Remimazolam in intensive care unit: Potential applications and considerations

Abstract

This manuscript explores the potential use of Remimazolam in the intensive care unit (ICU) and critical care units, considering its pharmacological characteristics, clinical applications, advantages, and comparative effectiveness over current sedatives and anesthetics. We reviewed existing PubMed and Google Scholar literature to find relevant studies on Remimazolam in ICU. We created search criteria using a combination of free text words, including Remimazolam, critical care, intensive care, sedation, anesthesia, pharmacokinetics, and pharmacodynamics. Relevant articles published in the English language were analyzed and incorporated. Remimazolam is an ultra-short-acting benzodiazepine derivative promising for sedation and anesthesia. It is a safer option for hemodynamically unstable, elderly, or liver or kidney issues. It also has comparable deep sedation properties to propofol in the ICU. Furthermore, it reduces post-procedural delirium and patient comfort and reduces the need for additional sedatives in pediatric patients. In conclusion, Remimazolam is an excellent alternative to current sedatives and anesthetics in the ICU. Its cost is comparable to that of current medications. Further research on its long-term safety in the ICU and its broader application and incorporation into routine use is necessary.

Key Words: Remimazolam; Intensive care; Critical care; Anesthesia; Sedation; Mechanical ventilation; Benzodiazepine

Core Tip: Remimazolam, an ultra-short-acting benzodiazepine, offers rapid onset, stable hemodynamics, and organ-independent metabolism, ideal for intensive care unit sedation and procedural anesthesia. Its advantages over traditional sedatives like midazolam and propofol include faster recovery, reduced hemodynamic instability, and a favorable safety profile. Remimazolam is effective for sedation in hemodynamically unstable patients and those with hepatic or renal impairment, highlighting its potential for broader clinical application. Further research is necessary to establish guidelines for its routine use.

INTRODUCTION

Remimazolam is an ultra-short-acting benzodiazepine that is metabolized by tissue ester hydrolysis. Its unique pharmacological properties make it a promising option for sedation in various clinical settings, and procedural anesthesia. In a bibliometric analysis by Hu et al[1] on Remimazolam in 184 studies, it was researched to have a rapid onset of action and recovery along with stable hemodynamics compared to midazolam and propofol. It can be used in intensive care unit (ICU) sedation and anesthesia. Remimazolam is not metabolized by the liver or the kidney. It may be a safe alternative for hepatic and renal impairment[1]. Remimazolam also appears to be superior to propofol in terms of hemodynamic stability and was successfully used in both induction and maintenance of anesthesia in procedures like Endoscopic retrograde cholangiopancreatography, carotid endarterectomy, transcatheter aortic valve implantation[2-4]. The authors also state that there is less vasopressor use during the procedure than in midazolam or propofol patients. It performed better than propofol for neuropsychiatric recovery after endoscopic procedures[5]. Remimazolam was also cost-effective and had a lower cost per procedure[6,7]. Increasing evidence comparing Remimazolam to Midazolam and propofol has emerged in the past five years. However, the usage in routine practice needs to catch up. In this Mini Review, we searched the literature for the potential use of Remimazolam in the ICU and critical care units.

PHARMACOLOGY

Remimazolam is a novel ultra-short-acting benzodiazepine that has unique pharmacologic characteristics that allow it to have a better sedative profile than current drugs[8]. Similar to Midazolam, it acts on Gama amino butyric acid receptors and has a metabolism that is organ-independent, similar to remifentanil[9]. Remimazolam causes an influx of chloride ions and leads to neural cell hyperpolarization. It decreases neuronal activity and causes sedative and anticonvulsant effects[10]. Remimazolam has a special chemical structure known as labile ester moiety. This part is rapidly broken down by tissue esterase enzymes in the body. This rapid hydrolysis allows Remimazolam to have an ultrashort duration of action[11]. This reduces the risk of prolonged sedation and related side effects, thereby making it useful for procedural sedation.

The favorable pharmacologic profile, rapid onset, organ-independent metabolism, short duration of action, superior safety, and availability of reversible agents allow Remimazolam to have numerous advantages over the currently available short-acting sedative drugs[12]. Table 1 shows the characteristics of Remimazolam and dosing in procedural anesthesia and ICU sedation.

Table 1 Characteristics of remimazolam.

Characteristics of remimazolam
Rapid onset of action with onset in 1-3 minutes, elimination Half-life 0.75 hour
Rapid offset due to break down by tissue esterase's and predictable recovery time
Less adjunct medication requirements like Fentanyl and faster neuropsychiatric recovery
Maintained respiratory and hemodynamic stability
Reversal agent available: Flumazenil
Induction and maintenance of procedural sedation bolus of 2.5-5 mg IV once and every 2 minutes as needed
General anesthesia or ICU sedation induction 6-12 mg/kg/h and maintenance 1-3 mg/kg/h

ICU: Intensive care unit.

PHARMACODYNAMICS AND PHARMACOKINETICS

Remimazolam molecule is water soluble and has a high organ-independent clearance rate since it is broken down by tissue esterase’s present in the body and not any specific organ. The drug also shows favorable respiratory side effects that are superior to propofol[13]. Remimazolam showed a distribution half-life of 0.5-2 minutes[14]. Total body clearance was found to be independent of body weight. A single dose of Remimazolam at 11.43 mg achieved a 90% effective dose (ED₉₀) probability for adequate sedation during colonoscopy[13]. It has been reported that an intravenous bolus of Remimazolam of 0.3 mg/kg was needed to achieve anesthetic induction in 94% of patients[15]. This small dose to achieve an anesthetic effect provides reassuring evidence of Remimazolam’s broad applicability in multiple care settings. Compared to midazolam, Remimazolam offers faster clearance and smoother recovery, potentially reducing the risk of prolonged sedation and delayed awakening. Additionally, its pharmacokinetic profile makes it less susceptible to drug interactions and accumulation, enhancing its safety and efficacy in clinical practice.

Compared to other anesthetic drugs, Remimazolam demonstrates comparable efficacy and safety, particularly in terms of respiratory depression, hypotension, and bradycardia. However, concerns regarding anaphylaxis have been raised, warranting further investigation and vigilance in clinical use. In a scoping review by Kempenaers et al[16], out of 6806 patients who received Remimazolam, Anaphylaxis was reported in only ten patients.

CLINICAL USE IN ICU

Remimazolam is an emerging medication for ICU sedation. It is effective for mild – severe depth of sedation. Chen et al[17] studied Remimazolam in twenty-three patients using mild-moderate sedation and found that it maintained respiratory and hemodynamic stability in mechanically ventilated post-operative patients. Tang et al[18] performed a similar study using Remimazolam for patients admitted to the ICU after noncardiac surgeries for mechanical ventilation. Remimazolam at the dose of 0.125 to 0.15 mg/kg/h. provided mild-moderate sedation. Tang et al[19], in their prospective comparative pilot study on sixty patients in the ICU, found that Remimazolam has similar deep sedation properties to propofol. (using Richmond Agitation and Sedation Scale RASS) there were no differences in ventilator-free days, extubation, length of ICU stays, or 28-day mortality. Adverse effects of hypotension were seen in both patient groups, and the difference was not statistically significant[19]. Remimazolam may be an effective medication for use in hemodynamically unstable ICU patients. Yao et al[7], in their study on sixty patients with Remimazolam compared to 46 patients with either propofol or midazolam, found that Remimazolam was comparable in terms of ICU length of stay, RASS scores, adverse events, and ICU mortality. Further, there were less heart rate variability and laboratory alterations with pH, serum Lactate, serum bicarbonate, blood gas analysis, and liver and kidney function compared to either propofol or midazolam. The total inpatient cost was also similar in both groups[7]. Another study by Qiu et al[20] on patients undergoing endoscopy found that Remimazolam decreased episodes of hypotension in these patients compared to propofol. Patients also required less phenylephrine compared to propofol (P < 0.01)[20]. The systolic blood pressure and cardiac output were better preserved in Remimazolam group (P = 0.01)[20]. Kim et al[8] also describe similar outcomes with shorter onset time and faster recovery than Midazolam during bronchoscopy procedures with no significant differences in adverse effects. Weaning from Remimazolam also appears to be shorter, with four min from discontinuation to alertness compared to fifteen minutes for propofol group (P < 0.01)[8]. This property makes it useful in procedural sedation. The use of Remimazolam has also been shown to reduce post-procedural delirium, which was also associated with a lower length of stay in the ICU (< 7 days)[21]. In a review of Remimazolam by Kempenaers et al[16] on 6806 patients, 1006 (14.7%) reported hypotension. In direct comparison with other anesthetic agents like propofol, hypotension was reported in 23% compared to 39%[16]. The abuse potential of Remimazolam was comparable to or slightly lower than midazolam for mild to deep sedation[22]. If needed Flumazenil 0.2 mg has proved to be safe in reversal of hypnotic effect of Remimazolam[23]. Remimazolam shows promise for sedation in the ICU, offering rapid onset and offset of action and precise titration of sedation levels. Its use may facilitate early extubation and reduce the duration of mechanical ventilation, thereby improving patient outcomes in critical care settings.

PROCEDURAL SEDATION IN THE ICU

The favorable pharmacological profile of Remimazolam could allow for its broad use in a variety of procedures. In a double-blind randomized control trial, Remimazolam showed a favorable sedation profile compared to midazolam in flexible bronchoscopy. Remimazolam showed effective and safe moderate sedation and faster neuropsychiatric recovery with a median of 6 minutes compared to 13.6 minutes with midazolam[24]. The recovery time did not differ between Remimazolam and sevoflurane in a study by Lee et al[25]. Remimazolam has also been evaluated in high-risk colonoscopy patients that required emergent intervention and patients with high-risk American Society of Anesthesiologists score (ASA). Remimazolam proved to be efficient and effective in moderate sedation for patients needing emergent high-risk colonoscopies and had a favorable safety profile comparable to low ASA patients[26]. A dose of 5 mg was given IV, followed by a 2.5 mg supplemental dose after 2 minutes[24]. Tang et al[19] and Qiu et al[20] found Remimazolam caused similar or lesser hypotensive episodes compared to propofol thus it may be a favorable agent for procedural sedation in the ICU.

SEPSIS IN ICU

The role of Remimazolam in the ICU for patients with sepsis has yet to be completely established; however, current research has illustrated that Remimazolam can be an effective and useful agent in inducing sedation. Using medium or high doses of Remimazolam to induce sedation in septic patients needed less rescue dosing compared to lower doses[27]. Changes in hemodynamic properties, including Mean arterial blood pressure, Blood urea nitrogen, Serum Creatinine, White blood cell count, and Tumor necrosis factor-alpha, remained stable throughout various doses of Remimazolam and showed safe recovery of renal and hepatic function[27]. Although no strong evidence of anti-inflammatory effects of Remimazolam in humans exists, it shows an anti-inflammatory effect in animal models. Remimazolam has been shown to reduce sepsis-associated liver injury (SALI) by inhibiting p38 phosphorylation in macrophages of rats. It then activates peripheral benzodiazepine receptors, accentuating the SALI's inflammatory response[28,29]. Remimazolam also reduced lipopolysaccharide induced inflammation in vitro and in vivo. This reduced the inflammatory mediators such as tumor necrosis factor alpha, interleukin (IL-6), and IL-1β[25]. Remimazolam has also shown neuroprotective effects through the anti-cholinergic pathway, α7nAChR-mediated Nrf2/HO-1 signaling pathway. This pathway is neurotoxic, and Remimazolam reduced systemic inflammation, neuroinflammation, and sepsis-related cognitive dysfunction in mice. These findings are promising for further research and use of Remimazolam in humans[30,31].

ANXIETY

Remimazolam may also play a vital role in reducing short-term anxiety, particularly prior to procedures, as well as for patients who need additional anxiety coverage in instances when their current treatment regimens are not sufficient. Its rapid onset of action and short half-life allows for a shorter pre procedural time reducing anxiety in patients. This also reduces the catecholamine release[32]. Long et al[33] in their study on 114 children on Remimazolam for laparoscopic inguinal hernia ligation, found nasal Remimazolam to be an effective anxiety-relieving medication perioperatively in children. Li et al[34] demonstrated that Remimazolam had comparable dental anxiety reduction to midazolam without its side effects of nausea, vomiting dizziness.

NAUSEA AND VOMITING

Patients may feel nauseous or even vomit after surgery; this can be due to a variety of reasons. Propofol has anti-emetic properties; however, some patients continue to have post-operative nausea vomiting (PONV) post-emergence while recovering in the post-anesthesia care unit with propofol. In a meta-analysis of sixteen studies with 1897 patients, Remimazolam was comparable to propofol for PONV[35]. Contradictory evidence exists comparing PONV in Remimazolam and sevoflurane or desflurane. Some studies suggest no difference[25,36,37] whereas other studies show a benefit with a reduction in rescue emetic use in first 24 hours for sevoflurane[38] and reduction in incidence of PONV with desflurane[39]. When Remimazolam is combined with remifentanil, this combination proved to be superior in suppressing PONV[40]. Further research is necessary to assess the effective suppression of PONV using Remimazolam.

PEDIATRIC USE OF REMIMAZOLAM

The pediatric population poses several challenges to using sedation methodology. Patients tend to be anxious, requiring specialized dosages and needing additional sedatives for routine procedures. In order to minimize anxiety, patient discomfort, and use of additional medications, Remimazolam provides a unique opportunity to reduce sedative burden in the pediatric population. Pediatric patients requiring MRI had significantly reduced anxiety, decreased hypotensive events, and no need for mechanical ventilation compared to patients receiving propofol[41]. Further, Remimazolam has been shown to reduce post-operative delirium when used either as a continuous infusion or bolus administration at the end of procedure[31,42]. Pediatric patients appear to benefit from using Remimazolam as it provides a predictable pharmacokinetic profile of high clearance rate, small central volume of distribution, short half-life, short recovery time, and stable hemodynamics[43,44]. However, several gaps exist in research due to the lack of large-size studies and longer follow-up times.

CONCLUSION

Remimazolam represents a promising addition to the current sedative and anesthetic agents, offering rapid onset, predictable pharmacokinetics, and a favorable safety profile. Its unique pharmacological properties make it well-suited for ICU and procedural anesthesia sedation, with potential benefits for both adults and pediatric populations. However, further research is needed to fully elucidate its efficacy, side effects, recovery profile in comparison and in combination with current medications, and long-term effects.