Anesthesia Management in a Patient With a History of Fulminant Malignant Hyperthermia and a Homozygous RYR1 p.Arg530His Variant Undergoing Laparoscopic Surgery: A Case Report

Introduction

Malignant hyperthermia (MH) is an uncommon but potentially life-threatening inherited condition precipitated by exposure to volatile anesthetic agents or suxamethonium. These triggering agents cause uncontrolled calcium release from the sarcoplasmic reticulum in skeletal muscle, leading to a marked hypermetabolic response. Variants in the ryanodine receptor type 1 (RYR1) gene are recognized as the principal genetic basis of MH susceptibility [1–3]. Accordingly, individuals considered susceptible to MH are recommended to avoid known triggering agents and to undergo regional anesthesia or total intravenous anesthesia (TIVA) when general anesthesia is necessary [4,5].

Remimazolam is an ultra–short-acting benzodiazepine that has been approved in Japan since 2020 for both the induction and maintenance of general anesthesia, making it a potential alternative for TIVA [6]. Experimental in vitro data have shown that remimazolam does not elevate intracellular calcium levels in cells expressing MH-related RYR1 variants [7,8]. However, clinical experience with remimazolam in MH-susceptible patients remains limited. Most published reports involve patients with suspected MH susceptibility based on family history [9–12], whereas a few reports describing its use in individuals with genetically confirmed MH are scarce [11,13] or a documented personal history of MH [14].

Furthermore, reports involving patients with a documented history of fulminant MH and genetically confirmed susceptibility are particularly rare, and to our knowledge, cases involving a homozygous likely pathogenic RYR1 variant have not been well described. Here, we report the anesthetic management of a patient who experienced fulminant MH approximately 4 decades earlier and was subsequently confirmed to have MH susceptibility due to a homozygous likely pathogenic RYR1 p.Arg530His variant, in whom remimazolam-based TIVA was successfully performed.

Case Report

Written informed consent for publication of this case report and the accompanying images was obtained from the patient. An 80-year-old man (height 159 cm, weight 49 kg) was scheduled to undergo laparoscopic inguinal hernia repair. At the age of 39, during surgery for lumbar disc herniation, the patient developed fulminant malignant hyperthermia. After administration of suxamethonium, masseter muscle rigidity was observed. Following the administration of halothane, tachycardia (120 beats min−1) with ventricular premature contractions occurred, and body temperature gradually increased. Because MH was suspected, the surgery was terminated and active cooling was initiated. Despite these measures, his condition progressed, with tachycardia reaching 160 beats min−1, severe hyperthermia (41°C), metabolic acidosis (pH 7.0465, base excess −14.0 mmol L−1), and hypercapnia (PaCO2 58.8 mmHg). Cola-colored urine was observed, and the creatine kinase level peaked at 59 000 IU L−1 on postoperative day 1. He was treated with dantrolene, which was investigational in Japan at the time, and survived without sequelae. His Clinical Grading Scale score was retrospectively estimated at 68, corresponding to an MH rank of 6 (“almost certain”). Subsequently, a muscle biopsy was performed, and susceptibility to MH was confirmed using a Ca2+-induced Ca2+ release (CICR) test with skinned muscle fibers.

He was receiving clopidogrel for internal carotid artery stenosis, which was changed to aspirin preoperatively. His medications also included amlodipine and Olmesartan for hypertension and ezetimibe for dyslipidemia. He ambulated with a cane, and preoperative assessment revealed no abnormalities. Given his prior lumbar surgery and antiplatelet therapy, spinal anesthesia was avoided, and general anesthesia was planned.

The anesthesia machine was prepared in accordance with established guidelines [1–3]. An initial supply of dantrolene, along with sterile distilled water for reconstitution, was kept readily accessible to allow immediate treatment should malignant hyperthermia (MH) be suspected [3]. Routine intraoperative monitoring comprised invasive arterial blood pressure measurement, electrocardiography, capnography, pulse oximetry, bispectral index (BIS) monitoring, and continuous measurement of core body temperature.

At induction, the patient’s baseline core temperature was 37.4°C. General anesthesia was initiated with remimazolam (12 mg/kg/h), fentanyl (50 μg), rocuronium (40 mg), and remifentanil (0.5 μg/kg/min). Mechanical ventilation was adjusted to a tidal volume of 400 mL, a respiratory rate of 10 breaths per minute, and an inspiratory-to-expiratory ratio of 1: 2. Anesthesia was maintained using continuous infusions of remimazolam and remifentanil, with rocuronium administered as needed. The remimazolam infusion rate was titrated according to BIS values. Supplemental rocuronium was given in 10-mg increments based on neuromuscular monitoring findings. Throughout the operation, end-tidal carbon dioxide (EtCO2) levels were maintained between 35 and 42 mmHg, and no clinically significant hemodynamic instability was observed.

At the completion of surgery, the patient’s core body temperature was 37.2°C. Neuromuscular blockade was antagonized with sugammadex. The patient recovered consciousness spontaneously without requiring flumazenil, and extubation was performed after adequate spontaneous ventilation had been confirmed. Arterial blood gas analysis revealed no evidence of respiratory or metabolic acidosis (PaCO2 42.1 mmHg, pH 7.419, base excess 2.4 mmol/L). The lactate level was within the normal range (0.8 mmol/L). Vital signs, including body temperature, heart rate, and blood pressure, were stable, and the patient was transferred to the ward in accordance with MH management guidelines [1–3]. Prior to transfer to the general ward, flumazenil (0.2 mg) was administered.

Postoperatively, non-invasive blood pressure and heart rate were continuously monitored until the following day. Body temperature was measured hourly and ranged from 35.9°C to 36.9°C. CK levels remained within the normal range (59–248 IU/L): 172 IU/L preoperatively, 161 IU/L on postoperative day 1, 108 IU/L on postoperative day 3, and 112 IU/L on postoperative day 6. Throughout the postoperative period, the patient exhibited no clinical signs suggestive of MH, such as hyperthermia, myalgia, or cola-colored urine. The postoperative course was uneventful and free of complications.

Genetic analysis was conducted in both the patient and his son. A comprehensive panel examining 50 genes associated with malignant hyperthermia, including RYR1 and CACNA1S (which encodes the voltage-gated calcium channel alpha-1S subunit), was performed. The patient was found to be homozygous for the RYR1 c.1589G>A (p.Arg530His) variant located in exon 15 (Figure 1).

Discussion

Propofol is commonly used for TIVA in patients who are susceptible to MH. In this case, however, remimazolam was chosen for a patient with a well-documented history of fulminant MH, and no clinical manifestations suggestive of MH occurred during either the intraoperative or postoperative periods.

Remimazolam is an ultra–short-acting benzodiazepine. Experimental in vitro investigations have shown that clinically relevant concentrations of remimazolam do not elevate intracellular calcium levels in human embryonic kidney (HEK-293) cells expressing mutant RYR1 [7]. Clinically, several reports have described the safe administration of remimazolam for general anesthesia in individuals suspected of having familial MH susceptibility, as well as in patients with clinically or genetically established MH [9–14]. However, most previous reports involved patients with suspected susceptibility or without a clearly documented prior MH episode. In contrast, the present case involved a patient with both a previous episode of fulminant MH and genetically confirmed MH susceptibility. This observation therefore provides additional clinical information regarding the feasibility of remimazolam-based TIVA in a high-risk MH-susceptible patient.

The RYR1 p.Arg530His variant is classified as “likely pathogenic” according to the ClinGen Malignant Hyperthermia Expert Panel–adapted ACMG/AMP guidelines and the diagnostic criteria by the European Malignant Hyperthermia Group (EMHG) [15] (Table 1). In this framework, a likely pathogenic classification indicates a greater than 90% probability that the variant is disease-causing.

Recent MH guidelines emphasize the growing importance of genetic testing, in conjunction with family history, for establishing a definitive diagnosis [1,3]. Individuals identified as carrying “pathogenic” or “likely pathogenic” variants are considered to be at increased risk of developing MH during exposure to triggering anesthetic agents. In the present case, anesthesia using remimazolam-based TIVA was performed without evidence of MH, supporting the feasibility of this approach in an individual with genetically confirmed susceptibility.

Additionally, a notable finding in the present case is that the patient was homozygous for the RYR1 c.1589G>A (p.Arg530His) variant. In the healthy Japanese population database maintained by the Tohoku Medical Megabank Organization (ToMMo), no heterozygous carriers of the RYR1 c.1589G>A (p.Arg530His) variant were identified among 61 106 individuals (Table 1). Similarly, in the Genome Aggregation Database version 4.1 (gnomAD v4.1 Exomes), the minor allele frequency is approximately 0.0029%, with 42 heterozygous carriers among 730 946 individuals and no reported homozygous cases (Table 1). These data indicate that homozygosity for RYR1 c.1589G>A (p.Arg530His) variant is extremely rare.

Previous studies suggest that biallelic RYR1 variants can influence the functional response of the ryanodine receptor. Rüffert et al reported that individuals homozygous for the RYR1 p.Arg614Cys variant exhibited stronger contracture responses in vitro than heterozygous carriers [16]. Furthermore, studies using knock-in mice expressing the pathogenic MH-associated RYR1 p.G2434R variant demonstrated significantly greater sensitivity to caffeine and KCl in homozygous mice than in heterozygous mice, even under resting conditions [17]. Based on these observations, a gene-dose effect may result in a more severe clinical phenotype in homozygous individuals than in heterozygous patients. It is possible that homozygosity for the RYR1 variant in the present patient may have contributed to the severity of the previous fulminant MH episode. However, previously reported homozygous MH-associated variants are exceedingly rare, and this interpretation remains speculative and cannot be confirmed based on a single clinical case.

In addition to considerations regarding MH susceptibility, the choice of remimazolam may also have been advantageous from a hemodynamic perspective. The patient had a history of cerebral infarction and internal carotid artery stenosis, necessitating careful avoidance of perioperative hypotension. Although propofol is considered safe in patients with MH-susceptibility, it is frequently associated with dose-dependent hypotension. Previous studies have reported that remimazolam is associated with less hypotension than propofol [18] and has the additional advantage of reversibility with flumazenil. Nevertheless, the potential hemodynamic benefits observed in this case should be interpreted cautiously, as conclusions cannot be drawn from a single observation. Further studies are required to clarify the safety profile of remimazolam in larger cohorts of patients with genetically confirmed MH susceptibility.

Conclusions

Remimazolam-based total intravenous anesthesia was successfully administered in a patient with genetically confirmed MH susceptibility carrying a homozygous likely pathogenic RYR1 variant, and the perioperative course was uneventful. Although conclusions cannot be reached from a single case, remimazolam may be a feasible anesthetic option in selected MH-susceptible patients, including those with cardiovascular risk factors, when administered under strict MH precautions. Further studies and accumulation of clinical experience are required to better define the safety profile of remimazolam in patients with genetically confirmed MH susceptibility.