Malignant Hyperthermia Patients Research Articles

Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants.

Remimazolam is a novel general anesthetic and its safety in patients with malignant hyperthermia (MH) is unknown. We used myotubes derived from the skeletal muscle of patients with MH to examine the response to ryanodine receptor 1 (RYR1) agonist and remimazolam in MH-susceptible patients. Patients underwent muscle biopsy for the Ca2+-induced Ca2+ release (CICR) rate test, a diagnostic tool for MH in Japan. Ten patients had myotubes obtained from skeletal muscle cultures, and the genes associated with malignant hyperthermia in these patients were analyzed. The EC50 of caffeine, cresol, and remimazolam to induce intracellular calcium concentration change were compared between myotubes from CICR-negative genetic test patients and myotubes from other patients. Eight of the ten were CICR-positive, five of whom had RYR1 causative gene mutations or variants. Two patients had CICR-negative genetic tests, and as expected had the highest EC50 (the concentration of a drug that gives a half-maximal response) in response to caffeine, 4CmC and remimazolam. Three patients had a positive CICR but no known variants in RYR1 or CACNA1S (voltage-gated calcium channel subunit alpha1S). Myotubes in these patients had significantly lower EC50s for all agents than myotubes in CICR-negative patients. When myotubes from a patient who was CICR-negative and had no gene variant were used as a control, myotubes from CICR-positive patients were more hyper-responsive than controls to all stimulants used. The EC50 for remimazolam was lowest for myotubes from CICR-positive, RYR1-mutant patients, at 206 µM (corresponding to 123 µg/mL). The concentration was more than 80-times higher than the clinical concentration. RYR1 gene variants in R4645Q and W5020G were shown to be causative gene mutations for MH. Intracellular calcium in myotubes from MH patients are elevated at high concentrations of remimazolam but not at clinically used concentrations of remimazolam. Remimazolam appears to be safe to use in patients with MH.

Clinical Features of Suspected Malignant Hyperthermia in China from 2015 to 2020: A Retrospective Study from China Malignant Hyperthermia Emergency Assistance Group.

Malignant hyperthermia (MH) is a rare but fatal pharmacogenetic disorder, triggered by inhalational anesthetics or succinylcholine. Since the first nonprofit academic organization China Malignant Hyperthermia Emergency Assistance WeChat-based Group (CMHEA Group) was established in 2015, they have actively participated in the diagnosis and treatment of MH patients. Based on the CMHEA Group, the aim of the study was to retrospectively analyze the characteristics of suspected MH in China from 2015 to 2020. We conducted a retrospective analysis of the suspected MH patients from 2015 to 2020, for analyzing the current clinical diagnosis, treatment and prognosis of MH in China. A total of 58 suspected MH cases occurred from 2015 to 2020, of these, 36 cases were collected with detailed data. The MH clinical grading score of 36 patients ranged from 33 to 73, with a median of 55. Abnormal hyperthermia and hypercarbia were the most common early signs of MH. Four patients were confirmed carrying six different potential MH-causative mutations. Of the total 58 cases, 14 patients (24.1%) received dantrolene and the whole mortality rate was 53.4%. Compared to the patients not receiving dantrolene treatment, the survival rate of patients receiving dantrolene treatment was significantly higher than that of patients not receiving dantrolene (78.6% vs 36.4%, p = 0.007). The current main diagnostic methods of suspected MH in China are still clinical diagnosis. Hence, it is critical to keep dantrolene for immediate accessibility with the introduction of domestic dantrolene to China. The WeChat group model has played an important but limited role in quick diagnosis and treatment of MH.

Risk of malignant hyperthermia in patients carrying a variant in the skeletal muscle ryanodine receptor 1 gene

Malignant hyperthermia is a life-threatening disorder, which can be prevented by avoiding certain anesthetic agents. Pathogenic variants in the skeletal muscle ryanodine receptor 1-gene are linked to malignant hyperthermia. We retrospectively studied 15 patients who presented to our clinic with symptoms of muscle dysfunction (weakness, myalgia or cramps) and were later found to have a variant in the skeletal muscle ryanodine receptor 1-gene. Symptoms, creatine kinase levels, electromyography, muscle biopsy and in vitro contracture test results were reviewed. Six out of the eleven patients, with a variant of unknown significance in the skeletal muscle ryanodine receptor 1-gene, had a positive in vitro contracture test, indicating malignant hyperthermia susceptibility. In one patient, with two variants of unknown significance, both variants were required to express the malignant hyperthermia-susceptibility trait. Neurologists should consider screening the skeletal muscle ryanodine receptor 1-gene in patients with myalgia or cramps, even when few to no abnormalities on ancillary testing.

Development of a water-soluble ryanodine receptor 1 inhibitor

Ryanodine receptor 1 (RyR1) is a Ca2+-release channel expressed on the sarcoplasmic reticulum (SR) membrane. RyR1 mediates release of Ca2+ from the SR to the cytoplasm to induce muscle contraction, and mutations associated with overactivation of RyR1 cause lethal muscle diseases. Dantrolene sodium salt (dantrolene Na) is the only approved RyR inhibitor to treat malignant hyperthermia patients with RyR1 mutations, but is poorly water-soluble. Our group recently developed a bioassay system and used it to identify quinoline derivatives such as 1 as potent RyR1 inhibitors. In the present study, we focused on modification of these inhibitors with the aim of increasing their water-solubility. First, we tried reducing the hydrophobicity by shortening the N-octyl chain at the quinolone ring of 1; the N-heptyl compound retained RyR1-inhibitory activity, but the N-hexyl compound showed decreased activity. Next, we introduced a more hydrophilic azaquinolone ring in place of quinolone; in this case, only the N-octyl compound retained activity. The sodium salt of N-octyl azaquinolone 7 showed similar inhibitory activity to dantrolene Na with approximately 1,000-fold greater solubility in saline.

RyR1 Mutation Associated with Malignant Hyperthermia Induces Cardiac Arrythmia via Mitochondrial Calcium Overload

Introduction The “leaky” gain-of-function mutations of the ryanodine receptor type 1 (RyR1) are linked to skeletal muscle disorders, including malignant hyperthermia (MH), which occurs in response to particular medications used during general anesthesia. In addition to a severe reaction to particular anesthetic drugs, sudden cardiac death (SCD) in MH patients has been also reported to occur in non-anesthesia conditions. However, the molecular mechanism of SCD associated with MH remains unresolved. Although the major RyR isoform expressed in the heart is RyR2, we previously reported a low level of RyR1 expression in cardiac mitochondria but not in the sarcoplasmic reticulum (SR). Hypothesis Chronic mitochondrial Ca2+ overload through the ‘leaky’ RyR1 expressed in the cardiac mitochondria induces mitochondrial injury and oxidative stress leading to cardiac arrhythmia. Methods We utilized a knock-in mouse model carrying a human RyR1 MH mutation Y522S (YS) and assessed in vivo and ex vivo cardiac function. Cardiac mitochondria and ventricular myocytes were isolated from heterozygous YS and wild type (WT) mouse hearts for in situ assays. Results Both WT and heterozygous YS hearts possessed RyR1 expression in the mitochondria but not in SR, but only the heterozygous YS hearts showed disrupted mitochondrial morphology, damaged myofibrils, and high cellular oxidative state. In addition, isolated YS mitochondria showed higher basal mitochondrial Ca2+ concentration, and depolarized mitochondrial membrane potential. However, isolated YS ventricular myocytes possessed higher levels of mitochondrial reactive oxygen species and slower cytosolic Ca2+ clearance compared to controls. However, pretreating YS mitochondria/ ventricular myocytes with a clinically approved anti-MH drug and a RyR blocker, dantrolene, prevented these changes and normalized their Ca2+ handling profiles. Although the in vivo basal cardiac function was comparable to the WT, the YS heart was insensitive to isoproterenol-induced positive inotropy and chronotropy due to a higher level of catecholamine signaling at baseline. However, ex vivo YS (but not WT) hearts frequently developed multiple ventricular extrasystoles in response to isoproterenol bolus. Optical mapping of YS hearts showed increased early after-depolarization (EAD) and premature ventricular contractions (PVC) in response to isoproterenol, which was effectively abolished by dantrolene treatment. Conclusion: Chronic mitochondrial Ca2+ overload via ‘leaky’ RyR1 disrupts cardiac mitochondrial functions and structures and increases the vulnerability to ventricular arrhythmia by catecholamine.

Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group

Malignant hyperthermia is a potentially fatal condition, in which genetically predisposed individuals develop a hypermetabolic reaction to potent inhalation anaesthetics or succinylcholine. Because of the rarity of malignant hyperthermia and ethical limitations, there is no evidence from interventional trials to inform the optimal perioperative management of patients known or suspected with malignant hyperthermia who present for surgery. Furthermore, as the concentrations of residual volatile anaesthetics that might trigger a malignant hyperthermia crisis are unknown and manufacturers' instructions differ considerably, there are uncertainties about how individual anaesthetic machines or workstations need to be prepared to avoid inadvertent exposure of susceptible patients to trigger anaesthetic drugs. The present guidelines are intended to bundle the available knowledge about perioperative management of malignant hyperthermia-susceptible patients and the preparation of anaesthesia workstations. The latter aspect includes guidance on the use of activated charcoal filters. The guidelines were developed by members of the European Malignant Hyperthermia Group, and they are based on evaluation of the available literature and a formal consensus process. The most crucial recommendation is that malignant hyperthermia-susceptible patients should receive anaesthesia that is free of triggering agents. Providing that this can be achieved, other key recommendations include avoidance of prophylactic administration of dantrolene; that preoperative management, intraoperative monitoring, and care in the PACU are unaltered by malignant hyperthermia susceptibility; and that malignant hyperthermia patients may be anaesthetised in an outpatient setting.

Next-generation sequencing and bioinformatics to identify genetic causes of malignant hyperthermia

Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disease with only two known causative genes, RYR1 and CACNA1S. Both are huge genes containing numerous exons, and they reportedly only account for 50-70% of known MH patients. Next-generation sequencing (NGS) technology and bioinformatics could help delineate the genetic diagnosis of MH and several MH-like clinical presentations. We established a capture-based targeted NGS sequencing framework to examine the whole genomic regions of RYR1, CACNA1S and the 16.6 Kb mitochondrial genome, as well as 12 other genes related to excitation-contraction coupling and/or skeletal muscle calcium homeostasis. We applied bioinformatics analyses to the variants identified in this study and also to the 48 documented RYR1 pathogenic variants. The causative variants were identified in seven of the eight (87.5%) MH families, but in none of the 10 individuals classified as either normal controls (N = 2) or patients displaying MH-like clinical features later found to be caused by other etiologies (N = 8). We showed that RYR1 c.1565A>G (p.Tyr522Cys)(rs118192162) could be a genetic hot spot in the Taiwanese population. Bioinformatics analyses demonstrated low population frequencies and predicted damaging effects from all known pathogenic RYR1 variants. We estimated that more than one in 1149 individuals worldwide carry MH pathogenic variants at RYR1. NGS and bioinformatics are sensitive and specific tools to examine RYR1 and CACNA1S for the genetic diagnosis of MH. Pathogenic variants in RYR1 can be found in the majority of MH patients in Taiwan.

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

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. 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. 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). 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.

Neurogenética

Findings in genomic sequencing will expand the knowledge of many inherited neurological disorders, which will make the diagnosis easier. Patient phenotype and clinical findings are the main elements to order the tests required. Whole exome sequencing techniques will be very useful to elucidate the genetic basis of a disease or to reveal the causes of uncommon neurological disorders. Genetic tests will be chosen depending on the suspected disease. Genetic counselling is essential for those who have neurological disorders and their families. Besides, the identification of genetic alteration will also allow preventing complications, for example malignant hyperthermia in patients with neuromuscular disorders. Future pharmacogenomics will enable the assessment of side effect risk and to individualize dosage and treatment.

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

ObjectiveThe histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases.MethodsWe performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987–2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible.ResultsThrough the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants.ConclusionsPatients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.

Incidence of malignant hyperthermia in patients undergoing general anesthesia: Protocol for a systematic review and meta-analysis.

Malignant hyperthermia (MH) continues to be of potential concern for clinicians whenever inhalational anesthetic agents or succinylcholine are used, because MH is a potentially fatal metabolic disorder. A systematic and comprehensive search will be performed using MEDLINE, EMBASE, and Google Scholar, for studies published up to November 2017. Peer-reviewed prospective cohort studies, retrospective cohort studies, and cross-sectional studies or reports issued by government organizations reporting the incidence or prevalence of MH will be eligible for inclusion. The quality of included studies will be assessed using the Newcastle-Ottawa scale and the modified risk of bias tool. Heterogeneity of estimates across studies as well as publication bias will be assessed. This systematic review and meta-analysis will be performed according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. All statistical analyses will be conducted using the Stata SE version 15.0. The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. To our knowledge, this systematic review and meta-analysis will be the first to evaluate existing research on the incidence of MH. Our study will provide an overall estimate of the incidence of MH. Subgroup analysis will assess the incidence of MH according to age, gender, geographical region, race, and the provoking agent if possible. The review will benefit patients, healthcare providers, and policymakers. Ethical approval and informed consent are not required, as the study will be a literature review and will not involve direct contact with patients or alterations to patient care. The protocol for this review has been registered in the PROSPERO network (registration number: CRD42017076628).

Malignant Hyperthermia‐associated Mutation of RyR1 Induces Mitochondrial Damages and Cellular Oxidation in the Heart

Human pedigrees carrying the ryanodine receptor type 1 (RyR1) mutations frequently show skeletal muscle (SM) disorders including malignant hyperthermia (MH). There are also case reports describing sudden cardiac death (SCD) in MH patients in the conscious condition without anesthesia. These observations cannot be explained as a secondary effect of their SM dysfunction; however, the molecular mechanism underlying cardiac phenotypes in MH is still unknown. We previously reported that a low level of RyR1 is expressed in the mitochondria (termed as mitochondrial RyR1: mRyR1), but not in the sarcoplasmic reticulum (SR) in the cardiomyocytes and serves as an important mitochondrial Ca2+ influx pathway in addition to the mitochondrial Ca2+ uniporter in cardiomyocytes. We also reported, using knock‐in mice carrying a MH‐related RyR1 mutation Y522S (YS) that YS hearts exhibit disrupted mitochondrial morphology as well as compromised mitochondrial functions with a high cellular oxidative state, which can account for cardiac phenotypes in MH. In addition, YS heart developed multiple ventricular extrasystoles by β‐adrenergic stimulation. Therefore, we hypothesize that YS‐RyR1s form “leaky channel” at mitochondria and induce mitochondrial Ca2+ overload, which alters the cellular Ca2+ handling in cardiomyocyte. Using isolated mitochondria or isolated cardiomyocytes under confocal microscope, we found that YS cardiomyocytes have higher basal mitochondrial Ca2+ concentration, depolarized mitochondrial membrane potential and slower cytosolic Ca2+ clearance as compared to WT. Moreover, pretreatment of RyR1 blocker dantrolene prevented these changes in YS cardiomyocytes and normalized their Ca2+ handling profiles similar to those in WT. In conclusion, these results indicate that chronic mitochondrial Ca2+ overload via leaky mutant mRyR1 damages cardiac mitochondrial functions/structures, reduces cytosolic Ca2+ buffering capacity and induces cellular oxidation, which may increase arrhythmogenic events in MH.Support or Funding InformationThis work was partly supported by American Heart Association (AHA) grant (14BGIA18830032 to J.O.‐U.), Medical Research Grant from W.W. Smith Charitable Trust (H1403 to J.O.‐U.) and NIH grants (2R01HL093671 and 1R01HL122124 to SSS).

Correlation of Molecular Dynamics Analysis and Calcium Signaling in Mutant Ryanodine Receptors

Ryanodine receptors (RyRs), located in the endoplasmic reticulum (ER) membrane, are required for intracellular Ca2+ release. Mutations in RyR1 can lead to severe genetic conditions that affect skeletal muscle, e.g., malignant hyperthermia (MH). More than 150 mutations in the RyR1 gene have been reported in MH patients. However, there were only a few experimental results confirming those mutations being responsible for the increment of the CICR sensitivities, since such a long cDNA of RyR1 not only required much complicated procedures for making desired mutations but also caused its low transfection efficiency of the mutant DNAs. We investigated properties of the RyR1 channels carrying disease-associated mutations at the N-terminal region. HEK293 cells expressing the mutant RyR1 channels exhibited alterations in Ca2+ homeostasis, i.e., enhanced caffeine sensitivity, decrease of ER Ca2+ contents, increases in resting cytoplasmic Ca2+ concentration, changes in mitochondrial morphology, changes in pattern of electrostatic interaction. These results suggest that exploration of the functional mutations of RyR1 is probably effective in preventive diagnosis of patients associated with MH disease.

'Jaws of steel' after rocuronium.

Sir, A 60-year-old lady was admitted to the Intensive Care Unit of our hospital with complaints of shortness of breath. She was a diagnosed case of dilated cardiomyopathy with left ventricular failure. Arterial blood gas analysis revealed severe hypoxia with metabolic acidosis. Adrenaline infusion was started to optimise blood pressure. Intravenous frusemide was administered to relieve pulmonary oedema. Bilevel positive airway pressure was applied to improve oxygenation. After 1 h, patient was still hypoxic with laboured respiration; hence, it was decided to intubate patient electively and start mechanical ventilation. Her airway assessment revealed Mallampati class of 2 with good mouth opening. Intravenous midazolam 1 mg and fentanyl 50 µg were given; as bag and mask ventilation was adequate, rocuronium intravenous 50 mg was administered to facilitate muscle relaxation for intubation. After 1 min, an attempt was made to open the mouth, but severe jaw stiffness did not allow it. Injection rocuronium 20 mg was repeated, and bag and mask ventilation was continued for another 2 min. Oxygen saturation was maintained at 95% on 100% oxygen with bag and mask ventilation. Again, intubation attempt was made; however, jaw could not be opened with any force. As last resort, blind nasal intubation was done. Bilateral chest auscultation confirmed tracheal intubation. Except for the jaw muscle rigidity, other muscle spasm or rigidity in the body was not observed. The patient's body temperature was 36°C. End tidal expired CO2 was 32 mm Hg with tidal volume of 400 ml and respiratory rate of 12/min on mechanical ventilation. Haemodynamics were deteriorating despite maximal inotropic therapy with progressively increasing metabolic acidosis. The patient had repeated episodes of ventricular fibrillation and received multiple defibrillatory shocks. The patient could not be revived despite all efforts. Masseter muscle rigidity (MMR) also referred as ‘jaw of steel’ is severe stiffness of the jaw, with inability to open the mouth causing difficult or impossible laryngoscopy.[1] MMR is commonly seen after administration of succinylcholine and volatile agents.[2] MMR has also been quoted as an early sign of malignant hyperthermia (MH).[3] Muscle spasm following succinylcholine causing masseter spasm can lead to clinical MH in 30% of cases.[4] However, implications related to non-depolarising muscle relaxants have also been reported.[5] Jenkins reported a case of MMR after vecuronium.[6] Masseter spasm after pancuronium administration in a patient undergoing aortic valvulotomy has been reported.[7] A similar case of persistent masseter spasm during anaesthesia has been reported, where the authors attributed the spasm to increased extreme pre-operative anxiety rather than rocuronium.[8] Fentanyl in high dose can cause rigidity but in the present case, it was used in a low dose. Masseter spasm has the potential to complicate airway management, but no reported case has been shown to progress to generalised rigidity and MH. In the present case, we did not observe any signs of MH such as raised temperature, raised EtCO2 and generalised muscle rigidity. Non-depolarising muscle relaxants can be used safely in MH patients. Failed intubation in such scenario can be an important cause of morbidity and mortality. Nasopharyngeal airways can be placed and ventilation carried out and can be life saving. Sporadic case reports have suggested different techniques for airway management after MMR like fibreoptic nasotracheal intubation, retrograde endotracheal intubation, surgical cricothyrotomy and use of Trachlight®.[9] Though rare, one must be aware of MMR after using muscle relaxants. In case of any incident of masseteric spasm, the aim should be to maintain adequate oxygenation by any means. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Is there a link between exertional heat stroke and susceptibility to malignant hyperthermia?

ObjectiveThe identification of a predisposition toward malignant hyperthermia (MH) as a risk factor for exertional heat stroke (EHS) remains a matter of debate. Such a predisposition indicates a causal role for MH susceptibility (MHS) after EHS in certain national recommendations and has led to the use of an in vitro contracture test (IVCT) to identify the MHS trait in selected or unselected EHS patients. The aim of this study was to determine whether the MHS trait is associated with EHS.MethodsEHS subjects in the French Armed Forces were routinely examined for MHS after experiencing an EHS episode. This retrospective study compared the features of IVCT-diagnosed MHS (iMHS) EHS subjects with those of MH-normal EHS patients and MH patients during the 2004–2010 period. MHS status was assessed using the European protocol.ResultsDuring the study period, 466 subjects (median age 25 years; 31 women) underwent MHS status investigation following an EHS episode. None of the subjects reported previous MH events. An IVCT was performed in 454 cases and was diagnostic of MHS in 45.6% of the study population, of MH susceptibility to halothane in 18.5%, of MH susceptibility to caffeine in 9.9%, and of MH susceptibility to halothane and caffeine in 17.2%. There were no differences in the clinical features, biological features or outcomes of iMHS EHS subjects compared with those of MH-normal or caffeine or halothane MHS subjects without known prior EHS episode. The recurrence rate was 12.7% and was not associated with MH status or any clinical or biological features. iMHS EHS patients exhibited a significantly less informative IVCT response than MH patients.ConclusionsThe unexpected high prevalence of the MHS trait after EHS suggested a latent disturbance of calcium homeostasis that accounted for the positive IVCT results. This study did not determine whether EHS patients have an increased risk of MH, and it could not determine whether MH susceptibility is a risk factor for EHS.

Malignant hyperthermia, a Scandinavian update.

Malignant Hyperthermia (MH) is a rare pharmacogenetic disorder, triggered by halogenated anesthetics and/or succinylcholine. In susceptible individuals, these drugs can activate an explosive life threatening clinical reaction. Leading symptoms are hypercarbia, muscle rigidity, and metabolic acidosis. MH is inherited in an autosomal-dominant manner and linked to mutations in the large ryanodine 1 gene (RYR1) gene in the majority of cases. Very few MH patients have been found to carry mutations in the CACNA1S gene. For this review a large litterature search was carried out and the Swedish MH database consisting of 436 probands who have undergone invitro muscle contraction test (IVCT) during 1984-2014 was analyzed. Twelve different MH causative mutations have been found in Swedish patients so far. These mutations lead to a disturbed calcium balance in striated muscle tissue. A muscle biopsy for the IVCT or finding of an approved causative mutation are required for the diagnosis. A Malignant Hyperthermia susceptible (MHS) patient should be anesthetized with trigger-free anesthesia. There are a few reports of MH-like reactions in patients unrelated to anesthesia. The outcome is dependent on early recognizing of the reaction and fast disconnection of the trigger agents and administration of dantrolene.

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness.

Variants in RYR1 are associated with the majority of cases of malignant hyperthermia (MH), a form of heat illness pharmacogenetically triggered by general anesthetics, and they have also been associated with exertional heat illness (EHI). CACNA1S has also been implicated in MH. The authors applied a targeted next-generation sequencing approach to identify variants in RYR1 and CACNA1S in a cohort of unrelated patients diagnosed with MH susceptibility. They also provide the first comprehensive report of sequencing of these two genes in a cohort of survivors of EHI. DNA extracted from blood was genotyped using a "long" polymerase chain reaction technique, with sequencing on the Illumina GAII or MiSeq platforms (Illumina Inc., USA). Variants were assessed for pathogenicity using bioinformatic approaches. For further follow-up, DNA from additional family members and up to 211 MH normal and 556 MH-susceptible unrelated individuals was tested. In 29 MH patients, the authors identified three pathogenic and four novel RYR1 variants, with a further five RYR1 variants previously reported in association with MH. Three novel RYR1 variants were found in the EHI cohort (n = 28) along with two more previously reported in association with MH. Two other variants were reported previously associated with centronuclear myopathy. The authors found one and three rare variants of unknown significance in CACNA1S in the MH and EHI cohorts, respectively. Targeted next-generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and EHI.

Safe duration of postoperative monitoring for malignant hyperthermia patients administered non-triggering anaesthesia: an update.

The postoperative care of malignant hyperthermia (MH) patients is subject to international variation, with a paucity of data in the literature to guide management. Over a series of three studies, our aim was to evaluate whether MH-susceptible patients (and relatives who had not yet been investigated), who had received a non-triggering anaesthetic, could be managed in the same way as the standard surgical population. Following a retrospective study, 206 anaesthetics were administered in a prospective second study to MH-susceptible/related individuals who were monitored for a minimum of one hour in the post anaesthesia care unit and a further 90 minutes in a step-down facility. No problems relating to MH were encountered. The postoperative monitoring time was subsequently changed and, in a third study, patients were managed no differently from standard surgical patients. One hundred and twenty-five anaesthetics were administered with no evidence of problems. This data shows that standard postoperative monitoring times are safe and appropriate in MH-susceptible patients.

Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States.

AMRA (adverse metabolic or muscular reaction to anesthesia) reports submitted to The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States from 1987 to 2006 revealed a 2.7% cardiac arrest and a 1.4% death rate for 291 malignant hyperthermia (MH) events. We analyzed 6 years of recent data to update MH cardiac arrest and death rates, summarized characteristics associated with cardiac arrest and death, and documented differences between early and recent cohorts of patients in the MH Registry. We also tested whether the available data supported the hypothesis that risk of dying from an episode of MH is increased in patients with inadequate temperature monitoring. We included U.S. or Canadian reports of adverse events after administration of at least 1 anesthetic drug, received between January 1, 2007, and December 31, 2012, with an MH clinical grading scale rank of "very likely MH" or "almost certain MH." We excluded reports that, after review, were judged to be due to pathologic conditions other than MH. We analyzed patient demographics, family and patient anesthetic history, anesthetic management including temperature monitoring, initial dantrolene dose, use of cardiopulmonary resuscitation, MH complications, survival, and reported molecular genetic DNA analysis of RYR1 and CACNA1S. A one-sided Cochran-Armitage test for proportions evaluated associations between mode of monitoring and mortality. We used Miettinen and Nurminen's method for assessing the relative risk of dying according to monitoring method. We used the P value of the slope to evaluate the relationship between duration of anesthetic exposure before dantrolene administration and peak temperature. We calculated the relative risk of death in this cohort compared with our previous cohort by using the Miettinen and Nurminen method adjusted for 4 comparisons. Of 189 AMRA reports, 84 met our inclusion criteria. These included 7 (8.3%) cardiac arrests, no successful resuscitations, and 8 (9.5%) deaths. Of the 8 patients who died, 7 underwent elective surgeries considered low to intermediate risk. The average age of patients who died was 31.4 ± 16.9 years. Five were healthy preoperatively. Three of the 8 patients had unrevealed MH family history. Four of 8 anesthetics were performed in freestanding facilities. In those who died, 3 MH-causative RYR1 mutations and 3 RYR1 variants likely to have been pathogenic were found in the 6 patients in whom RYR1 was examined. Compared to core temperature monitoring, the relative risk of dying with no temperature monitoring was 13.8 (lower limit 2.1). Compared to core temperature monitoring, the relative risk of dying with skin temperature monitoring was 9.7 (1.5). Temperature monitoring mode best distinguished patients who lived from those who died. End-tidal CO2 was the worst physiologic measure to distinguish patients who lived from those who died. Longer anesthetic exposures before dantrolene were associated with higher peak temperatures (P = 0.00056). Compared with the early cohort, the recent cohort had a higher percentage of MH deaths (4/291 vs 8/84; relative risk = 6.9; 95% confidence interval, 1.7-28; P = 0.0043 after adjustment for 4 comparisons). Despite a thorough understanding of the management of MH and the availability of a specific antidote, the risk of dying from an MH episode remains unacceptably high. To increase the chance of successful MH treatment, the American Society of Anesthesiologists and Malignant Hyperthermia Association of the U.S. monitoring standards should be altered to require core temperature monitoring for all general anesthetics lasting 30 minutes or longer.

Two different variants of p.2508 in Japanese malignant hyperthermia patients causing hypersensitivity of ryanodine receptor 1

Two different variants of p.2508 in Japanese malignant hyperthermia patients causing hypersensitivity of ryanodine receptor 1