Remimazolam Use in Awake Craniotomy for Patient with Morbid Obesity and Recurrent Glioma

Introduction

The continuous improvement of surgical techniques in the domain of neurosurgery has prompted anesthesiologists to modify their anesthetic approach, deviating from the conventional practice of general anesthesia. To ensure optimal outcomes for treatments within the eloquent cortex, it is imperative that patients and therapists maintain uninterrupted verbal communication. Awake craniotomy is a type of craniotomy that allows a neurosurgeon to remove tumors located in eloquent areas of the brain while the patient is fully conscious. Awake craniotomy is considered the criterion standard for maximum neurosurgical tumor excision. The procedure allows for reduced iatrogenic brain damage, by cognitive mapping during the intraoperative part of the procedure. The anesthetic techniques used during the procedure include the asleep-awake-asleep technique with orotracheal intubation or laryngeal mask, monitored anesthesia care technique, and asleep-awake anesthesia. Our preferred anesthetic technique is the monitored anesthesia care technique, which involves scalp block and analgo-sedation by intravenous infusion of remimazolam and remifentanil. The “awake” procedure is divided into 3 stages: opening the cranium (craniotomy), appropriate tumor removal, and surgical closure of the cranium. It is of the utmost importance that the patient does not experience any pain at any point during the procedure, and that they actively cooperate with the neurosurgeons and neuropsychologists during the resection of the tumor and stimulation of the relevant brain regions [1,2]. The primary challenges for the anesthesiologist are to ensure that the treatment is painless for the patient and to administer analgesic sedation drugs that are short-acting, controllable, and have a minimal risk of respiratory depression, which is of particular importance for patients with obesity. In this type of procedure, propofol and dexmedetomidine are used primarily to provide a safe and comfortable duration of anesthesia. This consideration assumes particular significance in patients with an elevated risk for respiratory complications. The use of any of these procedures carries a concomitant risk.

Since 2020, a novel pharmaceutical agent, remimazolam, has emerged in the medical market. Remimazolam besylate is a benzodiazepine with ultra-short-acting properties, exhibiting a reduced onset time and accelerated recovery, relative to that of other benzodiazepines. Remimazolam enhances the activation of GABA (γ-aminobutyric acid) receptors. Its benefits include an immediate onset of action, metabolism that is independent of any specific organ, a short duration of action, the absence of pain at the site of injection, and a reversal agent (flumazenil). Its safety profile, unique pharmacokinetics, and pharmacodynamics are such that it was authorized in many countries as of 2020 for the purpose of procedural sedation [3]. In the context of ensuring the safety and comfort of anesthesia during awake craniotomy procedures, there is a constant pursuit for the most suitable sedative agent to meet these objectives. The introduction of remimazolam in the market prompted a need for us to assess its efficacy in our clinical practice. The pharmacokinetic characteristics of remimazolam closely align with our ideal profile, making it a promising option. This novel drug enhances safety and comfort for patients at high risk of respiratory failure, eliminating the necessity for instrumental airway protection.

The objective of this report is to present a case of a 32-year-old male patient with morbid obesity requiring awake craniotomy and resection of a recurrent cerebral tumor, using the anesthetic regimen of remimazolam, fentanyl, and remifentanil, without the need for any reversal agents or airway protection devices.

Case Report

A 32-year-old male patient with a body mass index of 43.9 kg/m2 and a total body weight of 146 kg was deemed eligible for surgical removal of a tumor recurrence (low-grade glioma) in the left temporoparietal region, through craniotomy. The patient exhibited no other comorbidities or allergies, and was classified as American Society of Anesthesiologists Physical Status Classification System II. The decision was made to perform the “awake” procedure, due to the location of the tumor, which was discovered by functional magnetic resonance imaging to be within the Wernicke area, arcuate fasciculus (language comprehension), and motor cortex (Figures 1, 2).

The patient received the requisite anesthetics and analgesics (to be maintained throughout the craniotomy) and regional anesthesia, encompassing a blockade of the nerves in the head area, specifically the scalp block. The initiation of analgesia and sedation occurred subsequent to the patient’s installation of standard monitoring apparatus, which included electrocardiogram, pulse oximetry, invasive blood pressure measurement, and bispectral index monitoring. Concurrently with the intravenous bolus administration of 0.1 mg fentanyl, an infusion of remifentanil was initiated at a rate of 0.003 μg/kg/min. Following a period of approximately 2 min, 2.5 mg of remimazolam (Byfavo) was administered, and this was repeated after a further 2 min with an additional 2.5 mg of remimazolam. Ten minutes later, a further 2.5 mg of remimazolam was administered. The patient was assigned a score of 3 on the Modified Observer’s Assessment of Alertness Sedation scale, with a decrease in bispectral index from 98 to 80. A scalp block was then performed, involving the blocking of the left supraorbital, supratrochlear, zygomatic-temporal, auriculotemporal, and greater occipital nerves, with a total volume of 20 mL of 0.5% ropivacaine being administered. During this period, the patient did not respond to the painful stimuli associated with the block. The bispectral index remained within the range of 79 to 85. The patient’s blood pressure decreased from a baseline of 130/70 to 110/60 mmHg, while the heart rate decreased from 70 to 60 beats per min. A reduction in oxygen saturation from the initial value of 96% to 90% was observed (the patient was administered oxygen via a nasal cannula at a rate of 3 L/min). There was no further decrease in oxygen saturation, and the patient did not require respiratory support. Approximately 7 min after the blockade, the patient regained consciousness (bispectral index, 98), and blood pressure and heart rate values returned to the normal levels from before drug administration. Following the local anesthetic injection into the areas of the inserted pins (1% lignocaine solution), the neurosurgeon proceeded with the attachment of the Mayfield head holder. The patient did not experience any discomfort and was amenable to the decision to stabilize the head in a location that was convenient for the surgical team and relatively comfortable for the patient during the several hours of immobilization that were necessary during the procedure. Prior to the incision being made, the dose of 2.5 mg remimazolam was repeated, and the remifentanil infusion was continued. During the craniotomy, bispectral index values remained within the range of 80 to 95, and the patient’s vital signs remained stable throughout the procedure, with no fluctuations in blood pressure, heart rate, or oxygen saturation. The patient remained asleep and was able to respond to verbal commands, with a score of 3 on the Modified Observer’s Assessment of Alertness Sedation Scale. Subsequently, the surgical procedure commenced with the removal of the tumor. The infusion of remifentanil was completed, and the patient collaborated with a neuropsychologist and the surgeon to facilitate the removal of the tumor and stimulate the relevant neural pathways. The bispectral index values ranged from 96 to 98, while circulatory and respiratory parameters remained stable. No disturbances were identified by the neurophysiologist during monitoring of evoked potentials. Following the excision of the tumor and the neuropsychologist’s examination, the closure of the cranium was initiated. A subsequent administration of 2.5 mg of remimazolam was given, followed by the initiation of a remifentanil infusion, which was repeated approximately 15 min later. During the third phase of the procedure, the patient was asleep, with bispectral index values ranging from 80 to 90. There was no evidence of pain, and respiratory and circulatory parameters remained stable. The procedure took 3 h and 45 min, including anesthesia, and a total of 15 mg of remimazolam was administered (Figure 3). There was no requirement for the administration of flumazenil at any time during the procedure. The patient remembered only selected parts of the procedure, in particular, the conversation with the neuropsychologist.

Discussion

The objective of this report is to provide the first documented evidence of the use of remimazolam for sedating a 32-year-old man with obesity who needed an awake craniotomy and excision of a recurrent cerebral tumor. This procedure was performed under an anesthetic regimen of remimazolam, fentanyl, and remifentanil, obviating the requirement for any reversal agent or device for airway management.

The article presents a case of safe sedation in combination with regional anesthesia in a patient with morbid obesity for an awake craniotomy. Patients with obesity represent a particularly challenging group, with a high risk of hypoxia due to low respiratory reserves and difficulty maintaining airway patency. A patient with obesity suitable for the awake procedure presents a dual challenge. First, the forced positioning of the patient’s head in a Mayfield head holder, in conjunction with the presence of a sterile surgical field, results in challenging access to the airway. Second, the necessity of using a drug such as remimazolam (as an alternative to propofol or dexmedetomidine) that is short-acting and preferably contains a specific antagonist, so that it is effective in a brief period, allows for full cooperative engagement with the patient, and enables the examination by a neuropsychologist. These procedures are generally conducted under regional anesthesia, specifically, a scalp block combined with sedation [1]. A variety of sedative agents are used in routine practice, including propofol, dexmedetomidine, and ketamine in combination with propofol, as well as the administration of a low dose of an opioid [5–7]. Remimazolam is a relatively novel pharmaceutical agent that can be used for sedation in this category of procedure. This ultra-short-acting, water-soluble benzodiazepine is rapidly eliminated from nonspecific tissue by esterases, resulting in a rapid onset of action and a brief effect, with no cumulative effect. The drug produces a rapid sedative effect, with minimal negative impact on hemodynamic and respiratory function, even in patients with obesity [8,9]. The efficacy of remimazolam in sedating pediatric and adult patients has been well-documented, particularly in diagnostic procedures, such as gastrointestinal endoscopy. Extensive research, including metanalyses conducted on various patient populations, has focused on the use of remimazolam in these procedures [10–12]. The benzodiazepine has found successful application in sedation during bronchoscopy [13,14], as well as in general anesthesia, including cardiac surgery (eg, aortic valve replacement [15]), transplantology, such as anesthesia for liver transplants [16,17], and orthopedics. A case report details the use of remimazolam for the combined sedation and regional anesthesia of a patient with a humerus fracture and potential respiratory difficulties due to an enormous thyroid goitre [18]. Additionally, a case report describes the use of remimazolam for an awake craniotomy, with the patient breathing through a laryngeal mask, and with flumazenil used as an antagonist [19–21]. In the present case, the patient did not require the administration of flumazenil during any stage of the procedure. Vital parameters did not indicate the need for its use, and cooperation with the neuropsychologist was optimal. In a retrospective study by Sato et al of 36 patients eligible for craniotomy with intraoperative recovery, the use of propofol and remimazolam was compared, and the benefits of both drugs were similarly assessed. It is important to note that in all patients, the airway was secured with a supraglottic airway device, which precludes a comparison of the effect of drugs on the respiratory center. In a subsequent study by the author, a comparison was presented involving 52 patients on the use of propofol or remimazolam. In this study, remimazolam compared with propofol was associated with more rapid loss of consciousness and, after administration of flumazenil, with faster arousal times and improved intraoperative task performance. Teixeira et al used a similar approach, using remimazolam boluses in conjunction with an infusion of dexmedetomidine, obviating the need for respiratory instrumentation. Further research is required to ascertain the efficacy of remimazolam in patients with obesity undergoing neurosurgery. The literature includes a case report of the successful use of remimazolam to induce general anesthesia in a patient with morbid obesity with obstructive sleep apnea [22], in cardiac surgery for transcatheter aortic valve implantation [23], and for randomized single-center sedation trials of endoscopic procedures of the gastrointestinal tract, with the use of an opioid and without [9]. The findings of the aforementioned studies suggest that the use of remimazolam can potentially mitigate the risk of hypoxia in this specific patient population. To date, no comparable case descriptions have been identified in the existing literature regarding the successful application of remimazolam in neurosurgery for awake craniotomy in a patient with morbid obesity, without the necessity for respiratory instrumentation. Despite the administration of benzodiazepines, which have been identified as a significant predictor of post-traumatic stress disorder development, no symptoms indicative of post-traumatic stress were observed in the patient.

Conclusions

This report highlights the use of a new ultra-short-acting benzodiazepine, remimazolam, as an essential component of awake craniotomy anesthesia procedures in a high-risk patient with morbid obesity.

The implementation of safe sedation relies on the expertise of the anesthesiologist, who must possess both the requisite skills and an in-depth understanding of the pharmacological properties of the drugs used. The meticulous selection and appropriate use of these agents are designed to guarantee the comfort and security of patients undergoing diagnostic and surgical procedures. Moreover, in the context of neurosurgery, it is imperative that the selected pharmacological agent does not impede the monitoring of intraoperative evoked potentials. This domain remains under investigation, with most existing reports being based on case studies [24–27]. Remimazolam has emerged as a promising alternative to the conventional sedatives used for sedation during craniotomy with intraoperative awakening, exhibiting safety profiles even in patients with obesity with a high risk of airway obstruction.