Remimazolam-based total intravenous anesthesia in a patient with a confirmed diagnosis of malignant hyperthermia: a case report.

BACKGROUND: Malignant hyperthermia (MH) is a rare, life-threatening disorder of calcium homeostasis in skeletal muscle cells that is triggered by volatile anesthetics and succinylcholine, leading to a hypermetabolic reaction. The pathogenic ryanodine receptor 1 (RYR1) gene variant is critical. Patients susceptible to MH should avoid triggering agents, and total intravenous anesthesia (TIVA) is preferred. Remimazolam is safe in patients with suspected MH. CASE PRESENTATION: We present the first case of remimazolam treatment in a genetically confirmed patient with MH without MH development. A 72-year-old man with a family history of MH underwent remimazolam-based TIVA. After informed consent was obtained, a muscle biopsy and genetic testing were performed. Intraoperatively and postoperatively, the patient exhibited no signs of MH. An enhanced function of the RYR1 channel into releasing calcium was indicated, and the genetic testing revealed a pathogenic variant of RYR1. CONCLUSIONS: Remimazolam-based TIVA is safe in patients confirming the diagnosis of MH.

Rapid Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant Hyperthermia Events.

Purpose: Malignant hyperthermia (MH) is a rare genetic disorder but one of the most severe complications of general anesthesia. The mortality rate of MH has dropped from 70% in the 1960s to 15% because of dantrolene, the only currently accepted specific treatment for MH. In this study, we retrospectively identified the optimal dantrolene administration conditions to reduce MH mortality further. Methods: Our database performed a retrospective analysis of patients with MH clinical grading scale (CGS) grade 5 (very likely) or 6 (almost certain) between 1995 and 2020. We examined whether dantrolene administration affected mortality and compared the clinical variables associated with improved prognosis. Furthermore, a multivariable logistic regression analysis was used to identify specific variables associated with improved prognosis. Results: 128 patients met the inclusion criteria. 115 patients were administered dantrolene; 104 survived, and 11 died. The mortality rate of patients who were not administered dantrolene was 30.8%, which was significantly higher than those of patients who were administered dantrolene (P = 0.047). Among patients administered dantrolene, the interval from the first sign of MH to the start of dantrolene administration was significantly longer in the deceased than in the survivors (100 min vs. 45.0 min, P < 0.001), and the temperature at the start of dantrolene administration was also significantly higher in the deceased (41.6°C vs. 39.1°C, P < 0.001). There was no significant difference in the rate of increase in temperature between the two, but there was a substantial difference in the maximum temperature (P < 0.001). The multivariable analysis also showed that the patient's temperature at dantrolene administration and interval from the first MH sign to dantrolene administration was significantly associated with improved prognosis. Conclusions: Dantrolene should be given as rapidly as possible once MH has been diagnosed. Beginning treatment at a more normal body temperature can prevent critical elevations associated with a worse prognosis.

Malignant hyperthermia in a 16-day-old infant with congenital diaphragmatic hernia: a case report.

Malignant hyperthermia (MH) is a severe hypermetabolic disorder associated with dysregulation of calcium homeostasis and is triggered by inhalational anesthetics (isoflurane, sevoflurane, desflurane) and a depolarizing muscle relaxant (succinylcholine). We report the case of a 16-day-old infant undergoing laparoscopic surgery. The patient developed hyperthermia and hypercarbia with muscle rigidity. After the diagnosis of MH, dantrolene was administered with sufficient hydration. The patient was transferred to the pediatric intensive care unit for monitoring and treatment of acute renal injury due to myoglobinuria. Subsequently, two variants of the ryanodine receptor 1 (RYR1) gene were identified in the patient as the mutation point at c.1589G > A p.Arg530His and c.1841G > T p.Arg614Leu, which are known to be associated with MH. This was a rare case of MH in a 16-day-old infant that might be related to two RYR1 mutations inherited from the parents.

Retraction Note to: Functional analysis of newly identified RYR1 variants in patients susceptible to malignant hyperthermia.

The authors have retracted this article because they did not have permission to use the data in Tables 1 and 2.

Functional analysis of newly identified RYR1 variants in patients susceptible to malignant hyperthermia.

PURPOSE: This study aimed to evaluate whether the three ryanodine receptor type 1 (RYR1) variants (p.Ser2345Thr, p.Ser2345Arg, and p.Lys3367Arg) which we identified in Japanese malignant hyperthermia (MH) patients with a clinical grading scale rank of 6 were causative for MH. METHODS: We prepared human embryonic kidney (HEK)-293 cells transfected with wild-type RYR1 or one of the RYR1 variants, along with myotubes cultured from muscle pieces. Calcium kinetics were examined by calculating the 340/380-nm ratio under various caffeine and 4-chloro-m-cresol (4CmC) concentrations with the ratiometric dye Fura-2 AM. Half-maximal effective concentration (EC50) values were calculated from dose-response curves. Statistical analysis was based on one-way analysis of variance with a Dunnett's multiple comparison test, using a P value < 0.05 as evidence of statistical significance. RESULTS: In functional analysis using HEK-293 cells, we found significant reductions in the EC50 of p.Ser2345Thr and p.Ser2345Arg in comparison with wild-type RYR1 (P < 0.001), while the EC50 of p.Lys3367Arg was not significantly different (P = 0.062 for caffeine and P > 0.999 for 4CmC). On the other hand, functional analysis using myotubes showed significant differences in the EC50 values for all variants (P < 0.001 for all comparisons). CONCLUSIONS: p.Ser2345Thr and p.Ser2345Arg appear capable of causing a calcium metabolism disorder that leads to the onset of MH, and p.Ser2345Arg can be considered as a diagnostic mutation, because it meets the European Malignant Hyperthermia Group criteria. However, patients with p.Lys3367Arg might have mutations in genes other than RYR1 that are capable of causing MH.

Myotoxicity of local anesthetics is equivalent in individuals with and without predisposition to malignant hyperthermia.

PURPOSE: Malignant hyperthermia (MH) is an inherited muscle disorder caused by abnormal elevations of intracellular calcium (Ca2+) in skeletal muscle. There are several reports of myotoxicity caused by local anesthetics, and the increased intracellular Ca2+ is considered to be an important cause. However, there is insufficient evidence regarding myotoxicity in MH-susceptible individuals when large doses of local anesthetics are administered. This study investigated the effect of MH predisposition on myotoxicity. METHODS: Human skeletal muscle samples were obtained from 22 individuals to determine susceptibility to MH, and were evaluated according to whether their Ca2+-induced Ca2+ release (CICR) rates were accelerated or not. This study was performed using surplus muscle that remained after the CICR rate test. We calculated the 50% effective concentration (EC50) values of three local anesthetics, namely lidocaine, levobupivacaine, and ropivacaine using the ratiometric dye Fura-2 AM. Significance was tested using the unpaired t test. RESULTS: In the accelerated and unaccelerated groups, respectively, the mean ± SD of the EC50 values were 1.52 ± 0.72 and 1.75 ± 0.37 mM for lidocaine (p = 0.42), 0.72 ± 0.36 and 0.79 ± 0.46 mM for levobupivacaine (p = 0.68), and 1.21 ± 0.35 and 1.62 ± 0.57 mM for ropivacaine (p = 0.06). These values were similar in individuals with and without MH predisposition. CONCLUSION: The myotoxicity of local anesthetics was equivalent in individuals with and without predisposition to MH.

Genetic and functional analysis of the RYR1 mutation p.Thr84Met revealed a susceptibility to malignant hyperthermia.

PURPOSE: The aim of this study was to analyze the genetic and functional role of a novel RYR1 variant c.251 C > T (p.Thr84Met) identified in a patient with muscle weakness demonstrating MH susceptibility. METHODS: DNA testing of family members was conducted for assessment of pathogenicity of the genetic variant. For functional analysis, Ca2+ measurement using patient-derived myotubes and p.Thr84Met RYR1-transfected human embryonic kidney (HEK)-293 cells was performed to evaluate reactivity to RYR1 activators. The half-maximal effective concentration (EC50) values of two RYR1 activators, caffeine and 4-chloro-m-cresol (4CmC), were calculated from the acquired dose-response curves. The EC50 was compared between two groups: for myotubes, the control group and the patient, and for HEK-293 cells, WT and p.Thr84Met. RESULTS: Dose-response curves for caffeine and 4CmC were shifted to the left in both myotubes and HEK-293 cells compared to controls. The 50% effective concentration values for caffeine and 4CmC were significantly lower in both myotubes and HEK-293 cells compared to controls (P < 0.001 for all comparisons). CONCLUSIONS: Our results of functional testing indicated RYR1 hypersensitivity to caffeine and 4CmC. We conclude that the genetic variant was associated with MH susceptibility.

[Anesthetic management of a patient with Creutzfeldt-Jacob disease undergoing tracheal separation].

We gave anesthesia for tracheal separation in a patient with Creutzfeldt-Jakob disease. The patient, a 33-year-old woman, was bedridden and unable to communicate, and was going to undergo a tracheal separation procedure for repeated bouts of aspiration pneumonia. After a tracheostomy with local anesthesia and sedation with propofol, general anesthesia was induced and maintained with propofol (1.5-3.0 microg x ml(-1), target controlled infusion) and remifentanil (0.05-0.15 microg x kg(-1) x min(-1)). We did not use an anesthetic apparatus from the standpoint of infection control, and provided manual ventilation with a disposable Jackson-Rees circuit. During the operation, an entropy monitor indicated alternating extremely low (0-10) and high (90-100) values without circulatory change, probably due to a previously existing electroencephalographic abnormality. The surgery was uneventful, and spontaneous breathing and eyelid opening occurred about 10 minutes after discontinuation of remifentanil and propofol. In such infected patients, abnormal prion proteins can exist outside of the central nervous system throughout the period of anesthetic management. Therefore, careful infection control must be undertaken, even if the surgical site is not directly related to the central nervous system.