Treatment Of Malignant Hyperthermia Research Articles

Successful management of malignant hyperthermia without dantrolene – A case report

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

Rapid Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant Hyperthermia Events.

Malignant hyperthermia (MH) is a rare genetic disorder but one of the most severe complications of general anesthesia. The mortality rate of MH has dropped from 70% in the 1960s to 15% because of dantrolene, the only currently accepted specific treatment for MH. In this study, we retrospectively identified the optimal dantrolene administration conditions to reduce MH mortality further. Our database performed a retrospective analysis of patients with MH clinical grading scale (CGS) grade 5 (very likely) or 6 (almost certain) between 1995 and 2020. We examined whether dantrolene administration affected mortality and compared the clinical variables associated with improved prognosis. Furthermore, a multivariable logistic regression analysis was used to identify specific variables associated with improved prognosis. 128 patients met the inclusion criteria. 115 patients were administered dantrolene; 104 survived, and 11 died. The mortality rate of patients who were not administered dantrolene was 30.8%, which was significantly higher than those of patients who were administered dantrolene (P = 0.047). Among patients administered dantrolene, the interval from the first sign of MH to the start of dantrolene administration was significantly longer in the deceased than in the survivors (100 min vs. 45.0 min, P < 0.001), and the temperature at the start of dantrolene administration was also significantly higher in the deceased (41.6°C vs. 39.1°C, P < 0.001). There was no significant difference in the rate of increase in temperature between the two, but there was a substantial difference in the maximum temperature (P < 0.001). The multivariable analysis also showed that the patient's temperature at dantrolene administration and interval from the first MH sign to dantrolene administration was significantly associated with improved prognosis. Dantrolene should be given as rapidly as possible once MH has been diagnosed. Beginning treatment at a more normal body temperature can prevent critical elevations associated with a worse prognosis.

Dantrolene sodium fails to reverse robust brain hyperthermia induced by MDMA and methamphetamine in rats.

Hyperthermia induced by psychomotor stimulants may cause leakage of the blood-brain barrier, vasogenic edema, and lethality in extreme cases. Current treatments such as whole-body cooling are only symptomatic and a clear need to develop pharmacological interventions exists. Dantrolene sodium, a peripheral muscle relaxant used in the treatment of malignant hyperthermia, has been proposed as potentially effective to treat MDMA-hyperthermia in emergency rooms. However, debate around its efficacy for this indication persists. To investigate dantrolene as a treatment for illicit hyperthermia induced by psychomotor stimulant drugs, we examined how Ryanodex®, a concentrated formulation of dantrolene sodium produced by Eagle Pharmaceuticals, influences 3,4-methylenedioxymethamphetamine (MDMA)- and methamphetamine (METH)-induced hyperthermia in awake freely moving rats. We injected rats with moderate doses of MDMA (9 mg/kg) and METH (9 mg/kg) and administered Ryanodex® intravenously (6 mg/kg) after the development of robust hyperthermia (>2.5 °C) mimicking clinical acute intoxication. We conducted simultaneous temperature recordings in the brain, temporal muscle, and skin to determine the basic mechanisms underlying temperature responses. To assess the efficacy of dantrolene in attenuating severe hyperthermia, we administered MDMA to rats maintained in a warm ambient environment (29 °C), conditions which produce robust brain and body hyperthermia (>40 °C) and lethality. Dantrolene failed to attenuate MDMA- and METH-induced hyperthermia, though locomotor activity was significantly reduced. All animals maintained at warm ambient temperatures that received dantrolene during severe drug-induced hyperthermia died within or soon after the recording session. Our results suggest that dantrolene sodium formulations are not mechanistically suited to treat MDMA- and METH-induced hyperthermia.

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

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

Malignant hyperthermia – state of knowledge

Malignant hyperthermia (MH) is a relatively rare, but potentially lethal genetic disorder. That disease is characterized by hypermetabolic response of the skeletal muscles caused by exposure to triggering agents e.g. volatile anesthetics or depolarizing neuromuscular blockers.&#x0D; The object of this article was to review and assess the most recent published works about the epidemiology, etiology, pathomechanism, therapy of the MH and the new advances in all these fields.&#x0D; Authors scrutinized PubMed and Google Scholar using keywords: malignant hyperthermia, volatile anesthetics, ryanodine receptor mutation. In addition to this, the references of chosen articles were manually scoured for supplementary applicable articles. The literature was selected on the basis of a general medicine readership and prioritized clinical practice guidelines, systematic reviews and case reports.&#x0D; The references include the latest reports on malignant hyperthermia, apart from works of historical importance.&#x0D; Available treatment methods consist mainly of pharmacotherapy, symptomatic treatment and monitoring of vital parameters. Dantrolene is a first-choice drug in initial treatment of MH and is considered the only specific antidote.&#x0D; In spite of the constant advances in the areas of medicine there is still much to be discovered about MH. Further studies are necessary, as the amount of credible evidence is not adequate.

Malignant hyperthermia

Malignant hyperthermia manifests as hypermetabolism of striated voluntary muscle. Generally, this condition occurs during general anesthesia when inhalational anesthetics and succinylcholine are used. During the malignant hyperthermia attack, the oxygen consumption increases, lactate accumulates, the production of CO2 grows and excessive heat is generated. The crisis of malignant hyperthermia is a dangerous and potentially terminal complication of general anesthesia that requires rapid resolution in the shortest possible time. The only drug that can stop the acute state of malignant hyperthermia – dantrolen, is currently prohibited for import in Russia and is not legalized. Treatment of malignant hyperthermia is extremely difficult for all anesthesiologists in Russia and a great danger for patients with this condition.

Pathophysiology and Treatment of Malignant Hyperthermia

Malignant hyperthermia (MH) is caused by a genetic disorder of the skeletal muscle that induces a hypermetabolic response when patients are exposed to a triggering agent such as volatile inhaled anesthetics or depolarizing neuromuscular blockers. Symptoms of MH include increased carbon dioxide production, hyperthermia, muscle rigidity, tachypnea, tachycardia, acidosis, hyperkalemia, and rhabdomyolysis. Common scenarios for triggering agents are those used are during surgery and rapid sequence intubation. Hypermetabolic symptoms have a rapid onset; hence, prompt recognition and treatment are vital to prevent morbidity and mortality. The first-line treatment agent for an MH response is dantrolene. Further treatment includes managing complications related to a hypermetabolic response such as hyperkalemia and arrhythmias. This review is focused on the recognition and treatment considerations of MH in the emergency department to optimize therapy and improve patient morbidity and mortality.

INSTRUCTIONS: Pathophysiology and Treatment of Malignant Hyperthermia.

Advanced Emergency Nursing Journal: April/June 2021 - Volume 43 - Issue 2 - p E3 doi: 10.1097/TME.0000000000000354

Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence vs. Conjecture.

Exertional heat stroke (EHS) and malignant hyperthermia (MH) are life-threatening conditions, triggered by different environmental stimuli that share several clinical symptoms and pathophysiological features. EHS manifests during physical activity normally, but not always, in hot and humid environments. MH manifests during exposure to haloalkane anesthetics or succinylcholine, which leads to a rapid, unregulated release of calcium (Ca2+) within the skeletal muscles inducing a positive-feedback loop within the excitation-contraction coupling mechanism that culminates in heat stroke-like symptoms, if not rapidly recognized and treated. Rare cases of awake MH, independent of anesthesia exposure, occur during exercise and heat stress. It has been suggested that EHS and MH are mediated by similar mechanisms, including mutations in Ca2+ regulatory channels within the skeletal muscle. Rapid cooling, which is the most effective treatment for EHS, is ineffective as an MH treatment; rather, a ryanodine receptor antagonist drug, dantrolene sodium (DS), is administered to the victim to prevent further muscle contractions and hyperthermia. Whether DS can be an effective treatment for EHS victims remains uncertain. In the last decade, multiple reports have suggested a number of mechanistic links between EHS and MH. Here, we discuss aspects related to the pathophysiology, incidence, diagnosis and treatment. Furthermore, we present evidence regarding potential overlapping mechanisms between EHS and MH and explore current knowledge to establish what is supported by evidence or a lack thereof (i.e. conjecture).

Estratégia educativa com profissionais de enfermagem sobre hipertermia maligna em um centro cirúrgico cardiovascular

Objetivo: Avaliar o conhecimento da equipe de enfermagem do centro cirúrgico sobre hipertermia maligna, antes e após aula expositiva e implantar kit padronizado para tratamento, junto aos anestesiologistas. Método: Trata-se de uma pesquisa descritiva, prospectiva com abordagem quantitativa, com a enfermagem do centro cirúrgico da Instituição sede da pesquisa, situada na cidade de São Paulo, com participação de 43 profissionais. Aplicou-se questionário pré e pós aula expositiva. Resultados: Nos dados estatísticos pós-aula, houve diferença significante (p&lt;0,05) ao conhecimento da equipe sobre hipertermia maligna, por categoria profissional. As questões com pontuação significativa após aula foram: definição de hipertermia maligna, agentes desencadeantes e tratamento. Elaborou-se e implantou-se um kit de tratamento. Conclusão: Esta pesquisa agregou conhecimento para a equipe de enfermagem atuar com segurança e a disponibilização do kit específico proporcionou expertise e padronização de atendimento.

The current status of malignant hyperthermia.

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.

Pharmacological Treatment of Malignant Hyperthermia: Update 2019

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

ЗЛОКАЧЕСТВЕННАЯ ГИПЕРТЕРМИЯ: СОВРЕМЕННЫЕ ПОДХОДЫ К ПРОФИЛАКТИКЕ И ЛЕЧЕНИЮ

One of the most serious complications of modern anesthesia is malignant hyperthermia, which is a pharmacogenetic&#x0D; disease phenotype manifested by skeletal muscle hypermetabolism and rhabdomyolysis during or after general anesthe-&#x0D; sia with the use of inhaled anesthetics and succinylcholine. In Russia, the problem of malignant hyperthermia remains&#x0D; unresolved. This is mainly due to the fact that the only specific drug dantrolene created for the effective treatment of&#x0D; malignant hyperthermia is still not legalized and thus formally prohibited to import, disseminate and apply on the&#x0D; domestic pharmaceutical market. This article deals with the regulatory framework of specific treatment of malignant&#x0D; hyperthermia in Russia, allowing the possibility to legally import to the territory of the Russian Federation dantrolene&#x0D; as an unregistered drug, if it is a question of rendering medical assistance on vital indications to a particular patient, or&#x0D; its unauthorized use for vital indications in a situation of extreme necessity. The article presents the recommendations&#x0D; of domestic experts on the treatment of malignant hyperthermia. In this case, as a possible alternative to dantrolene,&#x0D; magnesium preparations are considered, whose role in the treatment of the crisis of malignant hyperthermia continues&#x0D; to be specified.&#x0D; Thus, given the increasing use of inhalation anesthesia by Russian anesthetists, to ensure the safety of patients with&#x0D; regard to the development of malignant hyperthermia, it is possible only in the case of official registration in the do-&#x0D; mestic dantrolene market. Also, in the territory of Russia, a network of relevant consultative and diagnostic centers&#x0D; should be established. These measures will undoubtedly increase the effectiveness of treatment and prevention of severe&#x0D; consequences of this disease in our country.

Hipertermia maligna no centro cirúrgico: a equipe de enfermagem sabe reconhecer e intervir?

Objetivo: Verificar o conhecimento da equipe de enfermagem do bloco cirúrgico (BC) sobre diagnóstico e tratamento da hipertermia maligna.Método: Pesquisa de campo, correlacional, análise quantitativa. Coleta de dados junto a 50 profissionais da equipe de enfermagem (34 técnicos e 16 enfermeiros)que atuam nos dois BC de um hospital particular de extraporte de São Paulo, que responderam dez questões de múltipla escolha (seis de diagnósticoe quatro de tratamento). Análise descritiva e comparação de médias por teste t de Student. Resultados: Obteve-se médias de acertos de 62,5%nas questões de diagnóstico e de 71,2% nas de tratamento; a porcentagem de acertos em diagnóstico foi significativamente menor do que em tratamento(p=0,007); média de acertos de 6,52 (6,4 para técnicos e 6,8 para enfermeiros); não houve significância quanto ao total de acertos entre os dois grupos(p&gt;0,05). Conclusão: Os profissionais demonstraram conhecimento razoável sobre hipertermia maligna, evidenciando mais de 50,0% de acertos.

Dantrolene Inhibition of Skeletal Muscle RYR in the Presence of CAM

Dantrolene is a muscle relaxant that has been used clinically as the treatment for malignant hyperthermia (MH). Our group recently reported that dantrolene inhibition of RyR1 and RyR2 required calmodulin (CaM)1. However, nothing more is known about the properties of dantrolene inhibition of RyR1 on single channels. Here, we characterized dantrolene inhibition on RyR1 in the presence of exogenous CaM at various cytosolic [Ca2+] and in the presence of other activators: ATP, halothane and domain peptide, DP4. RyR1 was isolated from rabbit skeletal muscle and incorporated into artificial lipid bilayers and their open probability, Po, was measured using single channel recording. Dantrolene caused inhibition of RyR1 and RyR2, but when CaM was presence in the cytoplasmic bath. In the presence of cytoplasmic [Ca2+] (100 nmol/l) and 2 mmol/l ATP, dantrolene inhibited both RyR1 and RyR2 with identical hyperbolic dose-responses with IC50 of 0.16 ± 0.03 μmol/l and with saturating Po of 52 ± 4 % of control. RyR1 has a bell-shaped cytoplasmic Ca2+ activation curve with half activation at 1.75 ± 0.62 μmol/l and half inhibition at 0.21 ± 0.02 mmol/l and a peak Po = 0.94 ± 0.06. Dantrolene reduced Po in sub-activating and inhibiting [Ca2+] but failed to reduce peak Po. Dantrolene caused 50-60% reduction in Po of RyR1 activated by cytoplasmic Ca2+ alone (100 nmol/l) or in conjunction with halothane (5 mmol/l) or DP4 (10 μmol/l). To conclude, dantrolene inhibits RyR1 activity by 1) decreasing RyR1 sensitivity to Ca2+ activation, 2) increasing sensitivity to Ca2+ inhibition and 3) decreasing channel activation halothane or by 4) reducing the effect of inter-domain disruption in the RyR1 protein.

Malignant hyperthermia

Malignant hyperthermia (MH) is a rare syndrome seen when susceptible individuals are exposed to one or more of various triggering agents, most commonly a depolarizing muscle relaxant or an inhalational anaesthetic agent. There is a dramatic rise in metabolic rate and oxygen consumption which if not treated promptly and effectively results, in the majority of cases, in the patient's death. Fatal responses to physical stress associated with the familial muscular disease known as MH are being increasingly reported in situations not related to anaesthesia or drugs. Moreover, cases of MH were recognized to be "induced" in the postoperative period when obviously the major effects of anaesthesia were no longer of important consideration. Therefore a more expanded concept of MH seems to develop, including the assumption that one of the other factors in MH is stress. The implication of this extends far beyond the scope of anaesthesiology. The acute hypermetabolic state in MH, resulting in acidosis, heat production and muscular activity is probably due to an inability to control calcium concentration within the skeletal muscle fiber, and may involve a generalized alteration in cellular or subcellular membrane permeability. The susceptibility to develop MH is controlled by several genetic factors. Evaluation of affected families is guided by in vitro analysis of drug-induced contractures in muscle biopsy specimens; a practical and reliable non-invasive test to predict the susceptibility is still being sought. At the present time there is incontrovertible evidence that the hydantoin derivate dantrolene sodium is the only known specific drug in treatment and prophylaxis of MH. A concept for the treatment of MH and guidelines for the management of a patient at risk are presented; medico legal aspects of the complication are stressed.

Dantrolene Inhibition of RyR2 requires Calmodulin

Dantrolene is a muscle relaxant that has been used clinically as the treatment for malignant hyperthermia. Dantrolene acts on skeletal and cardiac muscle by inhibiting Ca2+ release from the SR. However, single channel studies fail to see any effect of dantrolene on RyRs. Calmodulin (CaM) regulates RyR2 directly by binding to RyR2 and dantrolene influences CaM binding to RyR2. CaM can dissociate from RyR2 within ∼1 min so when RyR2 are isolated form cells and examined in artificial lipid bilayers, CaM is not usually present. Thus, we hypothesized that CaM is the missing protein required for dantrolene inhibition of RyR2.Single channel recordings were obtained from RyR2 isolated from sheep heart and incorporated into artificial lipid bilayers. Control RyR2 activity was measured for periods of 1 min, and then during 1 min exposure to dantrolene and then again after washout. This was repeated in the absence and presence of exogenous 100 nM CaM. In diastolic cytoplasmic [Ca2+] (100 nM), dantrolene (50 µM) reduced the mean open probability of RyR2 to 45 ± 6 % in the presence of CaM (n = 7, p < 0.05, student paired t-test) but had no significant effect when CaM was absent (95 ± 9 %, n=20, p = 0.24). Dantrolene exhibited a hyperbolic dose-response in the presence of CaM with an IC50 of 0.16 ± 0.03 µM and with a saturating relative Po (Emax) of 52 ± 4 %. Emax increased to one as cytoplasmic Ca2+ was increased to levels above 1 µM.In saponin permeablized mouse cardiomyocytes supplemented with 100 nM CaM, dantrolene reduced the frequency and amplitude of Ca2+ waves with an IC50 of 0.3 µM. However, when cells were depleted of CaM, dantrolene had no effect. Thus CaM is essential for inhibitory action of dantrolene.

Na+/H+ Exchange Blockers Reveal the Existence of a Skeletal Muscle Ca2+/H+ Exchanger, which is Altered in Malignant Hyperthermia Muscle Cells

In resting skeletal muscle fibers intracellular pH (pHi) is kept constant at a relatively alkaline level. The transporters involved in maintaining muscle pHi at rest are the Na+/H+ exchange system (NHE), and to a lesser extent the Na+- and Cl--dependent bicarbonate dependent transport systems. Many studies conducted in nerve and smooth cells have suggested a link between changes in intracellular free Ca2+ ([Ca2+]i) and changes in intracellular pH (pHi) suggesting a Ca2+/H+ exchange (Daugirdas et al, 1995). Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered by inhalational anesthetics and depolarizing neuromuscular blocking agents. We have measured [Ca2+]i and pHi simultaneously in Wt and heterozygous R163C myotubes using double barreled Ca2+-selective and single barreled pH+-selective microelectrodes. MH cells have a higher [Ca2+]i and a lower pHi than Wt cells. Treatment of both MH and Wt cells with the NHE inhibitors dimethylamiloride (DMA) or cariporide, caused an increase in [Ca2+]i and a decrease in pHi in a dose dependent manner. These effects were more prominent in MH than Wt myotubes. YM-244769, a high affinity reverse mode NCX3 blocker, did not modify [Ca2+]i overload or the drop in pHi elicited by DMA or cariporide in either cell type, suggesting that the change in [Ca2+]i was not the consequence to an activation of the reverse form of the exchanger. Gd3+ and dantrolene respectively were able to partially inhibit or fully reverse the DMA or cariporide-mediated elevation of [Ca2+]i and acidification in both types of cells. These results suggest the existence of a Ca2+/H+ exchange in skeletal myotubes, which appears to be altered in MH muscle cells.

Cost-effectiveness Analysis of Stocking Dantrolene in Ambulatory Surgery Centers for the Treatment of Malignant Hyperthermia

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.

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

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