Remimazolam

Mechanism of Action

• Remimazolam is an ultrashort-acting benzodiazepine with a metabolically labile carboxylic ester moiety similar to the design employed with remifentanil¹ (Figure 1).

• Sedation, anxiolysis, and amnesia are caused via GABA_A receptor agonism, specifically targeting the α1, α2, α3, and α5 GABA_A subtypes.²
• GABA_A receptor agonism increases chloride ion permeability, leading to hyperpolarization and inhibition of neuronal activity (Figure 2).
• Remimazolam is slightly more potent at the α1 GABA_A subtype than midazolam, which inhibits substantia nigra pars reticularis cell firing.
• Remimazolam also increases cytosolic calcium through G protein-coupled receptors on the endoplasmic reticulum, but the clinical significance of this is unknown.³

Pharmacokinetics/Pharmacodynamics

• Clinical results have demonstrated that remimazolam has predictable and reproducible pharmacokinetic (PK) and pharmacodynamic (PD) profiles, with a rapid onset and offset of action.
• Remimazolam follows first-order (linear) kinetics, both after bolus administration and during continuous infusion.
• Remimazolam follows a three-compartment model for the parent drug and a two-compartment model for its metabolite CNS7054.⁴

Onset of Action

• Remimazolam produces a rapid and dose-dependent sedative effect within 1-3 minutes when administered intravenously in adults.¹
• Studies comparing remimazolam with propofol have found that remimazolam has a longer induction onset time but a shorter time to return of consciousness and tracheal extubation, as well as a shorter postanesthesia care unit stay.²

Clearance

• Remimazolam exhibits high clearance that is approximately three times faster than midazolam, with an elimination half-life of 7-11 minutes, and a terminal half-life of 37-53 minutes.⁵ Clearance rate is similar between children and adults when adjusted for weight.
• The context-sensitive half-time (CSHT) of remimazolam is short and, similar to remifentanil, is relatively independent of infusion duration, reaching a maximum value after 2 hours of continuous infusion (Figure 3).²
  • After 4 hours of infusion, the CSHT of remimazolam is 17 minutes in children,2 and 6.8 minutes in adults.⁴

Metabolism and Excretion

• Unlike other benzodiazepines, remimazolam undergoes organ-independent elimination via cleavage of the molecule by CES1 (Figure 4).
• Metabolism yields a carboxylic acid metabolite (CNS 7054), which is considered pharmacologically inactive.²
• CNS 7054 is excreted primarily via the kidneys, with less than 1% of the parent drug excreted unchanged in urine.
• Renal impairment may lead to the accumulation of CNS 7054. However, this has not yet been shown to have clinical significance.¹
• Hepatic role: Although remimazolam is not dependent on hepatic cytochrome P450 enzymes for metabolism, the liver does play a role in CES1 expression and activity. Subsequently, hepatic impairment may reduce CES1 activity, thereby slowing remimazolam clearance.5 CES1 genetic variants may significantly influence its metabolism, and further research on drug-drug interactions is underway.

Clinical Use and Dosing

• Remimazolam is approved by the FDA for use in adults for procedural sedation. Its use in pediatric patients is currently off-label, although clinical experience and studies are emerging in this population.
• It can be used as an induction agent for general anesthesia (it has a lower risk of post-induction hypotension compared to propofol).
• It can also be used as a maintenance agent during general anesthesia.
• It can be used for ICU sedation, although data is limited.³

Dosing

• The typical single bolus dose for procedural sedation in adults ranges from 2.5 to 5 mg.
• For induction of general anesthesia, a temporary high-dose infusion of 12 mg/kg/h (≈0.2 mg/kg/min) is used for 1-5 min until loss of consciousness is observed.³
• Maintenance doses range from 1-2 mg/kg/h (approximately 17-33 µg/kg/min), with bolus doses of 0.1 to 0.2 mg/kg as needed.³
• There is a lack of universally established pediatric dosing guidelines, with most reports adapting dosing from adult data and often converting to µg/kg/min.³ Our institution (Nationwide Children’s Hospital) uses:
  • Primary sedation agent dosing:
    • Bolus dose: 20-200 µg/kg (max dose 5 mg)
    • Infusion dose: 3-5 µg/kg/min up to 30 µg/kg/min
  • Adjunct to general anesthesia agent dosing:
    • Bolus is not usually required
    • Infusion dose: 3-5 µg/kg/min up to 10 µg/kg/min

Reversal

• Like other benzodiazepines, the sedative effects of remimazolam can be reversed using the competitive antagonist, flumazenil.³

Awake Craniotomy

• Due to its favorable PK/PD profile, remimazolam has been used successfully in awake craniotomy procedures to facilitate a rapid and predictable onset and offset for neurological assessment.
• In one study comparing maintenance with remimazolam versus propofol, titrated to BIS values between 40 and 60, patients in the remimazolam group required 3 minutes less time to awaken for the awake portion of the procedure than those in the propofol group. Additionally, patients receiving remimazolam performed significantly better on intraoperative neurological assessments.³

ICU Sedation

• In a trial evaluating remimazolam for ICU sedation in adults, the investigators were able to reach adequate sedation levels using a bolus dose of 0.02-0.05 mg/kg over 1 min, followed by additional boluses of 0.005 mg/kg until the goal sedation level is reached. Once the desired sedation level is reached, an infusion of remimazolam was started at 0.2 – 0.35 mg/kg/h with titration increments of 0.05 mg/kg/h to maintain sedation goals.³