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      Remimazolam use for awake craniotomy

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      JA Clinical Reports
      Springer Berlin Heidelberg

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          Abstract

          To the Editor, We read the case reports by Sato et al. [1] and Yoshida et al. [2] with great interest. Certainly, remimazolam is an ultrashort-acting drug and may be suitable for the asleep-awake-asleep technique of awake craniotomy (AC) [3]. Moreover, the use of flumazenil can antagonize the effects of remimazolam, and we believe that remimazolam is a beneficial drug for ensuring an awake state and shortening the time to extubation. We have also experienced two AC procedures in which remimazolam was used (case 1: male, 85 kg; case 2: male, 87 kg). However, at this stage, we cannot affirm that remimazolam can be safely and successfully used for anesthetic management of AC. We are interested to hear the opinions of JACR readers regarding the following three points. First, we have the impression that the ability of remimazolam to suppress pharyngeal reflex is weaker than that of propofol, and the amount of sputum produced during anesthesia is increased. A muscle relaxant can be used during induction of anesthesia to suppress pharyngeal reflex, but the reflex becomes more pronounced when the muscle relaxant effect diminishes toward the awake phase. Second, remimazolam can maintain the intraoperative blood pressure at a higher level compared with propofol, which is one of the advantages of using remimazolam. Readers will also understand that intracranial pressure naturally increases when the blood pressure rises beyond autoregulation of cerebral blood flow, making it difficult for the surgeon to operate. Third, in one of our cases, the patient became agitated during the awake phase after antagonism with flumazenil. After immediately re-anesthetizing using propofol, the motor evoked potential (MEP) waveform temporarily disappeared. MEP gradually recovered, but there was a period when we could not monitor the MEP waveform, which was confusing for the surgeon and the MEP measurer. The precise mechanism for this response is unknown; however, we consider that remimazolam and propofol may have additively interfered with MEP. A previous study has reported that administration of midazolam or propofol moderately affected the MEP waveform [4], which suggests that it is important to verify the interaction between remimazolam and propofol. We believe that remimazolam for awake craniotomy is theoretically correct and should be recommended; however, considering the concerns outlined above, it is controversial to state that it is beneficial for all cases during AC, and we think that further study is necessary. We suggest that JACR readers should assess whether or not remimazolam is appropriate for use for AC on a case-by-case basis.

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          Remimazolam: Pharmacologic Considerations and Clinical Role in Anesthesiology.

          Midazolam, fentanyl, and propofol are commonly used for sedation in modern anesthesia practice. These agents possess characteristics that have afforded various anesthetics to be delivered and produce relatively safe and effective outcomes. However, each agent has certain drawbacks in clinical practice. Remimazolam, a novel benzodiazepine created out of so-called soft drug development, is an ultrashort-acting intravenous sedative-hypnotic currently being investigated in clinical trials. In this review, we evaluate the recent literature on the use of remimazolam in clinical practice as compared with current sedative agents, and we describe its potential roles for use in sedation. A literature search of the Medline database (2012-May 2016) was performed. Additional references were identified from a review of literature citations, manufacturer reports, and professional meeting abstracts. All premarket studies involving remimazolam as the primary study drug were evaluated. Literature describing the pharmacokinetics and pharmacodynamics of remimazolam, propofol, and midazolam was also included. Phase I and II studies in the United States have shown remimazolam to be a safe and effective option for procedural sedation. Unlike midazolam and propofol, remimazolam undergoes organ-independent metabolism to an inactive metabolite. Because remimazolam follows first-order pharmacokinetics, prolonged infusions or higher doses are unlikely to result in accumulation and extended effect, making it favorable for use as an intravenous anesthetic and for sedation in the intensive care unit. It is expected that phase III trials will further describe the niche that remimazolam may be able to occupy in clinical practice. Postmarket cost-benefit analyses will need to be performed.
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            Novel anesthetic agent remimazolam as an alternative for the asleep-awake-asleep technique of awake craniotomy

            To the Editor, Remimazolam is a novel ultrashort-acting benzodiazepine with the advantage of a faster onset and recovery than pre-existing benzodiazepines, such as midazolam [1]. Awake craniotomy (AC) is performed in patients with brain tumors that present in regions linked to language processing, with the aim of minimizing damage to language functioning [2]. There have been reports on administering dexmedetomidine [2], propofol [3, 4], and remifentanil, for the induction of anesthesia in AC; however, there are no reports on administering remimazolam. We describe anesthesia using remimazolam in the asleep-awake-asleep technique of AC. A 37-year-old man (height 175 cm, weight 58 kg) with a diagnosis of a brain tumor in the right cerebrum, without other medical histories, was scheduled for AC. Anesthesia management comprised a combination of general anesthesia and scalp blocks [4]. General anesthesia was induced with remimazolam (12 mg kg−1 h−1), remifentanil (0.1 μg kg−1 min−1), and fentanyl (75 μg). The patient lost consciousness 93 s after starting remimazolam infusion, with a cumulative dose of 20.3 mg. Bispectral Index (BIS) values were approximately 60. Rocuronium (20 mg) was administered, and I-gel® size 5 was inserted. Anesthesia was maintained with remimazolam (1 mg kg−1 h−1) and remifentanil (0.12–0.15 μg kg−1 min−1), and the BIS value remained approximately 50 to 60. Administration of remimazolam and remifentanil was discontinued at the request of the neurosurgeon to awaken the patient. After 26 min, the patient was fully awake, and the I-gel® was removed. He awoke clearly and was cooperative; therefore, language mapping was performed safely. There was no incidence of adverse events such as restlessness, seizure, and pain during the awakening period. Approximately 100 min after arousal, the awake phase was completed; anesthesia was reinduced with remimazolam (12 mg kg−1 h−1) and remifentanil (0.1–0.12 μg kg−1 min−1). The operation was successfully completed, and the I-gel® was removed 26 min after discontinuation of remimazolam. He experienced no delay in arousal or respiratory depression. The total dose of remimazolam was 327 mg. The operating time was 300 min, and the anesthesia time was 463 min. To date, propofol has primarily been used for anesthesia management of the asleep-awake-asleep technique of AC. However, the use of propofol has disadvantages, such as a risk of developing propofol infusion syndrome [5], vascular pain when infusing, and the absence of antagonist agents. Dexmedetomidine, a highly selective α2 agonist, has been widely used due to its sedative and analgesic effect and ability to preserve spontaneous breathing [2]. However, disadvantages of dexmedetomidine include delayed arousal, cardiovascular effects such as bradycardia and hypotension, and, as with propofol, the absence of an antagonist [4]. In this case, the patient fully awoke and was able to perform intraoperative language tasks during the AC. We suggest remimazolam to be an alternative option for general anesthesia for AC; it is an ultrashort-acting agent, and if delayed arousal occurred, flumazenil can be administered as an antagonist [1, 6]. Remimazolam could be safely and successfully used for anesthetic management of the asleep-awake-asleep technique of AC.
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              Anesthetic management for the sleep-awake-sleep technique of awake craniotomy using a novel benzodiazepine remimazolam and its antagonist flumazenil

              In awake craniotomy, complete arousal and sufficient analgesia are crucial for the patient to perform the tasks. Although propofol and dexmedetomidine have been used in the past, they sometimes cause delayed recovery, excitation, and insufficient awakening [1]. Remimazolam is a novel benzodiazepine that has recently been used for clinical anesthesia in Japan and is characterized by its ultrashort-acting property with flumazenil as an antagonist. We report a case of awake craniotomy in which the patient was anesthetized with remimazolam antagonized with flumazenil. A 48-year-old right-handed man was scheduled for awake craniotomy to prevent spatial cognitive impairment. The patient had his first generalized tonic seizure 6 weeks previously, and brain imaging revealed a 46-mm tumor in the right parietal lobe. The patient visited the operating theater before surgery, practiced the neurological assessment task, and also confirmed that the patient positioning was comfortable. On the day of surgery, anesthesia was induced with 6 mg/kg/h of remimazolam and a 100-μg remifentanil bolus, and a laryngeal mask was inserted. Supraorbital nerve block, auriculotemporal nerve block, and greater and lesser occipital nerve block were performed before skull pinning. During the initial asleep phase, the patient was artificially ventilated to control intracranial pressure with continuous infusion of remimazolam 0.75–1 mg/kg/h and remifentanil 0.1 μg/kg/min. After dural opening, remimazolam infusion was discontinued, and remifentanil was reduced to 0.03 μg/kg/min. Flumazenil was administered as a bolus of 0.3 mg when the bispectral index reached 75. The patient was awakened 3 min after flumazenil administration, and the laryngeal mask was removed. The patient was not in an agitated state, could speak, and did not complain of pain. Tumor resection was performed after confirmation of the absence of spatial cognitive dysfunction using the Raven color matrix test and the bisector test. The patient was awake for 2 h and 37 min. After tumor resection, the patient was re-anesthetized with propofol and remifentanil, and the laryngeal mask was re-inserted. After completion of surgery, propofol and remifentanil administration was discontinued, and the patient regained consciousness promptly. The overall operation time was 5 h and 22 min, and the anesthesia time was 8 h and 25 min. The postoperative interview revealed that the patient retained his memory during the awake phase, and there were no symptoms such as spatial neglect, apraxia, or paralysis. Despite the complexity of the task, the patient was able to perform it perfectly, and this anesthetic protocol was highly appreciated by the surgeons. Sato et al. reported a case of awake craniotomy using remimazolam without flumazenil [2]. In the present case, we used flumazenil and found that it facilitated safe and quick arousal. Flumazenil has been reported to induce seizures as a side effect; therefore, the dosage should be minimized [3]. We administered 0.3 mg, and a seizure attack was observed just after cortical stimulation, which was judged to be unrelated to flumazenil. We concluded that with its ultrashort-acting property and the availability of an antagonist, remimazolam in combination with flumazenil can be a powerful tool in awake craniotomy.
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                Author and article information

                Contributors
                shunsuke.tachibana@gmail.com
                knghymz@gmail.com
                yamakage@sapmed.ac.jp
                Journal
                JA Clin Rep
                JA Clin Rep
                JA Clinical Reports
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2363-9024
                15 March 2021
                15 March 2021
                December 2021
                : 7
                : 25
                Affiliations
                GRID grid.263171.0, ISNI 0000 0001 0691 0855, Department of Anesthesiology, , Sapporo Medical University School of Medicine, ; South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543 Japan
                Author information
                http://orcid.org/0000-0001-7452-4358
                Article
                428
                10.1186/s40981-021-00428-w
                7960819
                33723739
                a825be22-885a-4cb6-b5b6-be97e33b7b88
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 February 2021
                : 7 March 2021
                : 10 March 2021
                Categories
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                © The Author(s) 2021

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