Single-Agent Total Intravenous Anesthesia With Remimazolam for an Elderly Man Undergoing Ambulatory Oral Surgery: A Case Report

Abstract

Remimazolam is an ultrashort-acting benzodiazepine approved for procedural sedation in 2020 by the US Food and Drug Administration; however, dosing information originating from the US is limited. No existing literature details infusion rates of remimazolam delivered by manually adjusted infusion pumps. This case report describes the administration of manually infused remimazolam to an 86-year-old man for the surgical extraction of third molars under procedural sedation. Following an initial dose of 4 mg delivered over 1 minute, the remimazolam infusion was titrated according to the patient’s response from a starting rate of 15 mg/h to achieve deep sedation/general anesthesia. The maximum infusion rate was 30 mg/h, and a total dose of 14.1 mg of remimazolam was administered over 28 minutes. The surgery was successfully completed, the patient was satisfied with the anesthetic postoperatively, and he recovered and was discharged home without incident. Further studies are needed to fully characterize remimazolam infusions for a variety of patients using manually adjusted infusion pumps for use in the US.

Benzodiazepines have been used solely or in combination with other agents to provide sedation and amnesia during medical and dental surgical procedures.¹ The use of benzodiazepines can reduce patient anxiety, can reduce risk of intraoperative recall, and may help increase patient satisfaction.² Potential adverse effects of benzodiazepines include respiratory depression, hypotension, tachycardia, prolonged recovery, and postoperative confusion or delirium.² Due to these well-known adverse effects, anesthesia providers often avoid using benzodiazepines during short outpatient procedures or with high-risk patient populations such as geriatric patients or those who are cognitively impaired or have unstable cardiovascular disease.

Remimazolam (Byfavo; Eagle Pharmaceuticals) is an ultrashort-acting benzodiazepine that was approved by the US Food and Drug Administration (FDA) in 2020 for procedural sedation in procedures lasting 30 minutes or less.³ The FDA-approved dosage and administration instructions include bolus dosing for adult patients. The label also provides instructions to individualize and titrate remimazolam dosing to the desired clinical effect.³ Current studies completed in the US using remimazolam have been limited and have studied only bolus dosing to date.⁴ Recent studies in Europe and Japan have compared the efficacy and safety of remimazolam during procedural sedation, induction of general anesthesia, and maintenance infusions using target-controlled infusion (TCI) pumps.^5,6 Prior studies have demonstrated that remimazolam can be used safely in intubated patients and in natural airway sedations for nonpainful procedures, such as endoscopies and colonoscopies.^7,8 There has been no previous documentation of a single-agent total intravenous anesthetic (TIVA) approach utilizing remimazolam with a manually adjusted infusion pump for an elderly patient during a painful procedure. In this case report, we present an 86-year-old man who received remimazolam as a single-agent TIVA approach during the extraction of 3 molar teeth.

CASE PRESENTATION

The patient was an American Society of Anesthesiologists physical status (ASA-PS) II, 86-year-old White man (height, 157.5 cm; weight, 61 kg; body mass index, 24.6 kg/m²) who presented to the University of Pittsburgh School of Dental Medicine Department of Oral and Maxillofacial Surgery for the surgical extraction of his right maxillary third and mandibular second and third molars (teeth 1, 31, and 32, respectively) under deep sedation/general anesthesia. His past medical history included pneumonia more than 10 years prior that resolved with antibiotic treatment and insomnia managed with zaleplon (Sonata; Pfizer). He reported a past surgical history consisting of an appendectomy and endoscopic nasal surgery, both of which were well tolerated with no reported anesthetic complications. The patient had no known drug, food, or environmental allergies. He reported a healthy, active lifestyle, walking or swimming at least 30 minutes per day, which indicated that he exceeded 4 metabolic equivalents. The patient quit smoking cigarettes over 50 years ago, but he currently consumed alcohol in limited social settings and denied previous or current illicit drug use.

Upon physical examination on the morning of the surgery, the patient confirmed having appropriately fasted for more than 8 hours. Upon auscultation, his lungs were clear bilaterally with equal breath sounds, and he had a regular heart rate and rhythm with no identifiable murmurs. The airway evaluation performed with the patient in the seated position revealed a Mallampati II and Brodsky I with limited mouth opening. Indications for sedation included dental anxiety, limited mouth opening, and anticipated difficult surgical extractions. The anesthetic plan was reviewed with the patient at length. Verbal and written consent was obtained prior to starting the procedure.

In the operating suite, the patient was reclined in a semi-Fowler’s position, and standard ASA monitors (noninvasive blood pressure [BP] cuff on the right upper extremity, 5-lead electrocardiograph, and pulse oximeter) were applied. His preprocedural vital signs were as follows: BP, 171/70 mm Hg; mean arterial pressure (MAP), 109 mm Hg; heart rate, 61 beats/min in normal sinus rhythm; and oxygen saturation as measured by pulse oximetry (Spo₂), 95% on room air. A 20-gauge intravenous (IV) catheter was inserted in the left antecubital vein, secured with tape, and connected to an IV administration set with normal saline (NS). Supplemental oxygen (3 L/min) was administered via nasal cannula, and capnography was utilized. The patient’s pressure points (eg, head, neck, elbows, and knees) were padded, and he was protected with safety glasses and arm restraints and kept warm with a blanket.

Using 20 mL of NS, 20 mg of remimazolam was reconstituted and diluted to attain a 1-mg/mL solution. At 7:52 am, the patient was induced with an IV bolus of remimazolam 4 mg given over a 1-minute period. He closed his eyes and began to audibly snore 40 seconds after administration of the remimazolam was initiated and prior to completing the initial bolus. IV cefazolin 1 g was administered after the remimazolam induction bolus. At 7:54 am, an infusion of remimazolam 15 mg/h was initiated using a Medfusion Syringe Pump Model 3500 (Smiths Medical ASD Inc). The remimazolam infusion was titrated to general anesthesia as defined by no movement of the patient during surgical stimulation.

The surgery was initiated at 7:56 am with administration of 1.8 mL of 2% lidocaine with 1:100,000 epinephrine via a right inferior alveolar nerve (IAN) block. During the injection, the patient displayed purposeful movement of the lower extremities in response to the painful stimulus. Using the predetermined amount of 2 mg/h to 3 mg/h when indicated by patient movement or audible response during surgical stimulation, the remimazolam infusion was systematically increased to 17 mg/h at 7:56 am. Subsequent administration of local anesthesia included another right IAN block at 7:57 am with 1.8 mL of 10.5% bupivacaine with 1:200,000 epinephrine and local infiltration of the right maxillary third molar with 1.8 mL of 4% articaine with 1:100,000 epinephrine at 7:59 am. During the articaine injection, the patient exhibited an audible response to pain, so the remimazolam infusion was increased to 20 mg/h. The maxillary third molar proved to be a simple extraction and was completed without the use of a surgical drill. The patient tolerated this extraction without movement or audible response.

At 8:07 am, the surgical drill was first used during the extraction of the mandibular second and third molars, but the patient moved his upper and lower extremities bilaterally, so the remimazolam rate was increased to 22 mg/h. The remimazolam infusion was subsequently increased again to 25 mg/h at 8:09 am due to persistent, purposeful left arm movement during use of the surgical drill. At 8:12 am, the surgeon administered a final local anesthetic injection using 2% lidocaine with 1:100,000 epinephrine via another right IAN block. The patient reacted to this stimulus with left arm movement, and the remimazolam infusion was increased to 27 mg/h in response. The surgeon reported that the mandibular third molar proved to be difficult to extract. The patient moved his left arm at 8:14 am, so the remimazolam infusion was increased to 30 mg/h. This rate allowed the mandibular wisdom tooth to be extracted without further movement or audible pain response from the patient.

Post–curettage and irrigation, the surgeon placed collagen plugs into the surgical sites and began to suture. Due to the anticipated reduced surgical stimulation, the remimazolam infusion was decreased to 20 mg/h at 8:18 am. IV ketorolac 10 mg and ondansetron 4 mg were also administered at this time. At 8:20 am, the remimazolam infusion was decreased to 10 mg/h during the placement of the last 2 interrupted sutures. The surgical procedure was completed at 8:22 am, and the remimazolam infusion was discontinued. The total surgical time was 28 minutes, during which the patient received a total of 14.10 mg of remimazolam. The total fluid volume administered was 400 mL of NS.

At 8:25 am, the patient was repositioned into a more upright seated position, but he remained unresponsive to repeated taps on the left shoulder while his name was repeatedly stated at normal conversation volume. At 8:28 am, the patient was stimulated again in a similar manner, but this time he immediately awakened, gasped, and was noticeably startled. Time from ending the remimazolam infusion to the patient regaining consciousness was 6 minutes.

Throughout the case, the patient’s BP remained within adequate physiological range. The lowest recordings were in recovery at 8:30 am (BP, 111/61 mm Hg; MAP, 79 mm Hg), and the highest recordings were the preoperative values at 7:50 am (BP, 171/70 mm Hg; MAP, 109 mm Hg). The patient’s heart rate was highest (83 beats/min) at 8:00 am and lowest (61 beats/min) during both the preoperative and postoperative periods. Capnography waveforms captured via nasal cannula indicated that he remained spontaneously ventilating throughout the procedure. No periods of apnea or obstruction were observed, and no airway interventions (ie, chin lift, jaw thrust, nasopharyngeal airway) were indicated perioperatively. During the case, the patient had a Spo₂ within 3% of his baseline value of 95%, with his lowest Spo₂ of 92% at 8:05 am and highest Spo₂ of 96% at 8:00 am.

Upon regaining consciousness at 8:28 am, the patient was immediately alert and oriented appropriately. When asked how he was feeling, the patient stated, “I did not remember a thing,” and “That was the best sleep I had in a long time.” When asked what he last remembered prior to the sedation, he stated that he did not remember walking to the operating room and last remembered receiving preop instructions in the consultation room. The patient met discharge criteria at 8:38 am and was transferred via wheelchair to a waiting area, where he remained until his wife arrived. He remained lucid and able to converse effectively without slurred speech or reported mental fatigue. He denied pain, nausea, dizziness, headache, or head fog. Prior to leaving, he stated his satisfaction with the sedation and the absence of postoperative pain.

A follow-up telephone call was made approximately 24 hours after discharge when the patient was again asked about his satisfaction with the surgery and sedation. He stated being satisfied with both and reported no postoperative nausea and vomiting, dizziness, headache, mental fatigue, or head fog. When asked what he last remembered prior to being sedated, the patient recalled the insertion of the IV catheter and vaguely drifting off to sleep. He denied any recall from the time of surgery start to surgery stop and did not recall being startled upon emergence, but he did remember the wheelchair transfer and the multiple conversations held during his lengthy time in the postanesthesia care unit while awaiting transportation.

When asked to comment on his satisfaction with the sedation, the surgeon reported it to be a positive experience, rating it a 9 of 10. He also said that the surgery was very difficult due to the patient’s small mouth, trismus, and positioning of the teeth. The surgeon stated that “the patient’s movement during the case was minimal and did not hinder the surgical progression in any meaningful way.”

DISCUSSION

Remimazolam is an ultrashort-acting IV benzodiazepine with potent anxiolytic, anticonvulsant, muscle relaxant, and sedative-hypnotic properties.⁴ Comparable with other benzodiazepines, remimazolam has a highly selective affinity for the γ-aminobutyric acid type A (GABA_A) receptor complex. Remimazolam engages the benzodiazepine receptor binding site on these ligand-gated chloride ion channels, just like other benzodiazepines, which leads to positive allosteric modulation of GABA and ultimately produces neuronal hyperpolarization and central nervous system inhibition.^4,9,10 With structural modifications similar to remifentanil, remimazolam is rapidly hydrolyzed to a pharmacologically inactive metabolite, CNS 7054, via nonspecific tissue esterase activity.^9,10 However, carboxylesterase 1 (CES1) is the main esterase responsible for the metabolism of remimazolam.¹⁰ Remimazolam is highly bound to proteins (>91%, primarily albumin) and, along with CNS 7054, is excreted primarily in the urine.⁴ Remimazolam has also been reported to be pharmacologically antagonized with flumazenil, further contributing to its favorable safety profile.¹¹ Similar to other relatively lipophilic IV benzodiazepines like midazolam, the onset of sedation is rapid (1-2 minutes), and the magnitude of the drug’s effects are considered dose dependent.¹² Remimazolam has a unique anesthetic profile as it combines the pharmacodynamic properties of midazolam with pharmacokinetic properties similar to those of remifentanil.¹²

Remimazolam was initially approved for general anesthesia in Japan in January 2020 and in China in November 2021.¹³ Remimazolam was approved for procedural sedation by the US FDA in July 2020.¹³ The FDA-approved label for remimazolam recommends a 2.5-mg to 5-mg IV bolus injection over a 1-minute period. If needed, a supplemental dose of 1.25 mg to 2.5 mg may be given over a 15-second period.³ The FDA label also indicates that at least 2 minutes must elapse prior to administering any supplemental doses.³ The drug currently has FDA approval only for procedural sedation in adults undergoing procedures lasting 30 minutes or less.³

The pharmacokinetic properties of remimazolam appear to not be significantly altered in geriatric patients or those with higher ASA-PS scores.⁴ Doi et al⁶ noted that the use of remimazolam for induction and maintenance of intubated general anesthesia on ASA-PS III patients was exceptionally effective with a great safety profile that was dose independent.⁶ Furthermore, they concluded that it had less hemodynamic effects than propofol and an equivalent clinical recovery time (8-9 minutes). In a study by Eisenried et al,¹⁴ it was concluded that for ASA-PS I, nonobese men between 20 and 38 years of age, remimazolam could be used as an effective single-agent sedative without significant hemodynamic depression or respiratory depression requiring more than mild intervention (eg, chin lift, nasal cannula). Remimazolam has a short context-sensitive half-time (7-8 minutes after a 2-hour infusion), and the drug’s clearance appears to be independent of body weight for adults between 65 and 90 kg.¹²

The anesthesia providers in this case have used remimazolam in prior moderate and deep sedations on ASA-PS I to III patients aged 23 years to 70 years during dental and maxillofacial procedures via the on-label dosing instructions. In the anecdotal experiences of these providers, on-label bolus dosing has been observed to occasionally cause respiratory depression, apnea, and inconsistent planes of anesthesia that often interfered with the operator’s ability to complete the surgical procedure without additional anesthetic agents or airway interventions. Due to the inconsistency in sedation and undesirable changes in patient ventilation previously encountered with bolus dosing, the providers in this case determined that a remimazolam infusion would allow for a more consistent plane of anesthesia to be established.

There is limited existing literature detailing remimazolam infusion rates for deep sedation or general anesthesia via manually adjusted infusion pumps. Some of the existing literature on remimazolam infusions utilizes a mode of drug administration known as TCI. TCI utilizes a computer-controlled infusion pump that can calculate and deliver infusion rates to achieve desired plasma or effect-site drug concentrations.^15,16 The TCI mode of drug administration delivers anesthetic drugs based on patient parameters (eg, height, weight, age, sex), adjusting the infusion rates in real time to account for drug distribution and elimination.^15,16 The principles behind TCI pumps utilize the 3-compartmental pharmacokinetic model in an attempt to deliver precise drug doses that maintain a steady level of sedation or anesthesia while avoiding drug accumulation.¹⁶ This delivery method aims to reduce intraoperative awareness and better enhance patient safety and recovery.¹⁶ The existing literature comparing the use of TCI systems with manual administration of sedatives is inconclusive, with no definitive evidence that TCI is clinically superior.¹⁵ TCI systems are not currently available for use in the US as they lack FDA approval.¹⁵

To establish an infusion rate that would be comparable with the current FDA-approved on-label dosing for remimazolam, a total of 20 mg (1 vial) was intended to be titrated to effect within a maximum period of 30 minutes. The preoperative anesthetic plan in this case was to adhere to the on-label remimazolam instructions for use in ASA-PS III and IV patients due to the patient’s advanced age. The induction dose would be titrated to the clinical effect of somnolence without apnea, and the remaining amount of remimazolam available postbolus would be infused over the remaining 27 minutes. An initial infusion rate of 15 mg/h was determined preoperatively, and the anesthetic plan was to titrate the infusion rate by intervals of 2 mg/h to 3 mg/h to achieve the desired clinical effects (ie, no patient movement or audible response during surgical stimulation). This single-agent remimazolam anesthetic plan would ensure that the patient would not receive more than the on-label approved dosage (20 mg) in a 30-minute period. The anesthetic providers determined that propofol would be administered if the patient were to require an immediate rescue agent to maintain adequate depth of anesthesia that was not achieved by remimazolam alone. The executed anesthetic plan resulted in a maximum infusion rate of 30 mg/h and a total of 14.1 mg of remimazolam administered over 28 minutes. The surgery was successfully completed with the patient reporting satisfaction with amnesia and comfort. No anesthetic rescue agents or airway interventions were indicated, and recovery and discharge were unremarkable.

Although the patient reported no previous history of hypertension, he did report significant dental anxiety. This may have contributed to his elevated preoperative BP readings (BP, 171/70 mm Hg; MAP, 109 mm Hg) at 7:50 am (Table 1; Figure 2). His BP gradually decreased (BP, 155/78 mm Hg; MAP, 119 mm Hg) at 7:55 am following induction with remimazolam and prior to the administration of local anesthesia with epinephrine (Tables 1 and 2; Figures 1 and 2). The patient’s BP further decreased over the clinical course with multiple increases in the remimazolam infusion rate and total infusion time (Figure 2).

Table 1.

Perioperative Vital Signs

Time	Blood pressure (MAP), mm Hg	Heart rate, beats/min	Spo2, %	Respiratory rate, breaths/min
7:50 am	171/70 (109)	61	95a	14
7:55 am	155/78 (119)	69	93	13
8:00 am	158/69 (98) 1 PVC	83	96	14
8:05 am	140/69 (106) 1 PVC	72	92	15
8:10 am	129/58 (99) 1 PVC	69	94	15
8:15 am	132/62 (101) 3 PVCs	68	95	15
8:20 am	115/55 (79)	65	93	16
8:25 am	122/56 (85)	61	95	13
8:30 am	111/61 (79)	61	95a	12

Abbreviations: MAP, mean arterial pressure; PVC, premature ventricular contraction; Spo₂, oxygen saturation as measured by pulse oximetry.

^a Denotes Spo₂ while on room air.

Figure 2.

Perioperative Vital Signs and Remimazolam Infusion Rates During a Single-Agent Total Intravenous Anesthetic Using a Manually Adjusted Infusion Pump

The gold line represents the initial bolus of remimazolam, and the yellow line represents the maintenance infusion rate of remimazolam over time. The patient’s blood pressure, mean arterial pressure (MAP), and heart rate are illustrated over time.

Table 2.

Perioperative Infusion Dosages

Time	Remimazolam administration	Rate change (from prior), mg	Reason for rate adjustment
7:52 am	Induction bolus	+4	Induction initiated
7:54 am	Infusion initiated: 15 mg/h	+15	Maintenance infusion initiated
7:56 am	17 mg/h	+2	Local anesthesia administration: left foot movement
7:59 am	20 mg/h	+3	Local anesthesia administration: leg movement and audible pain response
8:07 am	22 mg/h	+2	Initial use of surgical drill
8:09 am	25 mg/h	+3	Surgical stimulation: left arm movement
8:12 am	27 mg/h	+2	Surgical stimulation: left hand and arm movement
8:14 am	30 mg/h	+3	Root tips removal: bilateral hand movement
8:18 am	20 mg/h	−10	Extractions completed: anticipated reduction in surgical stimulus
8:20 am	10 mg/h	−10	Final sutures placed: anticipated reduction in surgical stimulus
8:22 am	Infusion stopped; total: 14.10 mg	−10	Surgery completed: infusion terminated

Figure 1.

Single-Agent Total Intravenous Anesthetic With Remimazolam Using a Manually Adjusted Infusion Pump

The orange line represents the initial bolus of remimazolam, and the yellow line represents the maintenance infusion rate of remimazolam over time. Events during the procedure that influenced titration of the remimazolam infusion are illustrated with arrows.

The preoperative anesthetic plan was for a TIVA approach with remimazolam to achieve deep sedation with a natural airway. Although the patient’s BP had decreased from baseline, his verbal pain responses and movement during the local anesthetic injections indicated that deep sedation had not yet been achieved. This likely could have resulted from the clinician’s inexperience with remimazolam infusions. By gradually increasing the infusion rates over time due to the response to surgical stimulation, an adequate level of sedation and stabilization of the patient’s cardiovascular stress response was achieved (Table 2; Figures 1 and 2). Additionally, the patient did not have intraoperative recall and did not exhibit intraoperative movement that interfered with the progression of the surgical procedure.

At the beginning of the recovery period, the patient did not initially respond to a change in position, mild physical stimulation, or verbal commands. When the same audible and physical stimuli were repeated approximately 3 minutes later, the patient immediately awakened and remained conscious at a level consistent with his baseline throughout recovery and until meeting discharge criteria 16 minutes after stopping the infusion. The patient displayed vital signs and a neurologic status appropriate for discharge within 2 minutes after emergence, and the patient’s disposition remained steady throughout the hour spent waiting for his wife to drive him home.

Although off-label use of remimazolam has been reported in literature, few medical centers have acquired the drug, established internal guidelines for its use, and applied it to clinical practice.⁴ The Mayo Clinic is currently one of the first major academic centers in the US that is regularly incorporating remimazolam into perioperative practice.⁴ As of a publication from October 2023, they have used the agent in 5000 patients with over 20,000 doses administered.⁴ For procedural sedation, the Mayo Clinic typically administers 2-mg IV boluses every 15 seconds as needed with or without adjuncts (eg, ketamine, opiates).⁴ A IV bolus range of 1 mg to 5 mg every 2 minutes has been utilized to achieve desired clinical effects.⁴ The Mayo Clinic adheres to the FDA recommendations for dose reduction in patients with severe hepatic impairment (Child-Pugh score >9) due to suspected reduction in drug clearance.⁴ Dose adjustments are not indicated for patients with renal disease.⁴

The manual dosing regimen implemented for this case achieved a clinical effect that aligns with previous reports utilizing TCI administration. Further studies are needed to fully characterize remimazolam infusions to a variety of patients using manually adjusted infusion pumps, as commercially available infusion pumps and pharmacokinetic models for TCI (not available in the US) of remimazolam are limited.¹⁷ In addition, anesthesia depth monitoring indices, such as bispectral index or patient state index, are not well correlated with loss of consciousness in anesthesia utilizing remimazolam.¹⁷ This also limits the ability to extrapolate existing TCI data for remimazolam to manually adjusted infusion pumps. Dosing of remimazolam infusions is commonly reported to be calculated by patient total body weight (mg/kg/h).^5,6,13 Additional studies are required to assess weight-based dosing of remimazolam on manual adjusted infusion pumps compared with TCI administration. Potential clinical applications of remimazolam include premedication prior to anesthetic care, procedural sedation, sedation in the intensive care unit, and as an adjunct for intraoperative anesthetic care.¹⁸ Remimazolam’s favorable pharmacokinetic profile may be best used for procedural sedation in conjunction with an adjunct that provides analgesia (eg, ketamine, remifentanil, dexmedetomidine). Most of the existing clinical trials that utilize remimazolam for general anesthesia concurrently utilize paralytic agents and opioids with intubation and mechanical ventilation.^6,7,13 Although remimazolam is currently more expensive than other commonly used sedative medications, faster recovery times may help to counter the increased cost of the drug.⁴

CONCLUSION

This case report describes the successful use of remimazolam as an infusion for deep sedation in an elderly patient undergoing dental extractions. Using remimazolam via a combination of bolus and infusion techniques with a manually adjusted infusion pump appears to be effective for sedating elderly patients for dental and oral surgery procedures. However, additional studies are needed to further characterize the safety and efficacy of remimazolam administered via manually adjusted infusions.