Malignant Hyperthermia Episode Research Articles

Successful management of malignant hyperthermia without dantrolene – A case report

Malignant hyperthermia (MH) is a rare inherited genetic disorder implicated in a life-threatening catastrophic event under general anaesthesia. In India, the total number of reported cases are of the magnitude of single digit due to lack of reporting. The mortality of MH is dramatically decreased from 70-80% to less than 5%, due to an introduction of dantrolene sodium for treatment of MH, early detection of MH episode using capnography, and the introduction of diagnostic testing for MH.In India, there is enormous dependence on clinical grading scale rather than halothane caffeine contraction test due to the lack of availability of accredited testing facilities. In addition to this, the drug of choice dantrolene, is not readily available everywhere in India. The scarcity of quintessential monitoring techniques cannot be ignored in peripheral areas. Despite these limitations many reported cases have survived with vigilant monitoring, prompt diagnosis and aggressive supportive care.

Association of malignant hyperthermia and exertional heat illness in young athletes: An analysis of awareness among clinical and athletic first responders.

Malignant hyperthermia (MH), a rare inherited condition seen almost exclusively in the perioperative setting, is triggered by volatile anesthetics or an intravenous paralytic drug, succinylcholine. It can, however, occur without any exposure to anesthetic drugs, being associated with heat illness and rhabdomyolysis, thus presenting a little-known risk to young athletes exercising in hot environments. This study aimed to determine the first responder awareness of MH and its association with heat illness in young athletes within athletic and clinical environments. Awareness within the clinical milieu was assessed by an institutional chart review of 3296 charts. The identified heat illness cases were examined for treatment consistent with the management of a suspected episode of MH. Awareness among first responders in an athletic setting was examined by a survey administered to a total of 1,500 coaches and athletic trainers at the high school level along with emergency medical services providers across the United States. No treatment consistent with the suspicion of MH was noted among clinical first responders, suggesting a lack of awareness. Survey administration also revealed a limited amount of knowledge of MH and its potential role in heat illness. The results point to lack of awareness among pre-hospital and hospital-based first responders of the relationship between MH and heat illness in young athletes. An effort to educate these members of the healthcare community can contribute to an expeditious and life-saving intervention. First responders who may interact with a young athlete have low knowledge of MH and its relationship to heat illness. Similar lack of awareness exists among hospital personnel who care for young individuals with heat illness. Educating the first responders about this condition can speed up the time to intervene and save lives.

Evaluation of Malignant Hyperthermia Features in Patients with Pathogenic or Likely Pathogenic RYR1 Variants Disclosed through a Population Genomic Screening Program.

Malignant hyperthermia (MH) susceptibility is a heritable musculoskeletal disorder that can present as a potentially fatal hypermetabolic response to triggering anesthesia agents. Genomic screening for variants in MH-associated genes RYR1 and CACNA1S provides an opportunity to prevent morbidity and mortality. There are limited outcomes data from disclosing variants in RYR1, the most common MH susceptibility gene, in unselected populations. The authors sought to identify the rate of MH features or fulminant episodes after triggering agent exposure in an unselected population undergoing genomic screening including actionable RYR1 variants. The MyCode Community Health Initiative by Geisinger (USA) is an electronic health record-linked biobank that discloses pathogenic and likely pathogenic variants in clinically actionable genes to patient-participants. Available electronic anesthesia and ambulatory records for participants with actionable RYR1 results returned through December 2020 were evaluated for pertinent findings via double-coded chart reviews and reconciliation. Descriptive statistics for observed phenotypes were calculated. One hundred fifty-two participants had an actionable RYR1 variant disclosed during the study period. None had previous documented genetic testing for MH susceptibility; one had previous contracture testing diagnosing MH susceptibility. Sixty-eight participants (44.7%) had anesthesia records documenting triggering agent exposure during at least one procedure. None received dantrolene treatment or had documented muscle rigidity, myoglobinuria, hyperkalemia, elevated creatine kinase, severe myalgia, or tea-colored urine. Of 120 possibly MH-related findings (postoperative intensive care unit admissions, hyperthermia, arterial blood gas evaluation, hypercapnia, or tachycardia), 112 (93.3%) were deemed unlikely to be MH events; 8 (6.7%) had insufficient records to determine etiology. Results demonstrate a low frequency of classic intraanesthetic hypermetabolic phenotypes in an unselected population with actionable RYR1 variants. Further research on the actionability of screening for MH susceptibility in unselected populations, including economic impact, predictors of MH episodes, and expanded clinical phenotypes, is necessary.

Long-term Natural History of Pediatric Dominant and Recessive RYR1-Related Myopathy.

RYR1-related myopathies are the most common congenital myopathies, but long-term natural history data are still scarce. We aim to describe the natural history of dominant and recessive RYR1-related myopathies. A cross-sectional and longitudinal retrospective data analysis of pediatric cases with RYR1-related myopathies seen between 1992-2019 in 2 large UK centers. Patients were identified, and data were collected from individual medical records. Sixty-nine patients were included in the study, 63 in both cross-sectional and longitudinal studies and 6 in the cross-sectional analysis only. Onset ranged from birth to 7 years. Twenty-nine patients had an autosomal dominant RYR1-related myopathy, 31 recessive, 6 de novo dominant, and 3 uncertain inheritance. Median age at the first and last appointment was 4.0 and 10.8 years, respectively. Fifteen% of patients older than 2 years never walked (5 recessive, 4 de novo dominant, and 1 dominant patient) and 7% lost ambulation during follow-up. Scoliosis and spinal rigidity were present in 30% and 17% of patients, respectively. Respiratory involvement was observed in 22% of patients, and 12% needed ventilatory support from a median age of 7 years. Feeding difficulties were present in 30% of patients, and 57% of those needed gastrostomy or tube feeding. There were no anesthetic-induced malignant hyperthermia episodes reported in this cohort. We observed a higher prevalence of prenatal/neonatal features in recessive patients, in particular hypotonia and respiratory difficulties. Clinical presentation, respiratory outcomes, and feeding outcomes were consistently more severe at presentation and in the recessive group. Conversely, longitudinal analysis suggested a less progressive course for motor and respiratory function in recessive patients. Annual change in forced vital capacity was -0.2%/year in recessive vs -1.4%/year in dominant patients. This clinical study provides long-term data on disease progression in RYR1-related myopathies that may inform management and provide essential milestones for future therapeutic interventions.

Malignant hyperthermia in Poland: A survey study.

Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden, uncontrolled skeletal muscle hypermetabolism in response to inhalation anesthetics and depolarizing relaxants. The estimated incidence of MH is between 1:10,000 and 1:250,000 anesthetic procedures. In Poland, due to lack of reporting, the incidence of MH is unknown. Dantrolene is imported as a life-saving drug (target import) and temporally authorized for sale. The aim of the study was to evaluate the prevalence of malignant hyperthermia in Poland and to assess the accessibility to dantrolene in Poland. A questionnaire was conducted among the chiefs of anesthesia and intensive care units in Poland. During the years 2014 to 2019, 10 episodes of MH have been reported in 238 surveyed polish anesthesia departments. The estimated prevalence is 1:350,000. Eight patients survived the MH crisis. Dantrolene is stocked in 48 (20%) anesthesiology departments. Among the surveyed hospitals, only in 38 (16%) it is possible to administer dantrolene within 5 minutes of suspecting a MH reaction. Less than half units (44%) have an algorithm for the management of MH episode in the operating theaters. The results of the study revealed, that the prevalence of MH in Poland is lower than the prevalence reported in other countries. Access to dantrolene in Poland is limited.

Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders.

The ryanodine receptor (RyR) is a homotetrameric channel mediating sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contraction. Mutations in RyR1 and RyR2 lead to life-threatening malignant hyperthermia episodes and ventricular tachycardia, respectively. In this brief report, we use chemical cross-linking to demonstrate that pathogenic RyR1 R163C and RyR2 R169Q mutations reduce N-terminus domain (NTD) tetramerization. Introduction of positively-charged residues (Q168R, M399R) in the NTD-NTD inter-subunit interface normalizes RyR2-R169Q NTD tetramerization. These results indicate that perturbation of NTD-NTD inter-subunit interactions is an underlying molecular mechanism in both RyR1 and RyR2 pathophysiology. Importantly, our data provide proof of concept that stabilization of this critical RyR1/2 structure-function parameter offers clear therapeutic potential.

Malignant hyperthermia in Mazovia Province - are we adequately prepared?

Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden skeletal muscle hypermetabolism in response to inhalation anaesthetics and depolarising relaxants. The estimated incidence of MH is between 1 : 10,000 and 1 : 250,000 anaesthetic procedures. In Poland the incidence of MH is unknown. Dantrolene is imported as a life-saving drug and temporally authorised for sale. The aim of the study is to assess the incidence of MH and access to dantrolene in the Mazovia Province. Anonymous questionnaires were sent to anaesthesia departments in the Mazovia Province after prior contact by phone and e-mail. The survey was approved by the local ethical review board. Completed surveys were received from 60 respondents which represents 72% of anaesthesiology departments in Mazovia. In the last 5 years there have been 4 episodes of MH in the Mazovia Province. Three patients survived the MH crisis. In a centre that did not have access to dantrolene, the patient died. Dantrolene is found only in 11 (18.3%) anaesthesiology departments in Mazovia. Only 6 (10%) hospitals are able to administer dantrolene within 5 minutes of suspecting MH crisis, while 5 centres may receive it after a few days. Only 38% of units have an algorithm for dealing with MH crisis in the operating theatres. MH is rare, but if untreated, it can be fatal. Therefore prompt diagnosis and treatment are crucial to avoid fatal outcome. Every centre using inhalational anaesthetics and/or succinylcholine should have dantrolene. To ensure the safety of our patients, we must be better prepared.

Creation and Implementation of a Preoperative Malignant Hyperthermia Screening Tool.

Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disorder triggered by certain anesthetic agents. There is currently no standardized preoperative screening tool utilized to identify MH-susceptible individuals. This quality improvement (QI) project aimed to enhance preoperative screening for MH susceptibility (MHS) by implementing an evidence-based screening tool for surgical patients at 2 sites. This prospective descriptive QI project evaluated the success of implementing an MHS screening tool preoperatively and its impact on the anesthesia plan. Anesthesia professionals included the screening tool in their preoperative interview for surgical patients so that positively screened patients could receive MH prevention measures. A total of 95 patients at site A and 234 patients at site B were screened using the MH tool, a cumulative total of 21 patients were positively screened, and 1 anesthetic plan was altered. This MHS screening tool has the potential to prevent MH episodes when used consistently by staff.

Pharmacological Treatment of Malignant Hyperthermia: Update 2019

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle presenting as a hypermetabolic response to potent volatile anesthetics such as sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine. Following introduction of the hydantoin derivative dantrolene, the previously high mortality of fulminant MH episodes could be reduced from > 80% to less than 10%. For treatment of MH an initial intravenous bolus of 2.5 mg/kg dantrolene based on the actual body weight should be applied. If symptoms are not improving after the initial dose, up to 10 mg/kg dantrolene can be necessary within the first 24 h. In facilities where MH triggering anesthetics and depolarizing muscle relaxants are administered, at least 36 - 48 vials of dantrolene 20 mg should be stocked according to the recent German S1 guideline on MH. If none of these agents are ever used in the facility, the stockage of dantrolene is dispensable. Since dantrolene is not easily dissoluble, preparation requires time and manpower. Due to its pharmacological characteristics, ryanodex, a modern nanocrystalline dantrolene sodium suspension, might be a promising alternative in the treatment of MH.

An unusual ryanodine receptor 1 (RYR1) phenotype: Mild calf-predominant myopathy.

To identify the genetic defect causing a distal calf myopathy with cores. Families with a genetically undetermined calf-predominant myopathy underwent detailed clinical evaluation, including EMG/nerve conduction studies, muscle biopsy, laboratory investigations, and muscle MRI. Next-generation sequencing and targeted Sanger sequencing were used to identify the causative genetic defect in each family. A novel deletion-insertion mutation in ryanodine receptor 1 (RYR1) was found in the proband of the index family and segregated with the disease in 6 affected relatives. Subsequently, we found 2 more families with a similar calf-predominant myopathy segregating with unique RYR1-mutated alleles. All patients showed a very slowly progressive myopathy without episodes of malignant hyperthermia or rhabdomyolysis. Muscle biopsy showed cores or core-like changes in all families. Our findings expand the spectrum of RYR1-related disorders to include a calf-predominant myopathy with core pathology and autosomal dominant inheritance. Two families had unique and previously unreported RYR1 mutations, while affected persons in the third family carried 2 previously known mutations in the same dominant allele.

Life-threatening Episodes of Malignant Hyperthermia Following Halothane Anesthesia in Three Children: A Case Series and Review of Literature.

ABSTRACTMalignant hyperthermia (MH) is an inherited, pharmacogenetic disorder of the skeletal muscle, characterized by dangerous hypermetabolic state after anesthesia with succinylcholine and/ or volatile halogenated anesthetic agents, clinically manifested as hyperpyrexia and related complications like tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, rigid muscles, rhabdomyolysis and disseminated intravascular coagulation (DIC). Here we present a series of three cases of MH, admitted in our hospital in a span of 8 months for three different operative procedures to be done under general anesthesia (cleft lip repair, Duhamel's operation for Hirschsprung's disease and surgical repair of development dysplasia of hip), who developed probable hyperthermia owing to Halothane being used as an anesthetic agent.How to cite this articleLaha S, Giri PP, Saha A, Gupta PP, De A. Life-threatening Episodes of Malignant Hyperthermia Following Halothane Anesthesia in Three Children: A Case Series and Review of Literature. Indian Journal of Critical Care Medicine, January 2019;23(1):47-50.

Oral Management of Steinert's Disease and Role of Anxiolysis

Myotonic dystrophy type I (DM1) is a genetic autosomal dominant disorder; malignant hyperthermia is a possible complication. It may occur following administration of some halogenated general anesthetics, muscle relaxants, or surgical stress. The purpose of this case report is to evaluate the dental management of patients with Steinert's disease. The patient needed dental extraction. A locore-gional paraperiosteal anesthesia was performed using bupiva-caine without vasoconstrictor and sedation with nitrous oxide. The syndesmotomy of the elements 3.1, 4.1, and 4.2 was executed. The elements were dislocated through a straight lever and avulsed with an appropriate clamp. The socket was courted, washing with saline solution, inserting a fibrin sponge, and applying sutures (silk 3-0). Dental treatment of the patient with Steinert's dystrophy must be carried out under a hospital environment and the use of local anesthetic without vasoconstrictor and with use of nitrous oxide; anxiolysis is recommended. This case report describes the precautions to perform oral surgery in patients with Steinert's disease and emphasizes the role of anxiolysis to avoid episodes of malignant hyperthermia.

Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome.

Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available. We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. Twenty-two patients with recurrent rhabdomyolysis (CK>10000) or myalgia with hyperCKemia (>1.5×ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

Malignant Hyperthermia and Ryanodine Receptor Type 1 Gene (RyR1) Mutation in a Family in Singapore

Sporadic clinical episodes of malignant hyperthermia (MH) that develop during general anaesthesia (GA) have been reported in Singapore. However, there is no published local report of a confirmed case of MH susceptibility (MHS) by skeletal muscle contracture tests and/or molecular tests. We report 2 patients from an extended family who developed signs of clinical MH while under GA. The MH episodes were successfully treated with intravenous dantrolene sodium. Sequence analysis of the entire Ryanodine Receptor Type 1 (RyR1) coding gene was carried out in an index patient. The index patient was found to carry a c.7373G>A (p.Arg2458His) mutation in exon 46. This particular mutation satisfies the criteria for a MHS causative mutation. Hence, the index patient was considered to be MHS and did not need to undergo further muscle contracture testing. The same mutation was also found in 3 other members of his extended family. This is the first report of a Singaporean family with at least 4 members carrying a MH-causative mutation in RyR1 gene. This report serves to highlight the existence of the putative gene for MH in Singapore, and the need for clinical vigilance during anaesthesia involving the use of triggering agents.

P.227 - The Brody disease cohort study: clarification of the phenotype

Brody disease is a rare recessive myopathy characterized by exercise-induced muscle-stiffness, caused by mutations in the ATP2A1-gene, which encodes the sarcoplasmic reticulum calcium ATPase type 1 (SERCA-1) protein. Almost fifty years after the first patient with Brody disease was reported, the clinical picture is still unclear and results of ancillary investigations remain inconclusive. This may lead to incomplete recognition and under-diagnosis of the disease. Also, little is known about the natural course of the disorder and the effects of symptomatic treatment. To improve our understanding and provide better means of recognition we studied the largest cohort of patients with Brody disease so far, consisting of all 18 previously published and 17 new patients carrying 22 novel mutations. Our study shows that the main feature of Brody disease is exercise-induced stiffness of limbs, and often also of eyelids. Onset is in childhood and there is no or only mild progression of symptoms over time. Three patients had episodes of malignant hyperthermia. The key feature of physical examination is delayed relaxation after repetitive contractions. There is no weakness or atrophy, and some patients have a remarkable athletic build. All symptomatic treatments proved ineffective. Electromyography shows no myotonia but may reveal silent contractures, CK is normal or mildly elevated and muscle biopsy shows mild myopathic changes with selective type II atrophy. Based on this large cohort, we conclude that clinicians should think of Brody disease in cases of exercise-induced muscle stiffness, especially when combined with the above-mentioned features. When physical examination shows delayed relaxation (which must be specifically looked for) and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1-gene. Finally, Brody disease patients may be at risk for malignant hyperthermia and therefore appropriate preventive measures are recommended.

Administration of anaesthetic triggering agents to patients tested malignant hyperthermia normal and their relatives in New Zealand: an update.

Testing for malignant hyperthermia in New Zealand involves two tests-in vitro contracture testing of excised lateral quadriceps muscle and DNA analysis. In vitro contracture testing is regarded as the gold standard in malignant hyperthermia diagnosis but several publications have questioned the reliability of a normal result. Analysis of 479 anaesthetic records in 280 patients or their descendants throughout New Zealand who had tested negative for malignant hyperthermia, demonstrated there was no evidence of malignant hyperthermia episodes in this group who had been administered anaesthetic triggering agents. A wide range of anaesthetics were used over the study period. Analysis of each anaesthetic record was undertaken using the malignant hyperthermia grading scale which determines the likelihood that an anaesthetic event represents a malignant hyperthermia episode. Confirmation of the negative results was further supported by normal DNA analysis of patients in 48% of anaesthetics. There are advantages to using inhalational agents in certain situations and although demonstrating a zero risk of a malignant hyperthermia episode is not statistically possible, evidence in this large series suggests that the risk of an episode in these patients is extremely low and may be negligible. We suggest that anaesthetic triggering agents can be used safely in patients with normal in vitro contracture tests, and in their descendants.

Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.

In humans, hyperthermic episodes can be triggered by halogenated anesthetics [malignant hyperthermia (MH) susceptibility] and by high temperature [environmental heat stroke (HS)]. Correlation between MH susceptibility and HS is supported by extensive work in mouse models that carry a mutation in ryanodine receptor type-1 (RYR1Y522S/WT) and calsequestrin-1 knockout (CASQ1-null), 2 proteins that control Ca2+ release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1Y522S/WT and CASQ1-null mice to an exertional-stress protocol (incremental running on a treadmill at 34°C and 40% humidity). The mortality rate was 80 and 78.6% in RYR1Y522S/WT and CASQ1-null mice, respectively, vs. 0% in wild-type mice. Lethal crises were characterized by hyperthermia and rhabdomyolysis, classic features of MH episodes. Of importance, pretreatment with azumolene, an analog of the drug used in humans to treat MH crises, reduced mortality to 0 and 12.5% in RYR1Y522S/WT and CASQ1-null mice, respectively, thanks to a striking reduction of hyperthermia and rhabdomyolysis. At the molecular level, azumolene strongly prevented Ca2+-dependent activation of calpains and NF-κB by lowering myoplasmic Ca2+ concentration and nitro-oxidative stress, parameters that were elevated in RYR1Y522S/WT and CASQ1-null mice. These results suggest that common molecular mechanisms underlie MH crises and exertional HS in mice.-Michelucci, A., Paolini, C., Boncompagni, S., Canato, M., Reggiani, C., Protasi, F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.

Dantrolene requires Mg2+ to arrest malignant hyperthermia

Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons may develop lethally high body temperatures. Genetic predisposition mainly arises from mutations on the skeletal muscle ryanodine receptor (RyR). Dantrolene is administered to alleviate MH symptoms, but its mechanism of action and its influence on the Ca2+ transients elicited by MH triggers are unknown. Here, we show that Ca2+ release in the absence of Mg2+ is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg2+] (free [Mg2+]cyto) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca2+ waves in the presence of resting levels of free [Mg2+]cyto (1 mM). However, an increase of free [Mg2+]cyto to 1.5 mM could increase the period between Ca2+ waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg2+ is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg2+ affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg2+ from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode.

Dantrolene Shifts the Affinity of the Ryanodine Receptor for MG2+

Dantrolene is the only approved drug for the treatment of life-threatening malignant hyperthermia episodes. It has been shown by several studies that the voltage-dependent Ca2+ transient or force response is reduced by dantrolene; and indeed a binding domain for dantrolene on the ryanodine receptor (RyR) has been identified. However, studies of isolated RyRs have mostly failed to observe alterations in the conductance of ions through the channel in the presence of clinically relevant concentrations of dantrolene. This may be the case because the ionic conditions in bilayer studies typically do not match those occurring in the muscle fibre. To examine the mechanism of dantrolene action on the RyR we used mechanically skinned fibres where the imposed ionic conditions mimic those occurring in the body. The skinned fibre allowed us to track the effect of dantrolene on Ca2+ transients in the cytoplasm elicited by action potentials; and a recently developed technique allowed the detection of the activity of the RyR under defined ionic conditions, including basal levels of activity, with a high degree of sensitivity. By varying the [Ca2+] and [Mg2+] of the cytoplasm, with and without dantrolene present, we observed that dantrolene reduced RyR activity by altering its affinity for Mg2+.

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

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. 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. Of the 1,292 individuals diagnosedwith 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. Muscular body build and male sex are strongly associated with MHS.