Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review.

Malignant hyperthermia susceptibility (MHS) designates individuals at risk of developing a hypermetabolic reaction triggered by halogenated anaesthetics or the depolarising neuromuscular blocking agent suxamethonium. Over the past few decades, beyond the operating theatre, myopathic manifestations impacting daily life are increasingly recognised as a prevalent phenomenon in MHS patients. At the request of the European Malignant Hyperthermia Group, we reviewed the literature and gathered the opinion of experts to define MHS-related myopathy as a distinct phenotype expressed across the adult lifespan of MHS patients unrelated to anaesthetic exposure; this serves to raise awareness about non-anaesthetic manifestations, potential therapies, and management of MHS-related myopathy. We focused on the clinical presentation, biochemical and histopathological findings, and the impact on patient well-being. The spectrum of symptoms of MHS-related myopathy encompasses muscle cramps, stiffness, myalgias, rhabdomyolysis, and weakness, with a wide age range of onset mainly during adulthood. Histopathological analysis can reveal nonspecific abnormalities suggestive of RYR1 involvement, while metabolic profiling reflects altered energy metabolism in MHS muscle. Myopathic manifestations can significantly impact patient quality of life and lead to functional limitations and socio-economic burden. While currently available therapies can provide symptomatic relief, there is a need for further research into targeted treatments addressing the underlying pathophysiology. Counselling early after establishing the MHS diagnosis, followed by multidisciplinary management involving various medical specialties, is crucial to optimise patient care.

Molecular Modification of Transient Receptor Potential Canonical 6 Channels Modulates Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia.

BACKGROUND: Pharmacologic modulation has previously shown that transient receptor potential canonical (TRPC) channels play an important role in the pathogenesis of malignant hyperthermia. This study tested the hypothesis that genetically suppressing the function of TRPC6 can partially ameliorate muscle cation dyshomeostasis and the response to halothane in a mouse model relevant to malignant hyperthermia. METHODS: This study examined the effect of overexpressing a muscle-specific nonconducting dominant-negative TRPC6 channel in 20 RYR1-p.R163C and 20 wild-type mice and an equal number of nonexpressing controls, using calcium- and sodium-selective microelectrodes and Western blots. RESULTS: RYR1-p.R163C mouse muscles have chronically elevated intracellular calcium and sodium levels compared to wild-type muscles. Transgenic expression of the nonconducting TRPC6 channel reduced intracellular calcium from 331 ± 34 nM (mean ± SD) to 190 ± 27 nM (P < 0.0001) and sodium from 15 ± 1 mM to 11 ± 1 mM (P < 0.0001). Its expression lowered the increase in intracellular Ca2+ of the TRPC6-specific activator hyperforin in RYR1-p.R163C muscle fibers from 52% (348 ± 37 nM to 537 ± 70 nM) to 14% (185 ± 11 nM to 210 ± 44 nM). Western blot analysis of TRPC3 and TRPC6 expression showed the expected increase in TRPC6 caused by overexpression of its dominant-negative transgene and a compensatory increase in expression of TRPC3. Although expression of the muscle-specific dominant-negative TRPC6 was able to modulate the increase in intracellular calcium during halothane exposure and prolonged life (35 ± 5 min vs. 15 ± 3 min; P < 0.0001), a slow, steady increase in calcium began after 20 min of halothane exposure, which eventually led to death. CONCLUSIONS: These data support previous findings that TRPC channels play an important role in causing the intracellular calcium and sodium dyshomeostasis associated with RYR1 variants that are pathogenic for malignant hyperthermia. However, they also show that modulating TRPC channels alone is not sufficient to prevent the lethal effect of exposure to volatile anesthetic malignant hyperthermia-triggering agents.

Dietary Caffeine Synergizes Adverse Peripheral and Central Responses to Anesthesia in Malignant Hyperthermia Susceptible Mice.

Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca2+ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MH susceptibility. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MH susceptibility mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 (HET) MH susceptible mice are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane (HAL) maintenance anesthesia under experimental conditions that maintain normal core body temperature. HET mice receiving CAF (plasma CAF 893 ng/ml) have significantly shorter times to respiratory arrest compared with wild type, without altering blood chemistry or displaying hyperthermia or muscle rigor. Intraperitoneal bolus dantrolene before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline electroencephalogram (EEG) total power, but significantly shortens delay to isoelectric EEG, which precedes respiratory and cardiac arrest. CAF ± HAL are studied on RYR1 single-channel currents and HET myotubes to define molecular mechanisms of gene-by-environment synergism. Strong pharmacological synergism between CAF and HAL is demonstrated in both single-channel and myotube preparations. Central and peripheral nervous systems mediate adverse responses to HAL in a HET model of MH susceptibility exposed to dietary CAF, a modifiable lifestyle factor that may mitigate risks of acute and chronic diseases associated with RYR1 mutations. SIGNIFICANCE STATEMENT: Dietary caffeine at a human-relevant dose synergizes adverse peripheral and central responses to anesthesia in malignant hyperthermia susceptible mice. Synergism of these drugs can be attributed to their actions at ryanodine receptors.

Overactivation of the sodium-calcium exchanger and transient receptor potential in anesthesia-induced malignant hyperthermia.

Malignant hyperthermia is a pharmacogenetic disorder, which is an uncommon but frequently fatal intricacy of inhalation anesthesia in man. It causes a quick rise in body temperature to highly irreversible levels, which causes death in around three of four cases. The trigger anesthetics cause an anomalous, continued ascent in myoplasmic calcium levels. Possible mechanisms by which continuous release of sodium, calcium from skeletal muscle plasma membrane and sarcoplasmic reticulum stores respectively can produce the profound hyperthermia are discussed.

Efficacy of Malignant Hyperthermia Association of the United States-Recommended Methods of Preparation for Malignant Hyperthermia-Susceptible Patients Using Dräger Zeus Anesthesia Workstations and Associated Costs.

BACKGROUND: The objective of this study was to assess the efficacy and cost of Malignant Hyperthermia Association of the United States-recommended methods for preparing Dräger Zeus anesthesia workstations (AWSs) for the malignant hyperthermia-susceptible patient. METHODS: We studied washout profiles of sevoflurane, isoflurane, and desflurane in 3 Zeus AWS following 3 preparation methods. AWS was primed with 1.2 minimum alveolar concentration anesthetic for 2 hours using 2 L/min fresh gas flow, 500 mL tidal volume, and 12/min respiratory rate. Two phases of washout were performed: high flow (10 L/min) until anesthetic concentration was <5 parts per million (ppm) for 20 minutes and then low flow (3 L/min) for 20 minutes to identify the rebound effect. Preparation methods are as follows: method 1 (M1), changing disposables (breathing circuit, soda lime, CO2 line, and water traps); method 2 (M2), M1 plus replacing the breathing system with an autoclaved one; and method 3 (M3), M1 plus mounting 2 activated charcoal filters on respiratory limbs. Primary outcomes are as follows: time to obtain anesthetic concentration <5 ppm in the high-flow phase, peak anesthetic concentrations in the low-flow phase, and for M3 only, peak anesthetic concentration after 70 minutes of low-flow phase, when activated charcoal filters are removed. Secondary outcomes are as follows: cost analysis of time and resources to obtain anesthetic concentration <5 ppm in each method and a vapor-free Zeus AWS. Sensitivity analyses were performed using alternative assumptions regarding the costs and the malignant hyperthermia-susceptible caseload per year. RESULTS: Primary outcomes were as follows: M3 instantaneously decreased anesthetic concentration to <1 ppm with minimal impact of low-flow phase. M1 (median, 88 minutes; 95% confidence interval [CI], 69-112 minutes) was greater than M2 (median, 11 minutes; 95% CI, 9-15 minutes). Means of peak rebound anesthetic concentrations in M1, M2, and M3 were 15, 6, and 1 ppm, respectively (P < .001). Anesthetic concentration increased 33-fold (95% CI, 21-50) after removing charcoal filters (from 0.7 to 20 ppm). The choice of anesthetic agents did not impact the results. Secondary outcomes were as follows: M3 was the lowest cost when the cost of lost operating room (OR) time due to washout was included, and M1 was the lowest cost when it was not included. When the cost of lost OR time due to washout was considered the estimated cost/case of M3 was US $360 (M1, US $2670; M2, US $969; and a "vapor-free" Zeus AWS was US $930). The OR time and equipment costs represent the largest differentiators among the methods. CONCLUSIONS: Institutions in which demand for OR time has exceeded capacity should consider M3, and institutions with surplus OR capacity should consider M1.

Fatal awake malignant hyperthermia episodes in a family with malignant hyperthermia susceptibility: a case series.

PURPOSE: The present report of two fatal awake malignant hyperthermia (MH) episodes in an MH susceptible (MHS) family is intended to raise awareness among medical personnel and MHS individuals to the possibility of life-threatening non-anesthesia-triggered MH episodes and to provide a strong incentive for development of effective preventive measures. CLINICAL FEATURES: Two young athletic males (28 and 16 yr old), members of the same extended family with a history of anesthesia-related MH episodes and deaths, succumbed ten years apart on two different continents, with symptoms unrelated to anesthesia but strikingly similar to typical anesthetic-induced MH. Both suffered an abrupt surge in body temperature, tachycardia, tachypnea, muscle rigidity, hyperkalemia, and respiratory and metabolic acidosis. Despite aggressive resuscitation attempts, both developed cardiac arrest and died shortly upon arrival to hospital emergency departments. Autopsy analyses were negative for drugs, alcohol, or bacterial infection. Individual and familial genetic analyses revealed a novel, potentially pathogenic RYR1 variant (p.Gly159Arg) that co-segregates with the MHS phenotype in the family. Both fatal awake MH episodes are hypothesized to have been triggered by physical exertion compounded with a febrile illness that in one case was due to influenza type A. CONCLUSIONS: Life-threatening awake MH episodes may develop in some MHS individuals in the absence of anesthetic triggers. Potential triggers can be physical exertion in combination with a febrile illness. Malignant hyperthermia susceptible patients are recommended to be vaccinated against flu and restrict physical activities when febrile, wear an MH alert bracelet, and inform medical personnel of their MH history. Oral dantrolene is suggested to be available to MHS patients for administration with the early signs of awake MH.

RéSUMé: OBJECTIF: Ce compte-rendu de deux épisodes fatals d'hyperthermie maligne (HM) survenus en communauté, sans anesthésie, dans une famille susceptible à l'HM (SHM) a pour but premier de conscientiser le personnel médical et les personnes SHM quant au risque d'épisodes d'HM potentiellement fatals et non déclenchés par l'anesthésie. Notre deuxième objectif est d'encourager fortement la mise au point de mesures préventives efficaces. ÉLéMENTS CLINIQUES: Deux jeunes hommes sportifs (28 ans et 16 ans), membres de la même famille élargie ayant des antécédents d'épisodes d'HM et de décès liés à l'anesthésie, sont décédés à dix ans d'écart, sur deux continents, de symptômes non liés à l'anesthésie mais présentant une ressemblance frappante à une crise typique d'HM induite par l'anesthésie. Les deux hommes ont souffert d'une hausse rapide de leur température corporelle, de tachycardie, de tachypnée, de rigidité musculaire, d'hyperkaliémie et d'acidose respiratoire et métabolique. Malgré des tentatives vigoureuses de réanimation, les deux sont tombés en arrêt cardiaque et sont décédés peu après leur arrivée à l'urgence. Les analyses d'autopsie étaient négatives en ce qui touchait aux drogues, à l'alcool et aux infections bactériennes. Les analyses génétiques individuelles et familiales ont révélé une nouvelle variante du gène RYR1 potentiellement pathogène (p.Gly159Arg) qui est hérité en co-ségrégation avec le phénotype de SHM dans cette famille. On pense que ces deux épisodes fatals d'HM en éveil ont été provoqués par un effort physique combiné à une maladie fébrile qui, dans l'un des cas, était due à une influenza de type A. CONCLUSION: Des épisodes fatals d'HM en éveil peuvent survenir chez certaines personnes SHM en l'absence de déclencheurs anesthésiques. L'effort physique combiné à une maladie fébrile pourrait constituer un déclencheur potentiel. Les patients susceptibles à l'hyperthermie maligne sont encouragés à se faire vacciner contre l'influenza et à limiter leurs activités physiques lorsqu'ils souffrent de fièvre, à porter un bracelet d'alerte d'HM, et à informer le personnel médical de leurs antécédents d'HM. On suggère que du dantrolène par voie orale soit mis à la disposition des patients SHM afin d'être administré dès les premiers signes d'HM en éveil.

Almost-certain malignant hyperthermia during cardiopulmonary bypass: a case report and literature review.

Malignant hyperthermia is a well-known but potentially lethal disorder which is triggered by volatile anesthetics and depolarizing muscle relaxants. Early diagnosis and treatment could save lives. However, during cardiac surgery, hypothermia and cardiopulmonary bypass make the diagnosis of malignant hyperthermia extremely difficult than other surgeries. We report a case of almost-certain malignant hyperthermia, according to the clinical grading scale, in a patient undergoing on-pump coronary artery bypass grafting surgery. The patient underwent difficult weaning from cardiopulmonary bypass until intra-aortic balloon pump and temporary cardiac pacemaker had been implanted. Although dantrolene and corresponding treatments were administered recently, the patient died 12 days after surgery because of acute kidney failure and cardiac arrest. Therefore, it is important for us to previously recognize some specific signs of malignant hyperthermia during cardiopulmonary bypass to avoid severe outcomes.

Functional and structural characterization of a novel malignant hyperthermia-susceptible variant of DHPR-ß1a subunit (CACNB1).

Malignant hyperthermia (MH) susceptibility has been recently linked to a novel variant of ß1a subunit of the dihydropyridine receptor (DHPR), a channel essential for Ca2+ regulation in skeletal muscle. Here we evaluate the effect of the mutant variant V156A on the structure/function of DHPR ß1a subunit and assess its role on Ca2+ metabolism of cultured myotubes. Using differential scanning fluorimetry, we show that mutation V156A causes a significant reduction in thermal stability of the Src homology 3/guanylate kinase core domain of ß1a subunit. Expression of the variant subunit in ß1-null mouse myotubes resulted in increased sensitivity to caffeine stimulation. Whole cell patch-clamp analysis of ß1a-V156A-expressing myotubes revealed a -2 mV shift in voltage dependence of channel activation, but no changes in Ca2+ conductance, current kinetics, or sarcoplasmic reticulum Ca2+ load were observed. Measurement of resting free Ca2+ and Na+ concentrations shows that both cations were significantly elevated in ß1a-V156A-expressing myotubes and that these changes were linked to increased rates of plasmalemmal Ca2+ entry through Na+/Ca2+ exchanger and/or transient receptor potential canonical channels. Overall, our data show that mutant variant V156A results in instability of protein subdomains of ß1a subunit leading to a phenotype of Ca2+ dysregulation that partly resembles that of other MH-linked mutations of DHPR α1S subunit. These data prove that homozygous expression of variant ß1a-V156A has the potential to be a pathological variant, although it may require other gene defects to cause a full MH phenotype.

Ultrasound Elastography for Rapid, Real-time Detection of Localized Muscular Reaction in Malignant Hyperthermia-susceptible Pigs.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Halothane and caffeine induce excessive sarcoplasmic calcium liberation and skeletal muscle contracture in patients susceptible to malignant hyperthermia (MH) and are utilized for diagnosis in the in vitro contracture test. Intramuscular injection previously caused a marked local lactate increase in MH-susceptible but not in MH-nonsusceptible individuals in vivo. Using shear-wave elastography, this study evaluated localized changes in muscle stiffness after intramuscular injection of halothane and caffeine. METHODS: Microdialysis probes were placed into the gracilis muscle of 16 pigs (9 MH-susceptible and 7 MH-nonsusceptible). After local injection of either halothane or caffeine in different concentrations, changes of tissue elasticity surrounding the probe were examined by quantitative shear-wave elastography. Local lactate concentrations were analyzed spectrophotometrically. RESULTS: Ultrasound elastography detected a temporary increase in local muscle rigidity in MH-susceptible but not in MH-nonsusceptible pigs after 2.5 and 5 vol% halothane and after 10, 40, and 80 mM caffeine, whereas there were no differences in the control groups (median [interquartile range] for maximum effect after 5 vol% halothane: MH-susceptible: 97 [31 to 148] vs. MH-nonsusceptible: 5 [-6 to 18] kPa; P = 0.0006; maximum effect after 80 mM caffeine: 112 [64 to 174] vs. -3 [-6 to 35] kPa; P = 0.0002). These effects were seen rapidly within 5 min. Local lactate concentrations were higher in MH-susceptible versus nonsusceptible pigs after 1 and 2.5 vol% halothane and 10, 40, and 80 mM caffeine (2.5 vol% halothane: MH-susceptible: 2.8 [1.9 to 4.4] vs. MH-nonsusceptible: 0.6 [0.6 to 0.7] mmol/l; P < 0.0001; 80 mM caffeine: 5.2 [4.1 to 6.3] vs. 1.6 [1.2 to 2.4] mmol/l; P < 0.0001). After 10 vol% halothane, rigidity and lactate levels were increased in both MH-susceptible and MH-nonsusceptible animals. CONCLUSIONS: This pilot study revealed shear-wave elastography as a suitable technique for real-time detection of altered tissue elasticity in response to pharmacologic stimulation. By considering the variability of these results, further test protocol optimization is required before elastography could serve as a minimally invasive MH diagnostic test.

In vitro effects of levosimendan on muscle of malignant hyperthermia susceptible and non-susceptible swine.

BACKGROUND: The calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH. METHODS: Muscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 µg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D'Agostino & Pearson test for normal distribution and student's t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant. RESULTS: There were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (- 3.0 [- 5.2-0.2] mN) compared to MHS (- 7.5 [- 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 µg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 µg/ml in MHS muscle bundles (3.3 [0.9-6.1] mN) compared to MHN (- 0.7 [- 1.3-0.0] mN) (p < 0.0001). CONCLUSIONS: This in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo.

Malignant Hyperthermia: A Review.

Malignant hyperthermia is an uncommon, but potentially lethal condition that may be encountered during the perioperative period. There is wide variability in the manner in which malignant hyperthermia may manifest. For a patient to survive a malignant hyperthermia crisis, prompt recognition and treatment is of paramount importance. Perioperative nurses play a pivotal role in the successful management of malignant hyperthermia. The fictitious case study presented in this paper describes the identification, presentation, pathophysiology, and treatment of a general anesthesia patient with fulminant malignant hyperthermia.

Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia.

A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.

Skeletal Muscle Metabolic Dysfunction in Patients With Malignant Hyperthermia Susceptibility.

BACKGROUND: Malignant hyperthermia (MH), a pharmacogenetic disorder of skeletal muscle, presents with a potentially lethal hypermetabolic reaction to certain anesthetics. However, some MH-susceptible patients experience muscle weakness, fatigue, and exercise intolerance in the absence of anesthetic triggers. The objective of this exploratory study was to elucidate the pathophysiology of exercise intolerance in patients tested positive for MH with the caffeine-halothane contracture test. To this end, we used phosphorus magnetic resonance spectroscopy, blood oxygen level-dependent functional magnetic resonance imaging (MRI), and traditional exercise testing to compare skeletal muscle metabolism in MH-positive patients and healthy controls. METHODS: Skeletal muscle metabolism was assessed using phosphorus magnetic resonance spectroscopy and blood oxygen level-dependent functional MRI in 29 MH-positive patients and 20 healthy controls. Traditional measures of physical capacity were employed to measure aerobic capacity, anaerobic capacity, and muscle strength. RESULTS: During 30- and 60-second exercise, MH-positive patients had significantly lower ATP production via the oxidative pathway compared to healthy controls. MH-positive patients also had a longer recovery time with blood oxygen level-dependent functional MRI compared to healthy controls. Exercise testing revealed lower aerobic and anaerobic capacity in MH-positive patients compared to healthy controls. CONCLUSIONS: Results of this exploratory study suggest that MH-positive patients have impaired aerobic metabolism compared to healthy individuals. This could explain the exercise intolerance exhibited in MH-susceptible patient population.

Muscular body build and male sex are independently associated with malignant hyperthermia susceptibility.

PURPOSE: Malignant hyperthermia susceptibility (MHS) is a disorder of the regulation of calcium in skeletal muscle. Muscular individuals have been shown to have a 13.6-fold increased risk of death during malignant hyperthermia (MH) episodes and are more likely to experience a recurrence after initial treatment. Twenty-five percent of severe MH episodes have occurred in elite athletes. This study investigated the association between MHS and muscular body build. METHODS: Data were obtained from existing reports in the North American Malignant Hyperthermia Registry, including the Report of Muscle Biopsy and Contracture Testing (caffeine-halothane contracture test [CHCT]) as well as Adverse Metabolic or Muscular Reaction to Anesthesia (AMRA) reports. Malignant hyperthermia susceptible individuals were compared with MH negative individuals with regard to body build and reason for testing. Males were also compared with females. Both the CHCT and the AMRA forms were reviewed for comments. RESULTS: Of the 1,292 individuals diagnosed with MHS by CHCT, males were more likely to be diagnosed with the disorder than females (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.99 to 2.7; P < 0.001). Muscular individuals were more likely to be diagnosed with MHS than non-muscular individuals (OR, 1.94; 95% CI, 1.51 to 2.49; P < 0.001). Males were more likely to be tested after having a possible MH episode (OR, 2.33; 95% CI, 1.45 to 2.1; P < 0.001). Logistic regression showed that male sex (OR, 2.28; 95% CI, 1.93 to 2.7; P < 0.001) and muscular body build (OR, 2.17; 95% CI, 1.21 to 3.9; P = 0.01) were independently predictive of MHS. The interaction between muscular body build and male sex was not significant (P = 0.13). Indications for testing, MH episode vs family history of MH, did not differ between muscular and non-muscular individuals (P = 0.44). Eight of 839 AMRAs and two reports of CHCT had comments describing athletic abilities. Ryanodine receptor type 1 (RYR1) gene mutations were found in five of these athletes. CONCLUSION: Muscular body build and male sex are strongly associated with MHS.

Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review.

INTRODUCTION: Two potentially fatal syndromes, malignant hyperthermia (MH), an adverse reaction to general anesthesia, and exertional rhabdomyolysis (ER) share some clinical features, including hyperthermia, muscle rigidity, tachycardia, and elevated serum creatine kinase. Some patients with ER have experienced an MH event and/or have been diagnosed as MH susceptible (MHS). In order to assess the relationship between ER and MH further, we conducted a retrospective cohort study summarizing clinical and genetic information on Canadian patients with ER who were diagnosed as MHS. In addition, a systematic literature review was performed to compile further evidence on MH susceptibility and RYR1 and CACNA1S variants associated with rhabdomyolysis. METHODS: Demographic, clinical, and genetic information was collected on Canadian MHS patients who presented with rhabdomyolysis. In addition, we performed a systematic review of the literature published during 1995-2016 on genetic screening of the RYR1 and CACNA1S genes in patients with ER. RESULTS: Retrospective data on Canadian MHS patients with ER showed that ten out of 17 patients carried RYR1 or CACNA1S variants that were either known MH-causative mutations or potentially pathogenic variants. The systematic review revealed 39 different rare RYR1 variants, including 13 MH-causative/associated mutations and five rare potentially deleterious CACNA1S variants in 78% of patients with ER. CONCLUSION: Findings from the Canadian patient cohort and the systematic review all signal a potential association between MH susceptibility and ER. The presence of MH-causative mutations and putative deleterious RYR1 variants in ER patients without a history of adverse anesthetic reactions suggests their possible increased risk for MH.

Anesthesia-induced rhabdomyolysis or malignant hyperthermia: is defining the crisis important?

Anesthesia-induced rhabdomyolysis and malignant hyperthermia occur in response to the same agents and present with similar clinical features. Distinguishing between these diagnoses can be challenging in a clinical crisis yet making the distinction is critical as prompt appropriate management may be life-saving, whereas delayed recognition and/or inappropriate management will almost certainly result in death. This focused review examines the differences between these conditions and focuses on the emergency management of anesthesia-induced rhabdomyolysis.

Cystathionine ß-synthase-derived hydrogen sulfide is involved in human malignant hyperthermia.

Hydrogen sulfide is an endogenous gasotransmitter and its mechanism of action involves activation of ATP-sensitive K(+) channels and phosphodiesterase inhibition. As both mechanisms are potentially involved in malignant hyperthermia (MH), in the present study we addressed the involvement of the L-cysteine/hydrogen sulfide pathway in MH. Skeletal muscle biopsies obtained from 25 MH-susceptible (MHS) and 56 MH-negative (MHN) individuals have been used to perform the in vitro contracture test (IVCT). Quantitative real-time PCR (qPCR) and Western blotting studies have also been performed. Hydrogen sulfide levels are measured in both tissue samples and plasma. In MHS biopsies an increase in cystathionine ß-synthase (CBS) occurs, as both mRNA and protein expression compared with MHN biopsies. Hydrogen sulfide biosynthesis is increased in MHS biopsies (0.128±0.12 compared with 0.943±0.13 nmol/mg of protein per min for MHN and MHS biopsies, respectively; P<0.01). Addition of sodium hydrosulfide (NaHS) to MHS samples evokes a response similar, in the IVCT, to that elicited by either caffeine or halothane. Incubation of MHN biopsies with NaHS, before caffeine or halothane challenge, switches an MHN to an MHS response. In conclusion we demonstrate the involvement of the L-cysteine/hydrogen sulfide pathway in MH, giving new insight into MH molecular mechanisms. This finding has potential implications for clinical care and could help to define less invasive diagnostic procedures.

Is lymphocyte adenosine a diagnostic marker of clinical malignant hyperthermia? A pilot study.

OBJECTIVE: Malignant hyperthermia is a pharmacogenetic disorder typically triggered by potent inhalation anesthetics and/or the depolarizing muscle relaxant succinylcholine in malignant hyperthermia-susceptible individuals. Since lymphocytes express the same Ca channel mutation found in malignant hyperthermia-susceptible muscle, we investigated agonist-induced adenosine formation in lymphocytes as an index of sarcoplasmic reticulum Ca-release-induced adenosine 5'-triphosphate turnover as a potential minimally invasive functional malignant hyperthermia assay. DESIGN: Application of lymphocytes for malignant hyperthermia diagnosis. SETTING: Hospitals and university laboratory. SUBJECTS: Malignant hyperthermia-susceptible patients (n = 13) and normal subjects (n = 11). INTERVENTIONS: Adenosine formation due to malignant hyperthermia-triggering agent halothane or the ryanodine receptor Ca channels agonist 4-chloro-m-cresol was compared in blood lymphocytes from malignant hyperthermia-susceptible patients and normal subjects. MEASUREMENTS AND MAIN RESULTS: Cai and adenosine were measured in fresh or immortalized blood lymphocytes incubated with 0-10 mM 4-chloro-m-cresol or 0-10.7 mM halothane. Cai levels were significantly higher in immortalized malignant hyperthermia-susceptible B cells treated with 0.75 mM 4-chloro-m-cresol relative to controls. Similarly, at 1 mM 4-chloro-m-cresol or 0.96 mM halothane, adenosine levels were significantly higher in malignant hyperthermia-susceptible lymphocytes or immortalized B cells relative to controls. Receiver-operating characteristic analyses showed areas under the 4-chloro-m-cresol receiver-operating characteristic curves near more than or equal to 0.96 (p ≈ 0.0001), suggesting that 4-chloro-m-cresol-induced adenosine could readily distinguish between malignant hyperthermia-susceptible and normal controls cells. CONCLUSIONS: Both 4-chloro-m-cresol and halothane caused adenosine accumulation in blood lymphocytes. Adenosine accumulation was markedly increased in malignant hyperthermia-susceptible lymphocytes compared with controls reflecting higher than normal adenosine 5'-triphosphate degradation in the malignant hyperthermia-susceptible cells. Although 4-chloro-m-cresol receiver-operating characteristic curves revealed that adenosine accumulation could readily distinguish between normal and malignant hyperthermia-susceptible lymphocytes, independent confirmation is required with a substantially larger number of enrolled subjects to correctly appreciate the clinical utility of the novel lymphocyte-adenosine protocol for malignant hyperthermia testing.

Malignant hyperthermia, a Scandinavian update.

BACKGROUND: 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. METHODS: For this review a large litterature search was carried out and the Swedish MH database consisting of 436 probands who have undergone in vitro muscle contraction test (IVCT) during 1984-2014 was analyzed. RESULTS: 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. CONCLUSION: 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.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.