In general, TIVA with propofol is provided as “trigger-free” anesthesia for MH-susceptible patients. We chose remimazolam-based TIVA for general anesthesia in our patient suspected MH. The patient experienced intra- and postoperative period without developing MH or other adverse events. The successful administration of remimazolam-based TIVA in our MH patient with a confirmed diagnosis of MH underscores its potential as a “trigger-free” anesthetic option.

Remimazolam is a short-acting benzodiazepine rapidly hydrolyzed by tissue esterases. Midazolam, a benzodiazepine, as well as remimazolam, has demonstrated safety in MH-predisposed individuals [13], and its suitability in this context has been less explored. Remimazolam, similar to midazolam, may be considered safe for patients with malignant hyperthermia. Basic cellular experiments have shown that remimazolam does not enhance Ca2+ elevation in human embryonic kidney (HEK-293) cells expressing mutant-type ryanodine receptor RYR1 [7]. Although exposure to remimazolam increased Ca2+ levels in myotubes cultured from CICR-accelerated patients, like this case, the concentration of remimazolam was reported to be 80 times higher than the clinical concentration [8]. In addition, a few clinical cases have been reported in which remimazolam was safely used under general anesthesia in patients with suspected MH [9,10,11]. However, these cases were not definitively diagnosed as MH. To the best of our knowledge, this is the first report of the safe use of remimazolam in a patient with a confirmed diagnosis of MH using both genetic and CICR testing.

Moreover, remimazolam-based TIVA has been reported to have a milder effect on cardiac contractility than propofol-based TIVA, and patients treated with remimazolam are less likely to develop severe hypotension [14]. Remimazolam does not cause the infusion pain experienced with propofol and can be reversed with flumazenil. It can be used in patients with elevated CK levels, as in this case, without causing side effects, such as propofol infusion syndrome or rhabdomyolysis [15].

MH is an autosomal-dominant genetic disease of RYR1, and CACNA1S encodes the subunit alpha1 S of Cav1.1. DNA screening, muscle contracture testing, or both are recommended as first-line diagnostic tests for patients with suspected MH [3]. DNA analyses of peripheral venous blood samples are less invasive than muscle contracture tests that require muscle biopsy, but the probability of detecting disease-causing variants is low, at 30 to 50% [16]. RYR1 and CACNA1S variants are associated with MH and diverse forms of congenital myopathy [3]. In addition, among the over 400 reported RYR1 variants linked to MH [16], only those with a gain in calcium release function (increased sensitivity to RYR1 agonists) are pathogenic [2, 16, 17]. The variant curation expert panel of ACMG/AMP reported that RYR1 variants classified as pathologic and likely pathogenic comprised a quarter of the 335 MH-related variants, and two-thirds were classified as variants of uncertain significance (VUS) [2]. Despite negative DNA test results, predisposition cannot be ruled out [2, 3, 16]. Therefore, testing with muscle biopsy is the next step in diagnosis [3]. If variants suspected to be associated with MH are found and considered variants of VUS, further study of the Ca2+-regulating function of these variants is needed [2, 16, 17]. In addition, there is some discordance between the results of MH genetic analysis and diagnostic muscle contraction testing [18, 19]. In such cases, we recommend genetic analysis and CICR testing. The patient agreed to undergo two tests. Both tests revealed a pathogenic variant (p.Val2168Met) in RYR1 and the enhanced function of the RYR1 channel into releasing calcium from SR.

In conclusion, our study highlights the feasibility and safety of remimazolam-based TIVA in MH-prone patients. Further research and clinical validation are warranted to confirm the role of remimazolam in eliminating the risk of MH development during anesthesia.