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The ClinGen malignant hyperthermia susceptibility (MHS) variant curation expert panel specified the ACMG/AMP criteria for RYR1-related MHS and a pilot analysis of 84 variants was published. We have now classified an additional 251 variants for RYR1-related MHS according to current ClinGen standards and updated the criteria where necessary. Criterion PS4 was modified such that individuals with multiple RYR1 variants classified as pathogenic (P), likely pathogenic (LP) or variant of uncertain significance (VUS) were not considered as providing evidence for pathogenicity. Critera PS1 and PM5 were revised to consider LP variants at the same amino acid residue as providing evidence for pathogenicity at reduced strength. Finally, PM1 was revised such that if PS1 or PM5 are used PM1, if applicable, should be downgraded to supporting. Of the 251 RYR1 variants, 42 were classified as P/LP, 16 as B/LB, and 193 as VUS. The primary driver of 176 VUS classifications was insufficient evidence supporting pathogenicity, rather than evidence against pathogenicity. Functional data supporting PS3/BS3 was identified for only 13 variants. Based on the posterior probabilities of pathogenicity and variant frequencies in gnomAD, we estimated the prevalence of individuals with RYR1-related MHS pathogenic variants to be between 1/300 and 1/1,075, considerably higher than current estimates. We have updated ACMG/AMP criteria for RYR1-related MHS and classified 251 variants. We suggest that prioritization of functional studies is needed to resolve the large number of VUS classifications and allow for appropriate risk assessment. RYR1-related MHS pathogenic variants are likely to be more common than currently appreciated.

Hyperthermia, or extreme elevations in body temperature, can be life-threatening and may be caused by prescription drugs or illegal substances acting at a number of different levels of the neuraxis. Several psychotropic drug classes and combinations have been associated with a classic clinical syndrome of hyperthermia, skeletal muscle hyper-metabolism, rigidity or rhabdomyolysis, autonomic dysfunction and altered mental status ranging from catatonic stupor to coma. It is critical for clinicians to have a high index of suspicion for these relatively uncommon drug-induced adverse effects and to become familiar with their management to prevent serious morbidity and mortality. Although these syndromes look alike, they are triggered by quite different mechanisms, and apart from the need to withdraw or restore potential triggering drugs and provide intensive medical care, specific treatments may vary. Clinical similarities have led to theoretical speculations about common mechanisms and shared genetic predispositions underlying these syndromes, suggesting that there may be a common "thermic stress syndrome" triggered in humans and animal models by a variety of pharmacological or environmental challenges.

Malignant Hyperthermia(MH) was described 60 years ago and our understanding of the clinical and pathophysiologic features of this syndrome continue to advance. MH is attributed to a genetically determined susceptibility to an abnormal skeletal muscle cell calcium flux triggered by potent inhalation anesthetics (e.g., isoflurane) or succinylcholine. Since dantrolene sodium was approved in 1979 the mortality from malignant hyperthermia dropped substantially, but remains 4-10%. The exact incidence of malignant hyperthermia reactions is unknown but may be as high as one in 25,000 anesthetics. Variants in three genes cause the susceptibility to this disorder. The RYR1 gene is most common followed by CACNA1S and STAC3. While the caffeine-halothane contracture test and the in vitro contracture test are considered the gold standards for diagnosis of susceptibility to malignant hyperthermia, there have been important advances in genetic testing. Due to these advances, it is timely for the field to consider the utility and practicability of screening for malignant hyperthermia susceptibility using genomic testing. Here we pose a simple, but bold question; what would it take to end deaths from malignant hyperthermia? We review recent advances and propose a scientific and clinical pathway toward this audacious goal to provoke discussion in the field.

Purpose As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH). Methods We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework. Results Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance. Conclusion Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.

PurposePrevention of malignant hyperthermia (MH) requires an understanding of RYR1 variant pathogenicity to assess the risk of exposure to triggering agents. Personalized medicine, especially secondary findings and eventually genomic screening, will contribute toward this goal.MethodsWe specified ACMG/AMP criteria for variant interpretation for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework.ResultsSeven ACMG/AMP criteria were adopted without changes, ten were adopted with RYR1-specific modifications, and nine were dropped. The in silico (PP3 and BP4) and hot spot criteria (PM1) were evaluated quantitatively. REVEL gave an OR of 23:1 for PP3 and 16:1 for BP4 using trichotomized cut-offs of >0.85 (pathogenic) and ConclusionCuration of these variants will facilitate interpretation of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria are generalizable to other variant curation expert panels.

Study objective Malignant hyperthermia (MH) is a rare yet potentially fatal pharmacogenetic disorder triggered by exposure to inhalational anesthetics and the depolarizing neuromuscular blocking agent succinylcholine. Epidemiologic data on the geographic variation in MH prevalence is scant. The objective of this study is to examine the prevalence of recorded MH diagnosis in patients discharged from hospitals in four states in the United States. Design Observational study. Setting Healthcare Cost and Utilization Project (HCUP) State Inpatient Database (SID) for California (2011), Florida (2011), New York (2012) and Wisconsin (2012). Patients A total of 164 hospital discharges that had a recorded diagnosis of MH using the International Classification of Disease, 9th Revision, Clinical Modification code 995.86. Methods MH prevalence was assessed by patient demographic and clinical characteristics. Main results The prevalence of MH per 100,000 hospital discharges ranged from 1.23 (95% Confidence Interval [CI], 0.80–1.66) in New York to 1.91 (95% CI, 1.48–2.34) in California, and the prevalence of MH per 100,000 surgical discharges ranged from 1.47 (95% CI, 0.93–2.02) in New York to 2.86 (95% CI, 2.00–3.71) in Florida. The prevalence of MH in male patients was more than twice the prevalence in female patients. Of the 164 patients with MH diagnosis, 11% were dead on discharge. Conclusions There exists a modest variation in the prevalence of recorded MH diagnosis in hospital discharges in California, Florida, New York and Wisconsin. Epidemiologic patterns of MH diagnosis in hospital discharges appear to be similar across the four states. Further research is needed to better understand the geographic variation and contributing factors of MH in different populations.

Dantrolene—a nitrofurantoin derivative—was developed by Snyder et al. in 1967. After initial discovery of its muscle relaxation potential, investigations in a number of species demonstrated dose-dependent reductions in skeletal muscle tone that were long lasting, relatively nontoxic, and free of adverse effects such as respiratory impairment. Ellis et al. then published a number of papers investigating the means by which dantrolene produced these effects. Using a series of classic physiologic models, Ellis investigated potential sites of action for the new drug, eventually narrowing this down to the intracellular calcium-release mechanism. Ellis went on to play a pivotal role in the discovery of dantrolene’s effectiveness for the treatment of malignant hyperthermia, after reading a scientific bulletin about muscle rigidity in pigs affected by porcine stress syndrome, contacting Gaisford Harrison and sending dantrolene to him for trial.

Purpose: To examine the use of intravenous dantrolene in hospitalized patients. Materials and Methods: Medical Records of patients treated with intravenous dantrolene between 2007 and 2012 at 6 teaching hospitals were reviewed. Temperature, muscle rigidity, creatine kinase levels, and mortality were assessed in association with dantrolene use. Results: Twenty-five patients received intravenous dantrolene, 9 patients with neuroleptic malignant syndrome (NMS), 8 with hyperthermia due to sepsis, 4 with NMS and sepsis, 2 for malignant hyperthermia (MH), and 2 with hypermetabolic syndrome associated with juvenile diabetic ketoacidosis. Dantrolene was administered as a bolus of 1 - 3 mg/kg. Core temperature decreased after dantrolene administration in all groups but significant only for MH, NMS cases (Pre 102.3 ± 0.9d p < 0.001), in Sepsis cases (Pre 104.3 ± 1.5d p < 0.001). Mean rigidity scores decreased in all groups but significant only for NMS cases, and mean CK did not change significantly in any group. Conclusion: Dantrolene was associated with reductions in temperature and rigidity in hyperthermia of diverse origins in patients admitted to Intensive care settings.

Malignant hyperthermia (MH) remains a diagnostic challenge. This case report describes the anesthetic management of a suspected intraoperative MH episode and the subsequent, genetic sequence analysis of 3 genes associated with MH. The results of the molecular genetic testing revealed heterozygosity for a rare variant, c.12553G>A (p.Ala4185Thr), in the RYR1 gene encoding the ryanodine receptor. Although the RYR1 gene has previously been implicated in the pathogenesis of MH, (1) this particular variant has only been reported in one other case of MH; (2) the role for diagnostic genetic testing in the diagnosis of MH will be examined.

Context: Recent case reports on malignant hyperthermia (MH)-like syndrome in physically active populations indicate potential associations among MH, exertional heat stroke (EHS), and exertional rhabdomyolysis (ER). However, an expert consensus for clinicians working with these populations is lacking. Objective: To provide current expert consensus on the (1) definition of MH; (2) history, etiology, and pathophysiology of MH; (3) epidemiology of MH; (4) association of MH with EHS and ER; (5) identification of an MH-like syndrome; (6) recommendations for acute management of an MH-like syndrome; (7) special considerations for physically active populations; and (8) future directions for research. Setting: An interassociation task force was formed by experts in athletic training, exercise science, anesthesiology, and emergency medicine. The “Round Table on Malignant Hyperthermia in Physically Active Populations” was convened at the University of Connecticut, Storrs, September 17–18, 2015. Conclusions: Clinicians should consider an MH-like syndrome when a diagnosis of EHS or ER cannot be fully explained by clinical signs and symptoms presented by a patient or when recurrent episodes of EHS or ER (or both) are unexplained. Further research is required to elucidate the genetic and pathophysiological links among MH, EHS, and ER.

The Malignant Hyperthermia Association of the United States and the Department of Anesthesia at the University of Toronto sponsored a Scientific Conference on November 1-2, 2013 in Toronto, ON, Canada. The multidisciplinary group of experts, including clinicians, geneticists, and physiologists involved in research related to malignant hyperthermia (MH), shared new insights into the pathophysiology of diseases linked to the type-1 ryanodine receptor gene (RYR1) as well as the relationship between MH and “awake MH” conditions, such as exertional rhabdomyolysis and exertional heat illness. In addition, the molecular genetics of MH and clinical issues related to the diagnosis and management of disorders linked to RYR1 were presented. The conference also honoured Dr. David H. MacLennan for his contributions to our understanding of the genetics, pathogenesis, and treatment of MH and other RYR1-related myopathies. This report represents a summary of the proceedings of this conference.

As part of the Journal’s 60 anniversary Diamond Jubilee Celebration, a number of seminal articles from the Journal archives are highlighted in the Journal’s 61 printed volume and online at: www.springer.com/12630. This article, the last in our series, was selected on the basis of its novelty at the time of publication, its scientific merit, and its overall importance to clinical practice: Britt BA, Locher WG, Kalow W. Hereditary aspects of malignant hyperthermia. Can Anaesth Soc J 1969; 16: 89-98. Drs. Sheila Riazi, Kevin Nolan, and Henry Rosenberg provide expert commentary on this report that significantly contributed to our knowledge of what at the time, was a poorly understood anesthesia-related syndrome that lead to many deaths and much fear regarding this condition brought on by exposure to volatile anesthetic gases and depolarizing muscle relaxants.

Anesthesiologists providing care during off hours (ie, weekends or holidays, or cases started during the evening or late afternoon) are more likely to care for patients at greater risk of sustaining major adverse events than when they work during regular hours (eg, Monday through Friday, from 7:00 AM to 2:59 PM). We consider the logical inconsistency of using subspecialty teams during regular hours but not during weekends or evenings.We analyzed data from the Anesthesia Quality Institute's National Anesthesia Clinical Outcomes Registry (NACOR). Among the hospitals in the United States, we estimated the average number of common types of anesthesia procedures (ie, diversity measured as inverse of Herfindahl index), and the average difference in the number of common procedures between 2 off-hours periods (regular hours versus weekends, and regular hours versus evenings). We also used NACOR data to estimate the average similarity in the distributions of procedures between regular hours and weekends and between regular hours and evenings in US facilities. Results are reported as mean ± standard error of the mean among 399 facilities nationwide with weekend cases.The distributions of common procedures were moderately similar (ie, not large,.8) between regular hours and evenings (similarity index .59 ± .01) and between regular hours and weekends (similarity index, .55 ± .02). For most facilities, the number of common procedures differed by5 procedures between regular hours and evenings (74.4% of facilities, P.0001) and between regular hours and weekends (64.7% of facilities, P.0001). The average number of common procedures was 13.59 ± .12 for regular hours, 13.12 ± .13 for evenings, and 9.43 ± .13 for weekends. The pairwise differences by facility were .13 ± .07 procedures (P = .090) between regular hours and evenings and 3.37 ± .12 procedures (P.0001) between regular hours and weekends. In contrast, the differences were -5.18 ± .12 and 7.59 ± .13, respectively, when calculated using nationally pooled data. This was because the numbers of common procedures were 32.23 ± .05, 37.41 ± .11, and 24.64 ± .12 for regular hours, evenings, and weekends, respectively (ie,2x the number of common procedures calculated by facility).The numbers of procedures commonly performed at most facilities are fewer in number than those that are commonly performed nationally. Thus, decisions on anesthesia specialization should be based on quantitative analysis of local data rather than national recommendations using pooled data. By facility, the number of different procedures that take place during regular hours and off hours (diversity) is essentially the same, but there is only moderate similarity in the procedures performed. Thus, at many facilities, anesthesiologists who work principally within a single specialty during regular work hours will likely not have substantial contemporary experience with many procedures performed during off hours.

Introduction: A rare and atypical form of Neuroleptic Malignant Syndrome (NMS) can be a deceptive and life threatening condition if not diagnosed properly in acute and critical care settings. Methods: The management of a patient presenting with atypical NMS without prominent rigidity, but with extensive rhabdomyolysis after the administration of haloperidol and ziprasidone is described in this report. Results: Prompt recognition of atypical features of NMS was managed by intensive care unit admission, supportive care and pharmacotherapy, leading to a complete resolution of the syndrome and a favorable outcome verified by laboratory findings. Conclusion: Early stages and atypical features of NMS may be variable in presentation and clinical course. The absence of muscle rigidity may not rule out NMS. A strong clinical suspicion based on clinical history is crucial for early diagnosis and treatment. Termination of dantrolene therapy may not be necessary during rhabdomyolysis and elevated aminotransferase levels.

CLINICAL PROBLEM Volatile anesthetics and/or succinylcholine may trigger a potentially lethal malignant hyperthermia (MH) event requiring critical care crisis management. If the MH triggering anesthetic is given in an ambulatory surgical center (ASC), then the patient will need to be transferred to a receiving hospital. Before May 2010, there was no clinical guide regarding the development of a specific transfer plan for MH patients in an ASC. MECHANISM BY WHICH THE STATEMENT WAS GENERATED: A consensual process lasting 18 months among 13 representatives of the Malignant Hyperthermia Association of the United States, the Ambulatory Surgery Foundation, the Society for Ambulatory Anesthesia, the Society for Academic Emergency Medicine, and the National Association of Emergency Medical Technicians led to the creation of this guide. EVIDENCE FOR THE STATEMENT: Most of the guide is based on the clinical experience and scientific expertise of the 13 representatives. The list of representatives appears in Appendix 1. The recommendation that IV dantrolene should be initiated pending transfer is also supported by clinical research demonstrating that the likelihood of significant MH complications doubles for every 30-minute delay in dantrolene administration (Anesth Analg 2010;110:498-507). STATEMENT This guide includes a list of potential clinical problems and therapeutic interventions to assist each ASC in the development of its own unique MH transfer plan. Points to consider include receiving health care facility capabilities, indicators of patient stability and necessary report data, transport team considerations and capabilities, implementation of transfer decisions, and coordination of communication among the ASC, the receiving hospital, and the transport team. See Appendix 2 for the guide.

BACKGROUND Malignant hyperthermia (MH) is a rare yet potentially fatal pharmacogenetic disorder triggered by exposure to inhaled anesthetics and the depolarizing neuromuscular blocking drug succinylcholine. Epidemiologic research on MH is largely limited to inpatients. In this study, we examined the prevalence of recorded MH diagnosis in patients discharged from ambulatory surgery centers (ASCs). METHODS We analyzed the New York State Ambulatory Surgery Dataset for the years 2002 to 2011 and identified patients with a discharge diagnosis of MH due to anesthesia by using the International Classification of Disease, Ninth Revision, Clinical Modification code 995.86. MH prevalence was assessed by demographic, clinical, and ASC characteristics. RESULTS During the study period, 31 of 17,092,765 discharges from ASCs had a recorded diagnosis of MH, yielding a prevalence of 0.18 per 100,000 discharges (95% confidence interval, 0.12-0.25). The prevalence of recorded MH diagnosis per discharge differed significantly across age groups and surgical procedure categories. All patients with a recorded diagnosis of MH were from hospital-based ASCs and were discharged alive from ASCs. CONCLUSIONS The prevalence of recorded MH diagnosis in ASC patients is approximately 1 per 500,000 and varies considerably with surgical procedures.

Summary Background: Case reports have linked malignant hyperthermia (MH) to several genetic diseases. Objective/aim: The objective of this study was to quantitatively assess excess comorbidities associated with MH diagnosis in pediatric hospital discharge records. Patients and methods: Data for this study came from the Kids’ Inpatient Database (KID) for the years 2000, 2003, and 2006. The KID contains an 80% random sample of patients under the age of 21 discharged from short-term, non-Federal hospitals in the United States, with up to 19 diagnoses recorded for each patient. Using all pediatric inpatients as the reference, we calculated the standardized morbidity ratios (SMRs) and 95% confidence intervals (CIs) for children with MH diagnosis according to major disease groups and specific medical conditions. Results: Of the 5 916 989 nonbirth-related hospital discharges studied, 175 had a recorded diagnosis of MH. Compared with the general pediatric inpatient population, children with MH diagnosis were significantly more likely to be diagnosed with diseases of the musculoskeletal system and connective tissue (SMR 5.7; 95% CI: 3.9–7.9), diseases of the circulatory system (SMR 3.3; 95% CI: 2.1–4.8), and congenital anomalies (SMR 3.2; 95% CI: 2.3–4.4). The specific diagnosis that was most strongly associated with MH was muscular dystrophies (SMR 31.3; 95% CI 12.6–64.6). Conclusions: Diseases of the musculoskeletal system and connective tissue are significantly associated with MH diagnosis in children. Further research is warranted to determine the clinical utility of these comorbidities in assessing MH susceptibility in children.

A little over 50 years ago, Denborough and Lovell described the syndrome known today as malignant hyperthermia (MH). Little was known about this disorder at the time other than it carried a high fatality rate and was characterized by explosive hyperthermia in an otherwise apparently healthy individual undergoing general anesthesia. The unravelling of the principal features of the syndrome involved a combination of astute clinical observations, a fortuitous association with a similar syndrome in pigs, and assiduous laboratory investigations involving contributions from many countries. Seminal contributions to the understanding of MH were made by individuals associated with the University of Toronto, particularly Drs. Beverly Britt, Werner Kalow, Roderick Gordon, David MacLennan, and their many coworkers. In this issue of the Journal, Dr. MacLennan et al. continue to expand on earlier work in MH, particularly the molecular genetics of MH and the allied myopathy, Central Core Disease. Although the inheritance pattern of MH in humans was known by the 1980s, a turning point in the MH story occurred in 1990 when Dr. MacLennan’s team identified the mutation in the ryanodine receptor gene causal for MH in the swine model of MH. However, the molecular genetics of MH in humans has proven to be far more complex and obscure. This is due, in part, to the inherent complexity of the MH syndrome; to a variety of presentations that may be mimicked by several clinical situations; to a lack of typical phenotypic signs in the absence of anesthesia; to an association with several genes; and potentially, to scores of DNA variants that may lead to the pathophysiologic abnormality in MH, namely, calcium dysregulation in the skeletal muscle cell. Since MH may become manifest without warning and may progress rapidly to life-threatening hypercarbia, muscle breakdown, acidosis, and hyperthermia, much effort has been expended in attempting to identify those at risk for the syndrome. The mainstay diagnostic test for MH is the muscle biopsy contracture test first described by Drs. Britt and Kalow in the early 1970s. The test entails exposure of biopsied skeletal muscle to calcium-releasing agents, such as halothane, caffeine, ryanodine, and /or chloro-m-cresol. Since that time, the contracture test has served to clarify the inheritance of MH, the association with Central Core Disease, and multiple phenotypic presentations of the syndrome. Clearly, it is not applicable either to screening or to rapid identification of susceptibility. Furthermore, as with most laboratory tests, sensitivity and specificity are not 100%. Nevertheless, the test has served as the standard against which other tests are judged. One of the main current goals of research related to MH is the development of a minimally invasive, highly accurate diagnostic test for MH. Molecular genetics holds the promise of meeting that goal. In fact, clinical genetic testing for MH susceptibility is already available in many countries at the present time, but it requires careful patient selection because of the limited sensitivity of genetic testing. The road to the goal line of a sensitive and specific genetic test has proven to be replete with obstacles, just as it has been for many other inherited disorders. For instance, although the ryanodine receptor gene (RYR-1) and the ryanodine receptor or calcium release channel in the sarcoplasmic reticulum are most often associated with the syndrome, other calcium regulatory proteins, such as the dihydropyridine receptor and, more recently, calsequestrin, lead to intracellular calcium dysregulation and clinical MH H. Rosenberg, MD (&) Department of Medical Education and Clinical Research, Saint Barnabas Medical Center, Livingston, NJ, USA e-mail: hrosenberg@sbhcs.com

BACKGROUND: Malignant hyperthermia (MH) is a pharmacogenetic syndrome that variably expresses itself on exposure to triggering agents. MH prevalence in the United States is not well documented. In this study, we assessed the prevalence of MH in New York State hospitals. METHODS: Using New York hospital discharge data for the years 2001 through 2005, we identified all patients with a diagnosis of MH due to anesthesia using International Classification of Diseases, Ninth Revision, Clinical Modification code 995.86. MH prevalence was evaluated by demographic and clinical characteristics. RESULTS: Of the 12,749,125 discharges from New York hospitals during the study period, 73 patients had a recorded diagnosis of MH due to anesthesia. Nearly three quarters of the MH patients were male and 71% were patients from emergency/urgent admissions. The estimated prevalence rate of MH was 0.96 (95% confidence interval [CI] 0.67–1.24) per 100,000 surgical discharges and 1.08 (95% CI 0.75–1.41) per 100,000 discharges in which there was any indication of exposure to anesthesia. The estimated prevalence of MH for males was 2.5 to 4.5 times the rate for females. CONCLUSION: The prevalence of MH due to anesthesia in surgical patients treated in New York State hospitals is approximately 1 per 100,000. MH risk in males is significantly higher than in females.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:10,000 to 1: 250,000 anesthetics. However, the prevalence of the genetic abnormalities may be as great as one in 400 individuals. MH affects humans, certain pig breeds, dogs and horses. The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue. In humans the syndrome is inherited in an autosomal dominant pattern, while in pigs it is autosomal recessive. Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. Less than 1 % of variants have been found in CACNA1S but not all of these are causal. Diagnostic testing involves the in vitro contracture response of biopsied muscle to halothane, caffeine, and in some centres ryanodine and 4-chloro-m-cresol. Elucidation of the genetic changes has led to the introduction of DNA testing for susceptibility to MH. Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered. Increased understanding of the clinical manifestation and pathophysiology of the syndrome, has lead to the mortality decreasing from 80 % thirty years ago to

Recently, we analyzed data from the American Society of Anesthesiologist's (ASA) Anesthesia Quality Institute (AQI) to report the United States (U.S.) anesthesia workload by time of day and day of the week. The AQI data were reported using the Central Time zone. Times for the N = 613 calls to the Malignant Hyperthermia Association of the United States (MHAUS) Malignant Hyperthermia (MH) Hotline from August 1, 2012, through March 7, 2014, were adjusted similarly. The MH Hotline effectively provides at all times to each anesthesia group an additional board-certified anesthesiologist who has expertise in managing, diagnosing, and/or preventing MH crises. We compared the timing of calls with the MH Hotline consultants relative to times of most anesthesia workload nationally. The interval 6:30 AM to 6:30 PM Central Time on regular workdays accounted for most (P < 0.0001) calls to the MH Hotline (62.5% ± 2.0% [mean ± standard error]). However, the interval accounted for significantly less than the 82.2% of anesthesia minutes and 84.5% of general anesthesia minutes during that interval nationally (both P < 0.0001). Thus, most calls to the MH Hotline occurred when anesthesia groups nationwide were the busiest. Weekends accounted for 15.3% ± 1.5% of MH Hotline calls, significantly greater than the rates of 5.2% of anesthesia minutes and 4.3% of general anesthesia minutes during weekends nationally (both P < 0.0001). Thus, the MH Hotline was used proportionately more often when anesthesia providers have fewer colleagues present and available for consultation (all P < 0.0001). These findings may be expected of other (future) national support centers for anesthesia.

Background Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle, manifested as a life-threatening hypermetabolic crisis after exposure to anesthetics. Type I ryanodine receptor 1 is the primary gene responsible for susceptibility to MH as well as central core disease, a congenital myopathy that predisposes susceptibility to MH. More than 40 mutations in the RyR1 gene cluster in three coding regions: the N-terminus, central, and C-terminus regions. However, the frequency of mutations in each region has not been studied in the North American MH-susceptible population. Methods The authors tested 124 unrelated patients with MH susceptibility for the presence of mutations in the N-terminus (exons 2, 6, 9, 11, 12, and 17), central (exons 39, 40, 44, 45, and 46), and C-terminus (exons 95, 100, 101, and 102) regions. Results Fourteen mutations have been identified in 29 of 124 MH-susceptible patients (23%). Approximately 70% of the mutations, which include a novel mutation, Ala 2437Val, were in the central region. In 8 patients (28%), mutations were identified in the N-terminus region. Screening the C-terminus region yielded a novel mutation, Leu4824Pro, in a single patient with a diagnosis of central core disease. Conclusions The detection rate for mutations is only 23% by screening mutations (or exons) listed in the 2002 North American consensus panel. The implications from this study suggest that testing the central region first is currently the most effective screening strategy for the North American population. Screening more exons in the three hot spots may be needed to find an accurate frequency of mutations in the RyR1 gene.

Developed in the late 19th century, endotracheal intubation was met with reluctance, even fear, by those administering anesthesia. The progression from its gradual acceptance to today's routine use is traced in this essay.

To the Editor, The introduction of a lightweight mini vaporizer (AnaConDa; Sedana Medical, Sweden) that can be used with an intensive care unit (ICU) ventilator has led to a resurgence of interest in the use of potent volatile agents as an alternative to intravenous agents for longterm sedation or for treatment of status asthmaticus in patients requiring tracheal intubation. In an editorial comment concerning the use of sevoflurane for treatment of status asthmaticus, Wasowicz and Jerath review the benefits of using volatile anesthetics for these reasons and mention several of the potential dangers of administration of potent volatile anesthetic agents outside the operating room environment. Unfortunately, what is omitted from their discussion is the mention of the risk of malignant hyperthermia (MH), although the danger of MH is stated clearly in the report by Ruszkai et al. To underline this possibility, at the European Malignant Hyperthermia Group meeting in May 2014, Johannsen et al. reported on the development of MH in an ICU patient sedated with sevoflurane. In their case, the AnaConDa device was used for management of pneumonia in a 59-yr-old man and MH developed after five hours of sevoflurane anesthetic sedation. The signs included acute hemodynamic deterioration, metabolic and respiratory acidosis, increase of body temperature from 39.6-40.7 C over 30 min, and elevation of creatine kinase to 3,450 U L. Fortunately, the clinicians recognized the signs of MH and treated with dantrolene, and the patient survived. A subsequent in vitro contracture test substantiated the clinical diagnosis of MH. Although only low concentrations of potent volatile agents are used to achieve sedation in the ICU, the risk of developing MH still exists, and appropriate therapy with dantrolene and supportive care must be immediately available. Because early symptoms of developing MH crisis are rather non-specific and can be misleading to other more frequent diagnoses, e.g., sepsis, the awareness of MH is crucial for ICU physicians of any medical specialty wherever volatile anesthetics are applied. It is recommended that, when MH occurs as a result of sedation with volatile anesthetics, the details should be reported to the appropriate MH registry or similar database. Certainly, the Malignant Hyperthermia Association of the United States (www.mhaus.org) as well as the European Malignant Hyperthermia Group (www.emhg.org) would be interested in learning of such cases.

M alignant hyperthermia (MH) is an inherited ,disorder characterized by a hypermetabolic response to succinylcholine and/or potent volatile anesthetic agents (Table 1). It is inherited in humans as an autosomal dominant trait. MH-susceptible patients usually do not have symptoms or signs of problems other than during administration of anesthesia. As such, MH is a prototypical pharmacogenetic disorder, and the only "disease" of anesthesia. Because an MH crisis may occur wherever and whenever "trigger"-volatile agents are administered, it is appropriate to be prepared to diagnose and manage an MH crisis wherever general anesthesia is administered, be it a hospital, officg, or ambulatory center. The goal of this article is to provide the most recent information concerning prevention, diagnosis, treatment, and management of MH in the ambulatory setting. The article will address questions associated with managing MH-susceptible patients in a free-standing surgery center as well as a physician's office.

Background Malignant hyperthermia (MH) is a disorder of skeletal muscle manifested as a life-threatening hypermetabolic crisis in susceptible individuals after exposure to inhalational anesthetics and depolarizing muscle relaxants. Mutations in the gene encoding the skeletal muscle ryanodine receptor (RYR1) are considered a common cause of the disorder, and, to date, more than 20 RYR1 mutations have been reported in European and Canadian families. Some studies suggest that differences may exist in the frequencies and distribution of mutations in the RYR1 gene between European and North American MH families the frequency and distribution of mutations in the RYR1 gene. Methods Skeletal muscle samples from 73 unrelated individuals diagnosed as MH susceptible according to the North American MH caffeine-halothane contracture test were studied. Genomic DNA of MH-susceptible patients was investigated by polymerase chain reaction-based restriction fragment length polymorphism, single-strand conformation polymorphism, and sequencing analysis. The majority of known RYR1 mutations were analyzed using the restriction fragment length polymorphism method, whereas new mutations were searched by single-strand conformation polymorphism in exons 12, 15, 39, 40, 44, 45, and 46 of the gene. Results Seven known RYR1 mutations (Arg163Cys, Gly248Arg, Arg614Cys, Val2168Met, Thr2206Met, Gly2434Arg, and Arg2454His) were detected at frequencies of 2.7, 1.4, 1.4, 1.4, 1.4, 5.5, and 4.1%, respectively. In addition, three novel amino acid substitutions (Val2214Ile, Ala2367Thr, and Asp2431Asn) were detected at frequency of 1.4% each. These 10 mutations account for 21.9% of the North American MH-susceptible population. Conclusion Three novel candidate mutations in the RYR1 gene were identified in these MH patients. The frequency and distribution of RYR1 mutations observed in this North American MH population was markedly different from that previously identified in Europe. Larger-scale studies are necessary to clarify the type and frequency of mutations in RYR1 associated with MH in North American families.

Individuals from a large North American population were screened for the presence of the mutation in the alpha1 subunit of the voltage-dependent calcium channel (CACNA1S) that has recently been associated with malignant hyperthermia (MH). This Arg1086His mutation was screened for in 154 MH normal (MHN) individuals and 112 MH susceptible (MHS) individuals, who were diagnosed by the North American protocol of the in vitro contracture test. PCR and restriction enzyme analysis was used to test for the mutation. The Arg1086His mutation in the CACNA1S was not found in any of the MHN individuals. In contrast, two related individuals (grandfather and grandson, father and son of the MH proband) among the MHS group exhibited this mutation. However, a third MHS individual in the same family (granddaughter, cousin of the grandson) did not exhibit this mutation. These results indicate that this mutation may be associated with MH in this family. Genetic alterations in the CACNA1S associated with MH are present in approximately 1% of this North American MHS population.

Background The function or expression of subtypes of the sodium ion (Na+) channel is altered in biopsies or cultures of skeletal muscle from many persons who are susceptible to malignant hyperthermia (MH). ATX II, a specific Na+ channel toxin from a sea anemone, causes delayed inactivation of the channel similar to that seen in cell cultures of MH muscle. ATX II was added to skeletal muscle to determine whether altered Na+ channel function could increase the sensitivity of normal skeletal muscle to agents (halothane, caffeine, ryanodine) to which MH muscle is hypersensitive. Methods Studies were performed of fiber bundles from the vastus lateralis muscle of persons who were deemed not MH susceptible (MH-) or MH susceptible (MH+) according to the MH diagnostic test and of strips of diaphragm muscle from rats. Preparations in a tissue bath containing Krebs solution were connected to a force transducer. ATX II was introduced 5 min before halothane, caffeine, or ryanodine. Results ATX II increased the magnitude of contracture to halothane in preparations from most MH-, but not MH+, human participants. After ATX II treatment, preparations from 9 of 24 MH- participants generated contractures to halothane, 3%, that were of the same magnitude as those from MH+ participants. Preparations from four of six ATX II-treated healthy participants also gave responses of the same magnitude as those of MH-susceptible participants to a graded halothane challenge (0.5-3%). The contractures to bolus doses of halothane in specimens from male participants were more than three times larger than the contractures in specimens from female participants. In rat muscle, ATX II increased the magnitude of contracture to caffeine (2 mM) and decreased the time to produce a 1-g contracture to ryanodine (1 microM). Conclusions ATX II, which causes delayed inactivation of the Na+ channel in cell cultures similar to that reported in cultures of MH+ skeletal muscle, increased the sensitivity of normal muscle to three agents to which MH+ muscle is hypersensitive. The increased sensitivity to halothane, 3%, occurred in most (79%), but not all, MH- participants, and this effect was most evident in male participants. Therefore, abnormal function of the Na+ channel, even if it is a secondary event in MH, may contribute to a positive contracture test result for MH.

Anesthesia-induced malignant hyperthermia (MH) is a rare inherited disorder of skeletal muscle. Several mutations in the ryanodine receptor (RYR1) have been found to be causative of MH. The G1021A mutation in the RYR1 is one of the most frequently occurring mutations in European populations. MH normal (165) and MH susceptible (114) North American patients were screened for the presence of the G1021A mutation. This mutation was not found in any of the patients tested. These studies support the absence of this mutation in the normal population. Furthermore, these findings emphasize the importance of viewing the distribution of MH mutations as variable gene pools with frequencies dependent on the geographical location of the population examined.

In 1995, our department of anesthesiology established an airway team to assist in treating unanticipated difficult endotracheal intubations and an airway quality improvement (QI) form to document the use of emergency airway techniques in airway crises (laryngeal mask airway [LMA], flexible fiberoptic bronchoscopy, retrograde intubation [RI], transtracheal jet ventilation [TTJV], and cricothyrotomy). Over a 2-yr period, team members and staff anesthesiologists completed airway QI forms to document the smallest peripheral SpO2 during an airway crisis, the number of direct laryngoscopies (DL) performed before using an emergency airway technique, and the emergency airway technique that succeeded in rescue ventilation. Team members agreed to use the LMA as the first emergency airway technique to treat the difficult ventilation/difficult intubation scenario. A SpO2 valueor =90% during mask ventilation defined difficult ventilation. Inability to perform tracheal intubation by DL defined difficult intubation. An increase in the SpO2 value90% defined rescue ventilation. Review of airway QI forms from October 1, 1995 until October 1, 1997 revealed 25 cases of difficult ventilation/difficult intubation. Before airway rescue, the median SpO2 was 80% (range 50%-90%), and there were four median attempts at DL (range one to nine). The LMA had a success rate of 94% (95% confidence interval [CI] 77-100). Flexible fiberoptic bronchoscopy, TTJV, RI, and surgical cricothyrotomy had success rates of 50% (95% CI 0-100), 33% (95% CI 0-100), 100% (95% CI 37-100), and 100% (95% CI 37-100), respectively. LMA insertion as the first alternative airway technique was useful in dealing with unanticipated instances of simultaneous difficulty with mask ventilation and tracheal intubation.Twenty-five cases of simultaneous difficulty with mask ventilation and tracheal intubation occurred after the induction of general anesthesia during the study period. The laryngeal mask was used in 17 cases, and it provided rescue ventilation without complication in 94% of these cases (95% confidence interval 77-100).

Background: Malignant hyperthermia (MH) is a rare hypermetabolic syndrome of the skeletal muscle and a potentially fatal complication of general anesthesia. Dantrolene is currently the only specific treatment for MH. The Malignant Hyperthermia Association of the United States has issued guidelines recommending that 36 vials (20 mg per vial) of dantrolene remain in stock at every surgery center. However, the cost of stocking dantrolene in ambulatory surgery centers has been a concern. The purpose of this analysis is to assess the cost-effectiveness of stocking dantrolene in ambulatory surgery centers as recommended by the Malignant Hyperthermia Association of the United States. Methods: A decision tree model was used to compare treatment with dantrolene to a supportive care-only strategy. Model assumptions include the incidence of MH, MH case fatality with dantrolene treatment and with supportive care-only. Sensitivity analyses were performed to assess the robustness of the estimated cost-effectiveness. Results: The estimated annual number of MH events in ambulatory surgery centers in the United States was 47. The incremental effectiveness of dantrolene compared with supportive care was 33 more lives saved per year. The incremental cost-effectiveness ratio was $196,320 (in 2010 dollars) per life saved compared with a supportive care strategy. Sensitivity analysis showed that the results were robust for the plausible range of all variables and assumptions tested. Conclusion: The results of this analysis suggest that stocking dantrolene for the treatment of MH in ambulatory surgery centers as recommended by the Malignant Hyperthermia Association of the United States is cost-effective when compared with the estimated values of statistical life used by U.S. regulatory agencies.

Biopsies of human skeletal muscle were analyzed by an in vitro contracture test (IVCT) for responsiveness to a halothane challenge: noncontracting (nonresponsive; IVCT-) and contracting (IVCT+). A muscle biopsy that is IVCT+ indicates potential malignant hyperthermia (MH) susceptibility. Primary cultures were grown from portions of the skeletal muscle biopsies, and voltage-activated currents were measured by whole cell recording in the presence or absence of 2-5 microM intracellular arachidonic or oleic acids. In untreated IVCT- cells, Na+ currents were predominantly tetrodotoxin (TTX) insensitive, indicating that most of the current was carried through the embryonic SkM2 isoform of the Na+ channel. Inclusion of fatty acids in the recording pipette of IVCT- cells produced an increase in voltage-activated Na+ currents during 20 min of recording. Approximately 70% of currents in fatty acid-treated cells were TTX sensitive, indicating activation of the adult SkM1 isoform of the Na+ channel. In contrast to IVCT- cells, IVCT+ cells expressed Na+ currents that were predominantly TTX sensitive even in the absence of added fatty acid, thus showing a relatively large baseline functional expression of SkM1 channels. Addition of fatty acids to the recording pipette produced little further change in the magnitude or TTX sensitivity of the whole cell currents in IVCT+ cells, suggesting altered functional regulation of Na+ channels in MH muscle.

BACKGROUND Facilities with volatile anesthetic agents stock dantrolene for the treatment of malignant hyperthermia (MH). The availability of dantrolene at these facilities satisfies cost-utility norms even for sites with as few as 1 anesthetic per workday, based on the overall incidence of MH per anesthetic. We considered the stocking of dantrolene at facilities with succinylcholine alone (i.e., where volatile anesthetics are not available), by using registry data and estimates of the frequency of administration of succinylcholine during anesthesia. We determine the magnitude of the relative risk of the administration of succinylcholine for triggering MH. METHODS The relative risk of triggering MH by succinylcholine versus volatile agents was calculated using data from 2 sources. The ratio of the number of cases of MH among patients receiving succinylcholine to number among patients not receiving succinylcholine was estimated from the previously published cohort of 284 cases of MH from the North American MH Registry of the MH Association of the United States (MHAUS). The percentage of anesthetics with succinylcholine was estimated using anesthesia information management system data from a typical North American hospital comprising tertiary operating rooms, obstetrics unit, ambulatory surgical center, and endoscopy and radiological suites. RESULTS The relative risk of MH with versus without succinylcholine was 19.6 (lower 95% confidence limit > 16.1). Limiting to cases with volatile anesthetics, the relative risk was 9.1 (>7.5). Both relative risks exceed 1.0 (P < 0.0001). Because more than half of the reported cases of MH included the use of succinylcholine, the relative risk exceeded 1.0 provided fewer than half of anesthetics in North America included the use of succinylcholine. The incidences of succinylcholine use at the hospital were 5.8% and 11.6% for all anesthetics and for anesthetics with volatile agents, respectively. CONCLUSIONS Our results provide no insight into the triggering mechanism for MH (i.e., succinylcholine could in isolation have an extremely low incidence of inducing MH, yet markedly increase the risk when administered in combination with volatile anesthetics). Until more epidemiologic data are collected and analyzed, having dantrolene available, where succinylcholine may be used, is reasonable, and this practice should be maintained.