Article

Prevalence of malignant hyperthermia diagnosis in hospital discharge records in California, Florida, New York, and Wisconsin

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Abstract

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.

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... M alignant hyperthermia (MH) is a rare life-threatening disorder caused by dysregulation of intracellular calcium homeostasis in skeletal muscle and triggered by exposure to certain anesthetics in genetically predisposed individuals. 1 A progressively better understanding of the pathomechanism of MH, advances in anesthesia monitoring, and the introduction of dantrolene have been crucial in reducing MH mortality, which remains around 10%. 2 Variants in ryanodine receptor 1 (RYR1), 3 calcium voltage-gated channel subunit alpha1 S (CACNA1S), [4][5][6] and in SH3 and cysteine rich domain 3 (STAC3) genes 7 are associated with MH. The RYR1 gene-encoding the Ca 2+ release channel of skeletal muscle sarcoplasmic reticulum (RyR1)-is the major MH-associated locus, involved in more than half of MH cases, whereas variants in CACNA1S and STAC3 account for less than 1%. ...
... [11][12][13] The prevalence of MH diagnostic mutations is considerably greater than the reported incidence of clinical MH episodes (1:35,000 to 1:68,000 surgical discharges). 2 This striking discrepancy can be attributable to the fact that many mutation carriers may never be exposed to anesthetic triggers. 14 The discrepancy may also reflect a reduced-or incomplete-penetrance of the MH trait. ...
... Sex differences pervade the literature on MH, from the earliest epidemiologic reports 23,24 to the most recent survey demonstrating that the prevalence of MH in male patients doubles that of females. 2 It was also shown that more males than females test positive on the diagnostic contracture test for MH. 26 Sex-dependent susceptibility to MH is also present in mouse models. 37 Recently, male sex and body build subjectively assessed as muscular have been reported as independent predictors of MH susceptibility. ...
Article
What we already know about this topic: Malignant hyperthermia is a rare life-threatening disorder triggered in genetically predisposed individuals by exposure to certain anestheticsThe ryanodine receptor 1 (RYR1) gene, which encodes the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum, is the major malignant hyperthermia-associated locusMalignant hyperthermia diagnostic mutations are more prevalent than the reported incidence of clinical malignant hyperthermia episodes because many mutation carriers are never exposed to anesthetic triggers and some may have several uneventful anesthetics before developing malignant hyperthermia reaction WHAT THIS ARTICLE TELLS US THAT IS NEW: In a multicenter case-control study of 229 genotype-positive subjects with previous recorded exposure to trigger anesthetics, there were 93 malignant hyperthermia cases, for an overall penetrance for the analyzed RYR1 mutations of 40.6%The probability of developing malignant hyperthermia on exposureto triggers was 0.25 among all RYR1 mutation carriers and 0.76 in survivors of malignant hyperthermia reactions (95% CI of the difference 0.41 to 0.59)Young age, male sex, and the use of succinylcholine were major nongenetic risk factors influencing expression of the RYR1 mutations conferring malignant hyperthermia susceptibility BACKGROUND:: Malignant hyperthermia (MH) is a potentially lethal disorder triggered by certain anesthetics. Mutations in the ryanodine receptor 1 (RYR1) gene account for about half of MH cases. Discordance between the low incidence of MH and a high prevalence of mutations has been attributed to incomplete penetrance, which has not been quantified yet. The authors aimed to examine penetrance of MH-diagnostic RYR1 mutations and the likelihood of mutation carriers to develop MH, and to identify factors affecting severity of MH clinical expression. Methods: In this multicenter case-control study, data from 125 MH pedigrees between 1994 and 2017 were collected from four European registries and one Canadian registry. Probands (survivors of MH reaction) and their relatives with at least one exposure to anesthetic triggers, carrying one diagnostic RYR1 mutation, were included. Penetrance (percentage of probands among all genotype-positive) and the probability of a mutation carrier to develop MH were obtained. MH onset time and Clinical Grading Scale score were used to assess MH reaction severity. Results: The overall penetrance of nine RYR1 diagnostic mutations was 40.6% (93 of 229), without statistical differences among mutations. Likelihood to develop MH on exposure to triggers was 0.25 among all RYR1 mutation carriers, and 0.76 in probands (95% CI of the difference 0.41 to 0.59). Penetrance in males was significantly higher than in females (50% [62 of 124] vs. 29.7% [30 of 101]; P = 0.002). Males had increased odds of developing MH (odds ratio, 2.37; 95% CI, 1.36 to 4.12) despite similar levels of exposure to trigger anesthetics. Proband's median age was 12 yr (interquartile range 6 to 32.5). Conclusions: Nine MH-diagnostic RYR1 mutations have sex-dependent incomplete penetrance, whereas MH clinical expression is influenced by patient's age and the type of anesthetic. Our quantitative evaluation of MH penetrance reinforces the notion that a previous uneventful anesthetic does not preclude the possibility of developing MH.
... This leads to energy depletion, rapid production of carbon dioxide and heat, offsetting a series of clinical events. The anesthesiologist might first notice a rise in end-tidal CO2, nonreactive to increasing ventilation, followed by tachycardia, tachypnea, hypotension, metabolic and respiratory acidosis, hyperkalemia, cardiac dysrhythmias, skeletal muscle rigidity and hyperthermia [2,3]. ...
... The prevalence of malignant hyperthermia is estimated at 1.5-2.5/100 000 general anesthesia events, even though the prevalence of malignant hyperthermia susceptibility is estimated at 1/2000 by the Malignant Hyperthermia Association of the United States [2,3]. This discrepancy is likely caused by incomplete penetrance and variable expressivity. ...
Article
Purpose of review: We will give an overview of neuromuscular disorders that can be linked with malignant hyperthermia or malignant hyperthermia-like reactions, and suggest an appropriate approach to interpret the risks. Recent findings: An increasing number of neuromuscular phenotypes have been linked to malignant hyperthermia susceptibility (MHS). This is for an important part due to the highly variable phenotype associated with mutations in the ryanodine receptor 1 gene (RYR1), the gene most frequently associated with MHS. A RYR1-mutation or a clinical RYR1-phenotype does not automatically translate in MHS, but precautions should be taken nonetheless. In addition, several other genes and phenotypes are now considered to be associated with MHS. In contrast, several neuromuscular diseases that were long thought to be linked to MHS are now known to cause malignant hyperthermia-like reactions instead of malignant hyperthermia. This is highly relevant as not only the given preoperative advice differs, but also acute treatment. Summary: This review provides a summary of current evidence linking certain neuromuscular diseases to malignant hyperthermia or malignant hyperthermia-like reactions. We provide a guide for the clinician, to determine which patients are at risk of malignant hyperthermia or malignant hyperthermia-like reactions perioperatively, and to ensure adequate treatment in case such a severe acute complication occurs.
... Malignant hyperthermia (MH) is a rare and severe pharmacogenetic disorder of skeletal muscle [1] that manifests clinically as a hypercatabolic crisis caused by volatile anesthetic or succinylcholine exposure [1]. The prevalence is about 1/100 000 administered anesthetics in general population [2] but its mortality remains high (10% to 70%) [2].Classic clinical symptoms of MH include hypercarbia, tachycardia, masseter contraction and hyperthermia [1]. Severe cardiac arrhythmia leading to cardiac arrest may be seen later [3], but the occurrence of cardiac arrest with asystole immediately after sevoflurane administration is original. ...
... Malignant hyperthermia (MH) is a rare and severe pharmacogenetic disorder of skeletal muscle [1] that manifests clinically as a hypercatabolic crisis caused by volatile anesthetic or succinylcholine exposure [1]. The prevalence is about 1/100 000 administered anesthetics in general population [2] but its mortality remains high (10% to 70%) [2].Classic clinical symptoms of MH include hypercarbia, tachycardia, masseter contraction and hyperthermia [1]. Severe cardiac arrhythmia leading to cardiac arrest may be seen later [3], but the occurrence of cardiac arrest with asystole immediately after sevoflurane administration is original. ...
... ASC, ambulatory surgical center; free, freestanding; Or, operating room. [67][68][69][70] relationship to Dantrolene. ...
... 72 Given our new data, investigators may wish to pursue additional cost-benefit analyses, although MH incidence is still difficult to determine. 67,73,74 Conclusions This study presents evidence that succinylcholine is used frequently in many anesthetizing and sedating locations, including for cases in which difficult mask ventilation is encountered. Succinylcholine administered without volatile anesthetics triggers MH events that warranted dantrolene treatment. ...
Article
Full-text available
What we already know about this topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality. Methods: The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given. Results: Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities. Conclusions: Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.
... 1,4 Epidemiology Malignant hyperthermia is reported to occur in all racial groups with an estimated incidence of 1/15,000 to 1/75,000 anesthetics. 1,5,6 The true prevalence of MH susceptibility is underestimated because of incomplete penetrance and variable expression of the MH susceptibility trait. MH reactions can present with mild, nonspecific symptoms that go unrecognized; besides, due to incomplete penetrance, MH-susceptible individuals might undergo several uneventful anesthetics (on average three) prior to developing a fulminant MH reaction. ...
Article
Purpose: This continuing professional development module aims to prepare anesthesiologists for the timely recognition and management of a malignant hyperthermia (MH) reaction, which is crucial for averting its life-threatening complications and ultimately for the patient's survival. Principal findings: Malignant hyperthermia is a genetic disorder of skeletal muscle cells affecting myoplasmic calcium homeostasis. It can present with nonspecific signs of a hypermetabolic reaction, which can be fatal if treatment, including administration of dantrolene sodium, is not implemented promptly. Rapid evaluation and rejection of alternative diagnoses can lead to a prompt diagnosis and treatment and therefore will significantly reduce the complications, including renal failure, cardiac dysfunction, disseminated intravascular coagulation, and death. After the reaction, patients should be observed for a minimum of 24 hr because of the possibility of recrudescence. As it is a genetic condition, survivors and their family members should be referred to a specialized MH centre for further testing and counselling. Conclusions: The risk of dying from MH has increased over the past few years. A knowledgeable anesthesiologist who is diligent and attentive can recognize signs of an impending MH reaction and treat promptly to avoid complications of this deadly condition.
... MH may occur in any race and the exact prevalence of MH is unknown. The anesthesia related MH varies from 1 per 16 000 in Denmark to 1 per 100 000 in the New York State of the USA [11][12] . A recent study containing a total of 9 745 539 inpatient discharge records showed the overall prevalence of 1.68 per 100 000 inpatient discharges and 2.37 per 100 000 surgical inpatient discharges [13] . ...
Article
Full-text available
Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 ( RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.
... Intubation has been recommended after the first trimester (Miller 1994) but should be left at the discretion of the anesthesiologist, who should consider the medical comorbidities and pregnancy risk. It is also important to remember that succinylcholine is a potential trigger for malignant hyperthermia so appropriate treatment (e.g., dantrolene) may be used (Lu et al. 2017). In patients with personal or family history of malignant hyperthermia, the use of alternative non-depolarizing muscle relaxants (e.g., rocuronium) should be used at the discretion of the anesthesiologist (Abou-Arab et al. 2016). ...
Article
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Psychiatric disorders are common in pregnancy, affecting 15–29% of pregnant women. Untreated depression has negative health consequences for mother and fetus. Electroconvulsive therapy (ECT) is an effective option for the treatment of severe depression, high suicide risk, catatonia, medication-resistant illness, psychotic agitation, severe physical decline, and other life-threatening conditions. To our knowledge, however, there is no literature that consolidates all the evidence on maternal and fetal risks associated with untreated depression, medications, and ECT then translating it into one cohesive protocol that could serve as a management guide and a source of reassurance to health-care providers involved in such practice. Hoping to facilitate ECT access to perinatal patients, the authors combined their multidisciplinary clinical experience (in perinatal psychiatry, neuropsychiatry and neuromodulation, and anesthesiology) at three different centers in the USA (Brigham and Women’s Hospital/Harvard Medical School, The University of Chicago, and Brown University) with a careful and critical literature review and propose guidelines for the administration of ECT in pregnancy. A comprehensive review of the relevant literature regarding both ECT and psychotropic medications in pregnancy was performed, including meta-analyses of randomized controlled trials published in general medicine, anesthesiology, psychiatry, and obstetrics journals and guidelines. The indication and appropriateness of ECT in pregnancy must be carefully weighed against the risks of untreated maternal illness and those of alternative treatment options. The safety of ECT in pregnancy has been documented over the last 50 years. The adverse effects in pregnancy are similar to the risks of ECT in any individual. The most common risk to the mother is premature contractions and preterm labor, which occur infrequently and are not clearly caused by ECT. The rates of miscarriages were not significantly different from that of the general population. There have been no associations of ECT with congenital anomalies, either morphologic or behavioral, and no neurocognitive disturbances in the child. ECT is a reasonably safe and effective treatment alternative for management of many psychiatric disorders in pregnant patients. The authors provide recommendations for treatment modifications in pregnancy-based physiologic changes that occur during that period and consolidate them into a protocol that can assist clinicians in improving access and safety of ECT for pregnant patients.
... Malignant hyperthermia (MH) is a rare but lifethreatening pharmacogenetic muscle disorder characterized by abnormal hypermetabolic reactions and commonly triggered in susceptible individuals by volatile anesthetics or succinylcholine, or both. The incidence of MH is estimated between 1/5000 and 1/ 250000 anesthetics [1][2][3][4][5]. However, the real prevalence of MH susceptibility is very much higher because most people with MH-related genetic mutations never undergo any anesthesias during their lives. ...
Article
Full-text available
Background: Malignant hyperthermia is a rare but life-threatening pharmacogenetic muscle disorder characterized by abnormal hypermetabolic reactions and commonly triggered in susceptible individuals by volatile anesthetics or succinylcholine, or both. Unfortunately, the specific medicine dantrolene is not readily available in many countries including China. The aim of this study was to find the characteristics of malignant hyperthermia under the situation that dantrolene is not readily available. Methods: The cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. The inclusion criteria were the MH episodes only related to anesthesia. The exclusion criteria were dubious MH episodes only caused by Ketamine administration or MH episodes irrelevant to anesthesia. Independent samples t-test and Pearson's chi-squared test were applied to assess the difference between the survived and death cases. Results: Ninety-two cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. Median (IQR [range]) age was 18.5 (11.8-37.0 [0-70.0]) years. Compared with the survived cases, the death cases had higher maximum end-tidal partial pressure of CO2 (P = 0.033), the maximum arterial partial pressure of CO2 (P = 0.006), temperature first measured when the patient was first discovered abnormal (P = 0.012), and maximum temperature (P < 0.001). Besides, the death cases had less minimum pH (P < 0.001) and higher potassium (P < 0.001) and were more likely to have coagulation disorders (p = 0.018). Concerning treatment, cases used furosemide (P = 0.024), mannitol (P = 0.029), blood purification treatment (P = 0.017) had the advantage on the outcome. Creatine phosphokinase, myoglobin, and MB isoenzyme of creatine phosphokinase differed greatly among cases during the first week. 43 (46.7%) cases had congenital diseases. 12 (13.0%) cases were reported with abnormal laboratory test results or abnormal signs that are possibly relevant before anesthesia. Conclusions: In countries that dantrolene is not readily available, early warning, diagnosis, and prompt effective therapies are crucial for MH patients to survive.
... As Malignant hyperthermia (MH), proportion ranging from 1:35,000 to 1:68,000, is extremely rare autosomal dominant pharmacogenetic disorder that triggered in genetically predisposed individuals by any of the potent volatile anaesthetics, such as isoflurane, desflurane, sevoflurane or ensoflurane, with or without succinylcholine [1,2]. Some literature indicates the mortality of a fulminant MH episode is >70% without treated, but increased awareness, advances in monitoring, and availability of dantrolene, have substantially reduced the mortality to <8% [3,4]. ...
... Despite the discoveries in genetics and principal pathophysiology of MH [14], some aspects remain poorly understood even 50 years after its original description. One question concerns the unexplained discrepancy between the low prevalence of MH reactions (1 in 15-75000 general anesthetics) [15,16], and the relatively high combined prevalence of MH-causative RYR1 variants (1:2800 in the general population, according to the exome data from 60000 individuals (https://gnomad.broadinstitute.org/gene/ENSG00000196218?dataset=gnomad_r2_1). This discrepancy may be partly explained by lack of exposure of genetically predisposed individuals to MH-triggering agents. ...
Preprint
Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anesthetics and succinylcholine. MH is caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between the prevalence of risk genotypes and actual MH incidence remains unexplained. We investigated the role of pre-operative exercise and pyrexia as potential MH modifying factors. We included cases from 5 MH referral centers with 1) clinical features suggestive of MH, 2) confirmation of MH susceptibility on Contracture Testing (IVCT or CHCT) and/or RYR1 genetic testing, and a history of 3) strenuous exercise within 72 h and/or pyrexia >37.5 °C prior to the triggering anesthetic. Characteristics of MH-triggering agents, surgery and succinylcholine use were collected. We identified 41 cases with general anesthesias resulting in an MH event (GA+MH, n = 41) within 72 h of strenuous exercise and/or pyrexia. We also identified previous general anesthesias without MH events (GA-MH, n = 51) in the index cases and their MH susceptible relatives. Apart from pre-operative exercise and/or pyrexia, trauma and acute abdomen as surgery indications, emergency surgery and succinylcholine use were also more common with GA+MH events. These observations suggest a link between pre-operative exercise, pyrexia and MH.
... The overall prevalence of MH is difficult to estimate because of regional population differences, incomplete penetrance, and variable expressivity of the inherited neuromuscular disorders [32]. Data from an administrative national database of the United States reported an increasing incidence of 10. [36]. ...
Chapter
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Halogenated anesthetics and succinylcholine administration occasionally cause serious complications such as malignant hyperthermia, rhabdomyolysis, and hyperkalemia in patients with neuromuscular diseases. Sensitivity to anesthetic agents can accentuate dysautonomia, cardiomyopathy, dysrhythmias, atelectasis, and nosocomial infections. Pre-operative evaluation is important. Regional anesthesia should be used whenever feasible. We discuss the complications and peri-operative considerations of anesthesia administration to patients with neuromuscular disease.
Article
Resumen La hipertermia maligna (HM) de la anestesia es una enfermedad farmacogenética que se manifiesta de manera inconstante por un estado de hipermetabolismo del músculo esquelético durante la exposición a un agente anestésico volátil desencadenante. Los numerosos avances referentes a la fisiopatología de la HM han permitido evidenciar el gen RYR1, mayoritariamente implicado, y la instauración de procedimientos de detección por genética o prueba biológica. Sin embargo, formas de episodios de HM incompletas o abortadas por la mejoría de la monitorización anestésica o, también, fallecimientos perioperatorios inexplicados pueden conducir a una infravaloración de la incidencia de manifestaciones de HM durante la anestesia. Aunque se hayan realizado progresos considerables en las herramientas de genética molecular para la exploración detallada de los genomas de individuos, a veces se acompañan de dificultades mayores en el diagnóstico, porque las correlaciones genotipo-fenotipo que permitirían un diagnóstico de certeza todavía no existen. Actualmente, una organización nacional y europea dedicada a la HM ha permitido el establecimiento de recomendaciones en todos los ámbitos de la enfermedad: procedimiento terapéutico de urgencia y utilización del dantroleno en caso de episodios de HM, detección y evaluación del riesgo de HM en un individuo en la consulta de anestesia, riesgo de HM en los parientes, precauciones anestésicas en pacientes con una HM o considerados de riesgo y procedimiento de diagnóstico de la sensibilidad a la HM en un probando o sus parientes.
Article
Riassunto L’ipertermia maligna (IM) dell’anestesia è una patologia farmacogenetica che si manifesta in modo incostante con uno stato di ipermetabolismo del muscolo scheletrico in seguito all’esposizione a un agente anestetico volatile scatenante. I numerosi progressi nella fisiopatologia dell’IM hanno permesso di evidenziare il gene RYR1 principalmente implicato e l’implementazione di procedure di screening mediante test genetici o biologici. Tuttavia, forme di crisi di IM fruste o interrotte con il miglioramento del monitoraggio anestesiologico o ancora dei decessi perioperatori inspiegabili possono portare a sottovalutare l’incidenza delle manifestazioni di IM durante un’anestesia. Benché siano stati compiuti notevoli progressi negli strumenti di genetica molecolare nell’esplorazione dettagliata dei genomi degli individui, essi si accompagnano talvolta a maggiori difficoltà nella diagnosi poiché mancano ancora le correlazioni genotipo-fenotipo che consentirebbero una diagnosi di certezza. Oggi, un’organizzazione nazionale ed europea relativa all’IM ha permesso l’implementazione di raccomandazioni in tutti i settori della patologia: procedura terapeutica urgente e uso del dantrolene in caso di crisi di IM, screening e valutazione del rischio di IM in un soggetto in visita anestesiologica, rischio di IM nei parenti, precauzioni anestetiche in pazienti con un’IM o considerati a rischio e procedura per diagnosticare la suscettibilità all’IM in un paziente in corso di valutazione o nei suoi parenti.
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Historically, patients who developed malignant hyperthermia had an extremely high rate of mortality. Today, if treated appropriately, patients who experience an episode of malignant hyperthermia will most likely survive. This dramatic decrease in mortality associated with malignant hyperthermia is due to several factors, including an increased understanding of the disease, improved diagnostic and monitoring equipment, and the development of lifesaving pharmacologic agents. This article presents the very likely case of acute malignant hyperthermia in a 24-year-old man with special needs, who presented for restorative dentistry under general anesthesia in the outpatient clinic of The Ohio State University's College of Dentistry.
Article
Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anesthetics and succinylcholine. MH is caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between the prevalence of risk genotypes and actual MH incidence remains unexplained. We investigated the role of pre-operative exercise and pyrexia as potential MH modifying factors. We included cases from 5 MH referral centers with 1) clinical features suggestive of MH, 2) confirmation of MH susceptibility on Contracture Testing (IVCT or CHCT) and/or RYR1 genetic testing, and a history of 3) strenuous exercise within 72 h and/or pyrexia > 37.5 °C prior to the triggering anesthetic. Characteristics of MH-triggering agents, surgery and succinylcholine use were collected. We identified 41 cases with general anesthesias resulting in an MH event (GA + MH, n = 41) within 72 h of strenuous exercise and/or pyrexia. We also identified previous general anesthesias without MH events (GA-MH, n = 51) in the index cases and their MH susceptible relatives. Apart from pre-operative exercise and/or pyrexia, trauma and acute abdomen as surgery indications, emergency surgery and succinylcholine use were also more common with GA + MH events. These observations suggest a link between pre-operative exercise, pyrexia and MH.
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This book functions as a practical reference for recognizing various patient presentations, signs, and symptoms that must be considered when treating neuromuscular disorders (NMD). It emphasizes the importance of recognizing these preexisting conditions as this can be crucial to treating patients properly with appropriate medications and procedures. Concise yet comprehensive, this 10-chapter guide analyses various neuromuscular weaknesses including respiratory and progressive muscle weakness. Chapters address the involvement of multiple organ systems in NMD, with specific attention to cardiomyopathy, cardiac arrhythmias, and dystrophinopathies. Discussions also address the challenges practitioners face when treating vulnerable demographics such as pregnant women and those with hyper metabolic conditions. Written by experts in the field, Neuromuscular Urgencies and Emergencies is an invaluable resource for neurologists, emergency medicine physicians, physician assistants, and the interventional neurologist.
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Mutations in the skeletal muscle Ca 2+ release channel, the type 1 ryanodine receptor (RYR1), cause malignant hyperthermia susceptibility (MHS) and a life-threatening sensitivity to heat, which is most severe in children. Mice with an MHS-associated mutation in Ryr1 (Y524S, YS) display lethal muscle contractures in response to heat. Here we show that the heat response in the YS mice is exacerbated by brown fat adaptive thermogenesis. In addition, the YS mice have more brown adipose tissue thermogenic capacity than their littermate controls. Blood lactate levels are elevated in both heat-sensitive MHS patients with RYR1 mutations and YS mice due to Ca 2+ driven increases in muscle metabolism. Lactate increases brown adipo-genesis in both mouse and human brown preadipocytes. This study suggests that simple lifestyle modifications such as avoiding extreme temperatures and maintaining thermo-neutrality could decrease the risk of life-threatening responses to heat and exercise in individuals with RYR1 pathogenic variants.
Article
Malignant hypothermia (MH) is a potentially fatal hypermetabolic reaction of skeletal muscle. It is an autosomal dominant disorder that generally occurs in people with RYR1, CACNA1S, or STAC3 mutations. And these genetic abnormalities often cause the imperfection of calcium release channels of skeletal muscle. The incidence of MH among different racial groups across the world ranges from approximately 1:5,000-1:250,000, but there is no national statistic MH incidence in China. It is not clear whether there are racial or regional differences in the incidence, but patients under 18 years old may be more affected. MH can be triggered by anesthetics, or other stimuli, such as strenuous exercise, heat-stroke, and emotional stress. While viral infection, statins, hyperglycemia, and muscle metabolic dysfunctions might accelerate the onset of MH. The onset of MH is insidious and rapid, with the preclinical stage characterized by rigidity of the masseter muscle, a high level of end-tidal carbon dioxide, and a sharp and persistent increase in body temperature. Medical history, family history, clinical presentation, in vitro caffeine-halothane contracture testing (IVCT/CHCT) and genetic testing are commonly diagnostic methods of MH. As soon as the onset of MH is suspected, immediate cessation of exposure to stimuli, call for professional support, and access to dantrolene are the highest priorities. For symptomatic treatment, “5C principles” were summarized as an algorithm to guide clinicians.
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Most of the pediatric neuromuscular diseases often manifest by slowly progressive or fluctuating motor weakness. However, there are some neuromuscular conditions that present with acute weakness which could terrify parents as well as children and are often a diagnostic and therapeutic challenge for clinicians. A timely and methodical approach to diagnosis and subsequent treatment is paramount. This chapter discusses the common neuromuscular diseases that could present in the emergency department with a focus on characteristic symptoms, evaluation, treatment, and prognosis.
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N. Arora et al. (eds.), Neuromuscular Urgencies and Emergencies
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Background: Malignant hyperthermia is a rare but life-threatening pharmacogenetic muscle disorder characterized by abnormal hypermetabolic reactions and commonly triggered in susceptible individuals by volatile anesthetics or succinylcholine, or both. Unfortunately, the specific medicine dantrolene is not readily available in many countries including China. The aim of this study was to find the characteristics of malignant hyperthermia under the situation that dantrolene is not readily available. Methods: The cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. The inclusion criteria were the MH episodes only related to anesthesia. The exclusion criteria were dubious MH episodes only caused by Ketamine administration or MH episodes irrelevant to anesthesia. Independent samples t-test and Pearson’s chi-squared test were applied to assess the difference between the survived and death cases. Results: Ninety-two cases of malignant hyperthermia reported on the most commonly used databases in China from 1985 to 2020 were analyzed. Median (IQR [range]) age was 18.5 (11.8-37.0 [0-70.0 ]) years. Compared with the survived cases, the death cases had higher maximum end-tidal partial pressure of CO2 (P=0.033), the maximum arterial partial pressure of CO2 (P=0.006), temperature first measured when the patient was first discovered abnormal (P=0.012), and maximum temperature (P<0.001). Besides, the death cases had less minimum pH (P<0.001) and higher potassium (P<0.001) and were more likely to have coagulation disorders (p=0.018). Concerning treatment, cases used furosemide (P=0.024), mannitol (P=0.029), blood purification treatment (P=0.017) had the advantage on the outcome. Creatine phosphokinase, myoglobin, and MB isoenzyme of creatine phosphokinase differed greatly among cases during the first week. 43 (46.7%) cases had congenital diseases. 12 (13.0%) cases were reported with abnormal laboratory test results or abnormal signs that are possibly relevant before anesthesia. Conclusions: In countries that dantrolene is not readily available, early warning, diagnosis, and prompt effective therapies are crucial for MH patients to survive.
Article
Background: Malignant hyperthermia (MH) is an inherited muscle disorder induced by volatile anesthetics and depolarizing muscle relaxants. While the incidence of MH is high in young, there are few reports on the clinical features of pediatric MH. In this study, we selected pediatric cases from an MH database and analyzed the clinical findings by age group. We hypothesized that there would be age-related differences in the clinical characteristics. Methods: A retrospective analysis of MH data collected in our database during 1960 to 2020 was performed to identify pediatric subjects (≤18 years) with a Clinical Grading Scale of ≥35, indicating "very likely" or "almost certain" MH. We compared clinical characteristics among the 0 to 24 month, 2 to 12 year, and 13 to 18 year (youngest, middle, and oldest, respectively) age groups. Results: Data were available for 187 patients: 15 in the youngest age group, 123 in the middle-aged group, and 49 in the oldest age group. Of these, 55 patients (29.4%) had undergone muscle biopsy and muscle contracture test. The mortality rates during the study period were 13.3%, 13.8%, 20.4%, and 15.5% in the youngest, middle, and oldest cohorts and overall, respectively. In contrast, the overall mortality rate from 2000 to 2020 was 8.8%. The most frequent initial symptoms of MH were elevated temperature (46.7%) and generalized muscular rigidity (26.7%) in the youngest cohort, masseter spasm (35.0%) and generalized muscular rigidity (19.5%) in the middle cohort, and elevated end-tidal carbon dioxide (26.5%) and tachycardia (22.4%) in the oldest cohort. Physical examination revealed that elevated temperature, sinus tachycardia, and respiratory acidosis occurred frequently in all groups. The middle cohort had high frequencies of masseter spasm (58.4%; P = .02) and dark urine (75.5%; P = .01) compared to those in the oldest groups, and had a higher peak creatine kinase level compared to those in the 3 groups. Skeletal muscle symptoms tended to be more common in patients administered succinylcholine (generalized muscular rigidity, P = .053; masseter spasm, P < .0001; dark urine, P < .0001). In particular, masseter spasm and dark urine were more common in the middle cohort when succinylcholine was administered (masseter spasm: versus youngest cohort, P = .06, versus oldest cohort, P = .027; dark urine: versus youngest cohort, P = .0072, versus oldest cohort, P = .0015). Conclusions: The clinical characteristics of pediatric patients with MH vary according to age group. The difference in initial symptoms of MH depending on age group is noteworthy information for the early diagnosis of MH.
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Prompt attention to the common neuromuscular emergencies (NME) that could present during pregnancy is essential for maternal-fetal wellbeing. Pregnancy in itself has its own challenges in management, and dealing with an NME during that critical time period is of utmost importance. This chapter describes common neuromuscular emergencies that could present during pregnancy. Neurologists are often expected to deal with a neuromuscular emergency in a pregnant female. It is often difficult to evaluate and treat these patients without proper understanding of the disease process. The physiologic changes during pregnancy, labor, and puerperium increase the maternal risk of neuromuscular complications. The purpose of the chapter is not to detail about every single neurologic disorder which could happen in pregnant females but to focus on commonly encountered neuromuscular emergencies confronted by the treating physician and how to practically deal with it. Most common disorders are listed below according to the location of injury: 1. Spinal cord: Trauma 2. Nerve and nerve roots: Guillain-Barre syndrome, compression-related nerve injuries 3. NM junction: Myasthenia gravis 4. Muscle: Inflammatory muscle disease
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Background: In 1997, the International Classification of Diseases (ICD), 9th Revision Clinical Modification (ICD-9) coding system introduced the code for malignant hyperthermia (MH) (995.86). The aim of this study was to estimate the accuracy of coding for MH in hospital discharge records. Methods: An expert panel of anesthesiologists reviewed medical records for patients with a discharge diagnosis of MH based on ICD-9 or ICD-10 codes from January 1, 2006 to December 31, 2008 at six tertiary care medical centers in North America. All cases were categorized as possible, probable, or fulminant MH, history of MH (family or personal) or other. Results: A total of 47 medical records with MH diagnoses were reviewed; 68.1% had a documented surgical procedure and general anesthesia, and 23.4% (95% CI, 12.3-38.0%) had a possible, probable, or fulminant MH event. Dantrolene was given in 81% of the MH events. All patients judged to have an incident MH event survived to discharge. Family and personal history of MH accounted for 46.8% of cases. High fever without evidence of MH during admission accounted for 23.4%, and the reason for MH coding was unclear in 6.4% of cases. Conclusions: Approximately one quarter of ICD-9 or ICD-10 coded MH diagnoses in hospital discharge records refer to incident MH episodes and an additional 47% to MH susceptibility (including personal history or family history). Information such as surgical procedure, anesthesia billing data, and dantrolene administration may aid in identifying incident MH cases among those with an ICD-9 or ICD-10 coded MH diagnosis in their hospital discharge records.
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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.
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Malignant hyperthermia (MH) is a pharmacogenetic disease that causes abnormal hypermetabolic reaction to halogenated anesthetics and/or depolarizing muscle relaxants. In Brazil, there is a hotline telephone service for MH since 1991, available 24 hours a day in São Paulo. This article analyzes the activity of the Brazilian hotline service for MH in 2009. Prospective analysis of all phone calls made to the Brazilian hotline service for MH from January to December 2009. Twenty-two phone calls were received: 21 from the South/Southeast region of Brazil and one from the North region. Fifteen calls were requests for general information about MH. Seven were about suspected MH acute episodes, two of which were not considered as MH. In five episodes compatible with MH, all patients received halogenated volatile anesthetics (2, isoflurane; 3, sevoflurane) and one also used succinylcholine; there were four men and one woman, with a mean age of 18 years (2-27). The problems described in the five MH episodes were tachycardia (5), increased expired carbon dioxide (4), hyperthermia (3), acidemia (1), rhabdomyolysis (1), and myoglobinuria (1). One patient received dantrolene. All five patients with MH episodes were follow-up in the intensive care unit and recovered without sequelae. Susceptibility to MH was later confirmed in two patients by in vitro muscle contracture test. The number of calls per year in the Brazilian hotline service for MH is still low. The characteristics of MH episode were similar to those reported in other countries. The knowledge of MH in Brazil needs to be increased.
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We analyzed cases of malignant hyperthermia (MH) reported to the North American MH Registry for clinical characteristics, treatment, and complications. Our inclusion criteria were as follows: AMRA (adverse metabolic/musculoskeletal reaction to anesthesia) reports between January 1, 1987 and December 31, 2006; "very likely" or "almost certain" MH as ranked by the clinical grading scale; United States or Canadian location; and more than one anesthetic drug given. An exclusion criterion was pathology other than MH; for complication analysis, patients with unknown status or minor complications attributable to dantrolene were excluded. Wilcoxon rank sum and Pearson exact chi(2) tests were applied. A multivariable model of the risk of complications from MH was created through stepwise selection with fit judged by the Hosmer-Lemeshow statistic. Young males (74.8%) dominated in 286 episodes. A total of 6.5% had an MH family history; 77 of 152 patients with MH reported >or=2 prior unremarkable general anesthetics. In 10 cases, skin liquid crystal temperature did not trend. Frequent initial MH signs were hypercarbia, sinus tachycardia, or masseter spasm. In 63.5%, temperature abnormality (median maximum, 39.1 degrees C) was the first to third sign. Whereas 78.6% presented with both muscular abnormalities and respiratory acidosis, only 26.0% had metabolic acidosis. The median total dantrolene dose was 5.9 mg/kg (first quartile, 3.0 mg/kg; third quartile, 10.0 mg/kg), although 22 patients received no dantrolene and survived. A total of 53.9% received bicarbonate therapy. Complications not including recrudescence, cardiac arrest, or death occurred in 63 of 181 patients (34.8%) with MH. Twenty-one experienced hematologic and/or neurologic complications with a temperature <41.6 degrees C (human critical thermal maximum). The likelihood of any complication increased 2.9 times per 2 degrees C increase in maximum temperature and 1.6 times per 30-minute delay in dantrolene use. Elevated temperature may be an early MH sign. Although increased temperature occurs frequently, metabolic acidosis occurs one-third as often. Accurate temperature monitoring during general anesthetics and early dantrolene administration may decrease the 35% MH morbidity rate.
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Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder of skeletal muscle, characterised by an elevated calcium release from the skeletal muscle sarcoplasmic reticulum. The dihydropyridine receptor (DHPR) plays an essential role in excitation-contraction coupling and calcium homeostasis in skeletal muscle. This study focuses on the gene CACNA1S which encodes the alpha1 subunit of the DHPR, in order to establish whether CACNA1S plays a major role in MH susceptibility in the UK. We investigate the CACNA1S locus in detail in 50 independent MH patients, the largest study to date, to identify novel variants that may predispose to disease and also to characterise the haplotype structure across CACNA1S. We present CACNA1S cDNA sequencing data from 50 MH patients in whom RYR1 mutations have been excluded, and subsequent mutation screening analysis. Furthermore we present haplotype analysis of unphased CACNA1S SNPs to (1) assess CACNA1S haplotype frequency differences between susceptible MH cases and a European control group and (2) analyse population-based association via clustering of CACNA1S haplotypes based on disease risk. The study identified a single potentially pathogenic change in CACNA1S (p.Arg174Trp), and highlights that the haplotype structure across CACNA1S is diverse, with a high degree of variability.
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In 1992, 1812 individuals (1.2% of the population) were labelled at risk for malignant hyperthermia (MH) in seven families from Abitibi-Témiscamingue. To evaluate the effective risk in this population, a multidisciplinary study was undertaken which included clinical, genealogical and molecular aspects. This paper presents the clinical aspects of the study. For each of the 1546 individuals reached, all anesthetic exposures were screened for elements relevant to MH. Malignant hyperthermia events were analyzed with "the clinical grading scale." All 44 reports of caffeine halothane contracture tests were reappraised. Finally, genealogical study was done to complete each family tree up to the initial French settlers in order to identify links between these seven families through common ancestors. Following this reassessment, the families were compared and classified into four groups. Two families (1097 individuals) are not considered to be at a higher risk for MH than the population in general. Two families are still considered possibly at risk. Finally, one family (402 individuals) is highly at risk and two other families are probably at risk. Family trees did not show any link up to the colonization of Abitibi-Témiscamingue in the beginning of this Century but common ancestors were found around the 9th generation. This clinical reassessment will help to focus education and prevention on a much smaller group of individuals still considered potentially at risk for MH. By adequate evaluation of phenotypes, combined with the use of a genealogical approach, it will be possible to target families for molecular research.
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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 and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:5,000 to 1:50,000-100,000 anesthesias. However, the prevalence of the genetic abnormalities may be as great as one in 3,000 individuals. MH affects humans, certain pig breeds, dogs, horses, and probably other animals. The classic signs of MH include hyperthermia to marked degree, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH, specifically elevation of end-expired carbon dioxide, provides the clinical diagnostic clues. In humans the syndrome is inherited in autosomal dominant pattern, while in pigs in autosomal recessive. The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be used for identifying those at risk with greater frequency. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. Thanks to the dramatic progress in understanding the clinical manifestation and pathophysiology of the syndrome, the mortality from MH has dropped from over 80% thirty years ago to less than 5%.
Article
To the Editor: Malignant hyperthermia (MH) is an autosomal dominant condition in which certain anesthetics trigger calcium dysregulation in skeletal muscle, resulting in a catastrophic, life-threatening hypermetabolic syndrome.1 More than 50% of families with MH have mutations in the gene encoding the ryanodine receptor (RYR1).2 In a porcine model of MH, nonanesthetic, stress-induced deaths have been reported in pigs homozygous for the Arg614Cys mutation in the RYR1 gene,3 but this phenomenon has not been reported in humans with MH mutations. To our knowledge, we report the first case of nonanesthetic, stress-induced hyperpyrexic death in an individual with a history of MH.
Article
Objectives: Implementation of the International Statistical Classification of Disease and Related Health Problems, 10th Revision (ICD-10) coding system presents challenges for using administrative data. Recognizing this, we conducted a multistep process to develop ICD-10 coding algorithms to define Charlson and Elixhauser comorbidities in administrative data and assess the performance of the resulting algorithms. Methods: ICD-10 coding algorithms were developed by "translation" of the ICD-9-CM codes constituting Deyo's (for Charlson comorbidities) and Elixhauser's coding algorithms and by physicians' assessment of the face-validity of selected ICD- 10, codes. The process of carefully developing ICD-10 algorithms also produced modified and enhanced ICD-9-CM coding algorithms for the Charlson and Elixhauser comorbidities. We then used data on in-patients aged 18 years and older in ICD-9-CM and ICD-10 administrative hospital discharge data from a Canadian health region to assess the comorbidity frequencies and mortality prediction achieved by the original ICD-9-CM algorithms, the enhanced ICD-9-CM algorithms, and the new ICD-10 coding algorithms. Results: Among 56,585 patients in the ICD-9-CM data and 58,805 patients in the ICD-10 data, frequencies of the 17 Charlson comorbidities and the 30 Elixhauser comorbidities remained generally similar across algorithms. The new ICD-10 and enhanced ICD9-CM coding algorithms either matched or outperformed the original Deyo and Elixhauser ICD-9-CM coding algorithms in predicting in-hospital mortality. The C-statistic was 0.842 for Deyo's ICD9-CM coding algorithm, 0.860 for the ICD-10 coding algorithm, and 0.859 for the enhanced ICD-9-CM coding algorithm, 0.868 for the original Elixhauser ICD-9-CM coding algorithm, 0.870 for the ICD-10 coding algorithm and 0.878 for the enhanced ICD-9-CM coding algorithm. Conclusions: These newly developed ICD-10 and ICD-9-CM comorbidity coding algorithms produce similar estimates of comorbidity prevalence in administrative data, and may outperform existing ICD-9-CM coding algorithms.
Article
Study of phenotype and familial distribution of malignant hyperthermia (MH) suggests heterogeneity with MH possibly being a symptom of several disorders. Review of all reported family studies supports the concept of heterogeneity with autosomal dominant inheritance in about one-half of the families. There is no strong evidence for other mendelian patterns of inheritance, but sporadic and possibly multifactorially determined cases are common. MH is also seen in other musculoskeletal disorders. We report 12 Wisconsin families with MH and outline a preliminary approach to the counseling of MH patients and their families.
Article
Case reports have linked malignant hyperthermia (MH) to several genetic diseases. The objective of this study was to quantitatively assess excess comorbidities associated with MH diagnosis in pediatric hospital discharge records. 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. 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). 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.
Article
Malignant hyperthermia (MH) is a rare but life-threatening disease that occurs during general anesthesia. The actual prevalence of MH remains unclear, and the association between MH and various anesthetic drugs remains controversial because of a lack of universal reporting. Using the Japanese Diagnosis Procedure Combination database, we collected data of inpatients who had general anesthesia between July and December 2006-2008. Patients' age, gender, diagnoses, procedures, and the use of drugs during anesthesia, including volatile agents, muscle relaxants, and propofol, were investigated. Univariate comparisons were made to examine the relationship of each anesthetic drug or demographic factor with the occurrence of MH. Of 1,238,171 surgical patients undergoing general anesthesia, we identified 17 MH patients. Only one in-hospital death was identified. Men were significantly more likely to contract MH(odds ratio: 3.49; 95% CI 1.14 -10.7; P=0.029). No MH patient was found among 19,871 suxamethonium users. The prevalence of MH was relatively high in users of sevoflurane and rocuronium compared with nonusers but was not statistically significant [corrected].. No single drug was significantly associated with the occurrence of MH. Data should be continuously compiled, and further analyses with larger numbers of cases are necessary to identify possible causative agents.
Article
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. 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. 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. 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.
Article
Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disorder with an estimated mortality of less than 5%. The purpose of this study was to evaluate the current incidence of MH and the predictors associated with in-hospital mortality in the United States. The Nationwide Inpatient Sample, which is the largest all-payer inpatient database in the United States, was used to identify patients discharged with a diagnosis of MH during the years 2000-2005. The weighted exact Cochrane-Armitage test and multivariate logistic regression analyses were used to assess trends in the incidence and risk-adjusted mortality from MH, taking into account the complex survey design. From 2000 to 2005, the number of cases of MH increased from 372 to 521 per year. The occurrence of MH increased from 10.2 to 13.3 patients per million hospital discharges (P = 0.001). Mortality rates from MH ranged from 6.5% in 2005 to 16.9% in 2001 (P < 0.0001). The median age of patients with MH was 39 (interquartile range, 23-54 yr). Only 17.8% of the patients were children, who had lower mortality than adults (0.7% vs. 14.1%, P < 0.0001). Logistic regression analyses revealed that risk-adjusted in-hospital mortality was associated with increasing age, female sex, comorbidity burden, source of admission to hospital, and geographic region of the United States. The incidence of MH in the United States has increased in recent years. The in-hospital mortality from MH remains elevated and higher than previously reported. The results of this study should enable the identification of areas requiring increased focus in MH-related education.
Article
Administrative databases are increasingly used for studying outcomes of medical care. Valid inferences from such data require the ability to account for disease severity and comorbid conditions. We adapted a clinical comorbidity index, designed for use with medical records, for research relying on International Classification of Diseases (ICD-9-CM) diagnosis and procedure codes. The association of this adapted index with health outcomes and resource use was then examined with a sample of Medicare beneficiaries who underwent lumbar spine surgery in 1985 (n = 27,111). The index was associated in the expected direction with postoperative complications, mortality, blood transfusion, discharge to nursing home, length of hospital stay, and hospital charges. These associations were observed whether the index incorporated data from multiple hospitalizations over a year's time, or just from the index surgical admission. They also persisted after controlling for patient age. We conclude that the adapted comorbidity index will be useful in studies of disease outcome and resource use employing administrative databases.
Article
Questionnaires were sent to all anesthesia departments in Denmark to determine the total number of anesthetics given per year, and the distribution of different types of anesthesia. All cases of suspected malignant hyperthermia forwarded to the Danish Malignant Hyperthermia Register during a 6.5 yr period were reviewed and divided into subgroups according to clinical criteria. The incidence of suspected malignant hyperthermia in these subgroups was calculated in relation to type of anesthesia. The results are based on information about 386,250 anesthetics and 154 cases of suspected malignant hyperthermia. All cases of malignant hyperthermia occurred during general anesthesia, and more than 75% during anesthesia with a combination of potent inhalation agents and succinylcholine. The incidence of fulminant malignant hyperthermia was low: 1 in 250,000 total anesthetic procedures, but 1 in 62,000 anesthetic procedures with a combination of potent inhalation agents and succinylcholine. Masseter spasm occurred in 1 of 12,000 anesthetic procedures in which succinylcholine was administered. Suspicion of malignant hyperthermia was raised in 1 of 16,000 anesthetics total, but in 1 of 4,200 anesthetics with the above-mentioned combination of agents.
Article
The contracture produced by caffeine in isolated strips of human muscle was measured in normal specimens and in samples from three volunteers who had recovered from severe episodes of malignant hyperthermia and who came from at-risk families. The hyperthermia was not accompanied by rigidity in one patient and his family but the rigidity was pronounced in the other two. The muscle from the non-rigid patient reacted as normal. The muscles from the two patients who had had rigidity showed enhanced sensitivity to caffeine and to the potentiating effect of halothane. The calcium accumulation of isolated sarcoplasmic reticulum was not affected by halothane in preparations from control muscle but was inhibited in those from the rigid patients. the observations suggest that the metabolic error in hyperthermia with rigidity causes intracellular calcium metabolism to be vulnerable to drugs. Malignant hyperthermia with and without rigidity seem to be disease entities with different ætiologies.
Article
Malignant hyperthermia (MH), heat stroke, and exercise-induced rhabdomyolysis (ER) were suspected to be related syndromes. However, it is not known whether individuals with history of ER have an increased incidence of susceptibility to MH. To establish an association between ER and susceptibility to MH, the authors determined the MH status in patients with a history of MH-like episodes induced by physical stress. Twelve unrelated patients with ER, 18 patients with anesthesia-induced MH, and 28 controls were investigated with the in vitro contracture test (IVCT) according to the European MH Group protocol and the ryanodine contracture test. In addition, all patients were screened for genetic mutations, and histology was performed on muscle specimens. Ten ER patients had positive IVCT results, one patient had a negative test result, and one patient showed equivocal responses. Samples from patients with positive IVCT results showed pronounced contractures after exposition to ryanodine, as opposed to specimens from patients with negative IVCT results, which developed contractures slowly. Three ER patients had mutations at the ryanodine receptor gene. All anesthesia-induced MH patients had positive IVCT results, two of them presented the C1840T mutation. The control patients had normal contracture test results and no typical MH mutations. Histologic examination determined no specific myopathies in any patient. Regarding these results, the authors recommend performing muscle biopsies for histologic examination and IVCT in patients with ER. In addition, the patient should be seen by a neurologist and screened for genetic abnormalities to shed light on the genetics of MH.
Article
To the Editor: Malignant hyperthermia (MH) is an autosomal dominant condition in which certain anesthetics trigger calcium dysregulation in skeletal muscle, resulting in a catastrophic, life-threatening hypermetabolic syndrome.1 More than 50% of families with MH have mutations in the gene encoding the ryanodine receptor (RYR1).2 In a porcine model of MH, nonanesthetic, stress-induced deaths have been reported in pigs homozygous for the Arg614Cys mutation in the RYR1 gene,3 but this phenomenon has not been reported in humans with MH mutations. To our knowledge, we report the first case of nonanesthetic, stress-induced hyperpyrexic death in an individual with a history of MH.
Article
Exertional heat stroke (EHS) is usually triggered by strenuous exercise performed under hot and humid environmental conditions. Although the pathogenesis of an EHS episode differs from that of a clinical malignant hyperthermia (MH) crisis, both conditions share some similarities in symptoms, such as the abnormal increase in core temperature. By use of (31)P magnetic resonance spectroscopy, we analyzed the muscle energetics of 26 post-EHS subjects for whom in vitro halothane/caffeine contracture tests were abnormal and investigated possible similarities with subjects susceptible to MH. An early decrease of pH was noted during the first minute of exercise in EHS subjects as compared with controls. EHS subjects were divided into two subgroups according to the diagnostic score previously developed for MH subjects. The 19 subjects (73%) with a score higher than 2 displayed significantly larger caffeine-induced and earlier ryanodine-induced contractures on muscle biopsies as compared with the rest of the group (7 subjects). The results demonstrate that muscle energetics are abnormal in subjects who have experienced EHS and suggest a possible link between MH and EH, although all EHS cannot be considered as MH.
Article
Malignant hyperthermia (MH) is a pharmacogenetic clinical syndrome that manifests as a hypermetabolic crisis when a susceptible individual is exposed to an anesthetic triggering agent. Clinical signs include unexplained elevation of end-tidal carbon dioxide, muscle rigidity, acidosis, tachycardia, tachypnea, hyperthermia, and evidence of rhabdomyolysis. This process is a result of an abnormally increased release of calcium from the sarcoplasmic reticulum, which is often caused by an inherited mutation in the gene for the ryanodine receptor (RYR1) that resides in the membrane of the sarcoplasmic reticulum. The gold standard for determination of MH susceptibility is the caffeine-halothane contracture test. However, it is invasive, requiring skeletal muscle biopsy and is not widely available. Researchers have begun to map mutations within the ryanodine receptor gene (chromosome 19q13.1) responsible for conferring MH susceptibility. Ryanodine receptor mutations are found in at least 25% of known MH susceptible individuals in North America. Mutation analysis has recently become available in the United States and is expected to play an integral role in the diagnosis of MH susceptibility in the future.
Article
To examine potential sources of errors at each step of the described inpatient International Classification of Diseases (ICD) coding process. The use of disease codes from the ICD has expanded from classifying morbidity and mortality information for statistical purposes to diverse sets of applications in research, health care policy, and health care finance. By describing a brief history of ICD coding, detailing the process for assigning codes, identifying where errors can be introduced into the process, and reviewing methods for examining code accuracy, we help code users more systematically evaluate code accuracy for their particular applications. We summarize the inpatient ICD diagnostic coding process from patient admission to diagnostic code assignment. We examine potential sources of errors at each step and offer code users a tool for systematically evaluating code accuracy. Main error sources along the "patient trajectory" include amount and quality of information at admission, communication among patients and providers, the clinician's knowledge and experience with the illness, and the clinician's attention to detail. Main error sources along the "paper trail" include variance in the electronic and written records, coder training and experience, facility quality-control efforts, and unintentional and intentional coder errors, such as misspecification, unbundling, and upcoding. By clearly specifying the code assignment process and heightening their awareness of potential error sources, code users can better evaluate the applicability and limitations of codes for their particular situations. ICD codes can then be used in the most appropriate ways.
Article
Implementation of the International Statistical Classification of Disease and Related Health Problems, 10th Revision (ICD-10) coding system presents challenges for using administrative data. Recognizing this, we conducted a multistep process to develop ICD-10 coding algorithms to define Charlson and Elixhauser comorbidities in administrative data and assess the performance of the resulting algorithms. ICD-10 coding algorithms were developed by "translation" of the ICD-9-CM codes constituting Deyo's (for Charlson comorbidities) and Elixhauser's coding algorithms and by physicians' assessment of the face-validity of selected ICD-10 codes. The process of carefully developing ICD-10 algorithms also produced modified and enhanced ICD-9-CM coding algorithms for the Charlson and Elixhauser comorbidities. We then used data on in-patients aged 18 years and older in ICD-9-CM and ICD-10 administrative hospital discharge data from a Canadian health region to assess the comorbidity frequencies and mortality prediction achieved by the original ICD-9-CM algorithms, the enhanced ICD-9-CM algorithms, and the new ICD-10 coding algorithms. Among 56,585 patients in the ICD-9-CM data and 58,805 patients in the ICD-10 data, frequencies of the 17 Charlson comorbidities and the 30 Elixhauser comorbidities remained generally similar across algorithms. The new ICD-10 and enhanced ICD-9-CM coding algorithms either matched or outperformed the original Deyo and Elixhauser ICD-9-CM coding algorithms in predicting in-hospital mortality. The C-statistic was 0.842 for Deyo's ICD-9-CM coding algorithm, 0.860 for the ICD-10 coding algorithm, and 0.859 for the enhanced ICD-9-CM coding algorithm, 0.868 for the original Elixhauser ICD-9-CM coding algorithm, 0.870 for the ICD-10 coding algorithm and 0.878 for the enhanced ICD-9-CM coding algorithm. These newly developed ICD-10 and ICD-9-CM comorbidity coding algorithms produce similar estimates of comorbidity prevalence in administrative data, and may outperform existing ICD-9-CM coding algorithms.
Malignant hyperthermia death holds many lessons
  • H Rosenberg
  • A Rothstein
Rosenberg H, Rothstein A. Malignant hyperthermia death holds many lessons. APSF Newsletter 2006;21(1):32-4.
Agency for Healthcare Research and Quality
  • A Elixhauser
  • C Steiner
  • L Palmer
Elixhauser A, Steiner C, Palmer L. Clinical Classifications Software (CCS), 2004. Rockville, MD: U.S. Agency for Healthcare Research and Quality; 2004(Report # 2004-02).
Department of Health and Human Services, Agency for Healthcare Research and Quality
  • Healthcare Agency
  • Quality Research
Agency for Healthcare Research and Quality. AHRQ Quality Indicators: Patient Safety Indicators-Technical Specifications. Rockville (MD): Department of Health and Human Services, Agency for Healthcare Research and Quality; 2008.