoring during remimazolam use, a strong beta wave power at anesthesia induction¹⁸ and a relatively high Bispectral index value during the anesthesia maintenance phase¹⁹ are observed. In addition, typical EEG changes seen with propofol or inhalation anesthetics that have been used as de-facto standard anesthetics, including spindle wave EEG or decrease in PSI may not be observed, requiring careful interpretation. Therefore, in the present cases, general anesthesia was induced with remimazolam alone while confirming the loss of responsiveness of the patient as well as a decrease in EEG frequency and PSI values, as shown in Figure 2. If we were not sure of sedation on EEG, we would have discontinued the use of remimazolam and replaced the anesthesia method since the sedation state would have been difficult to interpret. Then, the remimazolam dose was lowered and fixed to a level that did not cause arousal. This titration was performed at the discretion of the attending anesthesiologist based on the PSI values and visual inspection of raw EEG. In terms of the PSI, Chae et al.²⁰ showed a definitive dose–response relationship for PSI and the probability of LOC. However, they also indicated that PSI does not seem to be a reliable surrogate of LOC under remimazolam bolus injection based on their data, where a lowered PSI did not guarantee LOC occurrence. Recently, Zhao et al.²¹ revealed that PSI could predict a patient’s state of consciousness under sedation using remimazolam tosylate, despite the wide variability in the correlation between PSI and MOAA/S. Therefore, PSI value may be considered as one of the decision-making factors, along with raw EEG, vital signs, and patient response.

In the present cases, according to pharmacokinetic simulations, after fixing the remimazolam dose, RzCe decreased steeply, then declined gradually, and stabilized approximately in 1 h. In the present cases, the increase in PCe with propofol administration coincided with the decrease in RzCe. The additional dose of propofol may have contributed as a “safety margin” for sedation, in case the fixed amount of remimazolam was inadequate due to changes in the required depth of sedation. Recently, Masui et al. published a remimazolam PK model.^10,22 Therefore, real-time simulation to precisely estimate the decrease in RzCe after fixing the remimazolam dose would be possible in future cases.

High-dose opioids used concomitantly during anesthesia may decrease EEG frequency,²³ resulting in the overestimation of the sedative effect. In the present cases, during anesthesia induction, remifentanil was used for tracheal intubation, after which it was lowered to a dose that was not expected to affect EEG (i.e., remimazolam effect-site concentration of <6.2 ng/mL²³). This contributed to accurately estimating the dose of remimazolam and propofol required to adequately sedate each patient before the surgical procedure, with reference to EEG unaffected by opioids.

Previous phase II/IIIb studies have reported a median remimazolam maintenance dose of 1 mg/kg/h when a sufficient amount of remifentanil for analgesia was administered.²⁴ The package insert for remimazolam also indicates that anesthesia maintenance should be started at 1 mg/kg/h then increased or decreased as needed and that the maximum maintenance dose is 2 mg/kg/h. The insert does not state a minimum dose. Clinically, pharmacokinetic or pharmacodynamic variabilities may lead to the possibility that the actual dose may be less than the starting dose (i.e., 1 mg/kg/h). Indeed, cases have been reported in which the minimum dose of remimazolam required during maintenance of anesthesia was 0.1–0.3 mg/kg/h.^25
–28 In the present cases, after the remimazolam dose was lowered to 0.3 mg/kg/h and maintained, the PSI value increased slightly. Therefore, the dose was not lowered any further, and propofol was additionally administered. Also, the attending anesthesiologists had background knowledge of pharmacokinetic/pharmacodynamic simulation that the resultant RzCe of 0.25 µg/mL corresponds to remimazolam 0.3 mg/kg/h, indicating that the probability of the MOAA/S ⩽1 (i.e., equal or deeper than the level where a subject responds only after painful trapezius squeeze) is less than 5%,²⁹ which may have dictated clinical behavior. It is undeniable that remimazolam 0.3 mg/kg/h alone could have been maintained without the addition of propofol. In the present cases, propofol was added for the “safety margin” for the sedation, as mentioned earlier.

Soehle et al. demonstrated that, for the recommended ranges of the PSI (25–50), the corresponding PCe ranges between 1.2 and 2.6 µg/mL.³⁰ In the present cases, the target concentration for propofol was started at 1 µg/mL. This is a reasonable initial dose because a previous study⁴ in which sevoflurane and propofol were concomitantly administered as sedatives used the same propofol target concentrations (i.e., 1 µg/mL). If sedation had been inadequate, the higher PCe would have been targeted; however, this was unnecessary in all three of the present cases.

In the present cases, the doses of remimazolam (0.2–0.3 mg/kg/h) and PCe (1 µg/mL) were much smaller than their respective standard doses, which may be due to pharmacodynamic interaction between remimazolam and propofol. In the present cases, the combination of remimazolam 0.3 mg/kg/h propofol 1 µg/mL was sufficient to maintain anesthesia, but considering the pharmacokinetic/pharmacodynamic variability, this combination is unlikely to be appropriate for all patients. The authors aim for a concept report; the authors do not recommend this particular dose combination.

In addition, the time from discontinuation of remimazolam to eye-opening (8–13 min) in the present cases was shorter than the average of 14 min in nonelderly patients (age 64 years or younger) in a previous phase II study,¹⁹ and flumazenil was unnecessary in all patients because of spontaneous recovery of consciousness. It was presumed that the sedative effect obtained by the interaction of remimazolam and propofol diminished more rapidly after administration than after the maintenance of anesthesia with remimazolam alone and the termination of administration. Future pharmacodynamic studies are required to demonstrate this quantitatively.

The use of local or regional anesthetics used for neuraxial blockade has been found to reduce the requirement of midazolam and propofol for general anesthesia,^31
–34 probably by decreasing ascending sensory input into the brain. From this context, the requirement of each of the concomitantly used remimazolam and propofol may be reduced when regional anesthesia technique is additionally performed, although further study with larger populations is required.

To the best of our knowledge, this is the first report in which remimazolam and propofol were concomitantly used for general anesthesia based on their pharmacodynamic interaction. This anesthetic combination may be beneficial in reducing the doses of each anesthetic and avoiding delayed recovery from anesthesia, although further study is needed to confirm this.

Conclusions

We experienced three cases in which general anesthesia was induced with remimazolam and maintained with relatively small doses of remimazolam and propofol TCI. The time required for recovery from anesthesia was 8–13 min. This anesthetic combination may be beneficial for reducing doses of each anesthetic and avoiding delayed recovery from anesthesia, although further study is needed to confirm these findings.

Footnotes

Acknowledgements

The authors would like to thank the Scientific English Editing Section of Fukushima Medical University for editing a draft of this manuscript.

Authors’ note

Presented in abstract form at the 20th Annual Meeting of the Japan Society of Intravenous Anesthesia, Osaka, Japan, November 28, 2022 ().

Authors’ information

YW: Senior Resident, Department of Anesthesiology, Fukushima Medical University. SO: Associate Professor, Department of Anesthesiology, Fukushima Medical University; Deputy Director, Center for Pain Management, Fukushima Medical University Hospital; Director, Surgical Operation Department, Fukushima Medical University Hospital. SI: Professor and Chair, Department of Anesthesiology, Fukushima Medical University. This work was carried out at Fukushima Medical University Hospital, 1 Hikarigaoka, Fukushima, Fukushima 960-1295, Japan.

Authors’ contributions

YW and SO treated the patients and wrote the manuscript. SK helped to design the case report. All authors reviewed and approved the final draft.

Availability of data and material

Not applicable.

Consent for publication

Written informed consent was obtained from the patients for publication of this case report.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethics approval and consent to participate

In our institution, IRB approval is not required for a case report.

Informed consent

Written informed consent for publication was obtained from the patients.

ORCID iD

Shinju Obara

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Total intravenous anesthesia management with simultaneous use of remimazolam and propofol: A case series of three patients