RYR1-Related Rhabdomyolysis: A Spectrum of Hypermetabolic States Due to Ryanodine Receptor Dysfunction.

Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.

Magnesium sulfate - An effective agent could delay the progression of fulminant malignant hyperthermia.

Malignant hyperthermia (MH) is a life-threatening disease that occurs during general anaesthesia following exposure to succinylcholine (SCh), a depolarizing muscle relaxant, and volatile anaesthetics. Susceptibility to MH most commonly arises from mutations in the RyR1 gene, the Ca2+ release channel of skeletal muscle. Fulminant MH (f-MH) is the most dangerous form of MH, which presents a hypermetabolic cascade state, including very high temperature and carbon dioxide production, increased heart rate and oxygen consumption, mixed acidosis, rigid muscles, and rhabdomyolysis. Dantrolene is the only specific drug therapy for MH on the market. Without dantrolene, the reported mortality of f-MH is as high as 42.3%. Based on the participation of catecholamine in the hyperhaemodynamic response of f-MH and the demonstrated effective control of catecholamine release of magnesium sulfate, combined with the fact that magnesium and calcium have opposite effects on muscle contraction, I hypothesized that magnesium sulfate could be a choice for delaying the progression of f-MH while waiting for dantrolene treatment.

Succinylcholine Use and Dantrolene Availability for Malignant Hyperthermia Treatment: Database Analyses and Systematic Review.

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.

Cost-benefit Analysis of Maintaining a Fully Stocked Malignant Hyperthermia Cart versus an Initial Dantrolene Treatment Dose for Maternity Units.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The Malignant Hyperthermia Association of the United States recommends that dantrolene be available for administration within 10 min. One approach to dantrolene availability is a malignant hyperthermia cart, stocked with dantrolene, other drugs, and supplies. However, this may not be of cost benefit for maternity units, where triggering agents are rarely used. METHODS: The authors performed a cost-benefit analysis of maintaining a malignant hyperthermia cart versus a malignant hyperthermia cart readily available within the hospital versus an initial dantrolene dose of 250 mg, on every maternity unit in the United States. A decision-tree model was used to estimate the expected number of lives saved, and this benefit was compared against the expected costs of the policy. RESULTS: We found that maintaining a malignant hyperthermia cart in every maternity unit in the United States would reduce morbidity and mortality costs by $3,304,641 per year nationally but would cost $5,927,040 annually. Sensitivity analyses showed that our results were largely driven by the extremely low incidence of general anesthesia. If cesarean delivery rates in the United States remained at 32% of all births, the general anesthetic rate would have to be greater than 11% to achieve cost benefit. The only cost-effective strategy is to keep a 250-mg dose of dantrolene on the unit for starting therapy. CONCLUSIONS: It is not of cost benefit to maintain a fully stocked malignant hyperthermia cart with a full supply of dantrolene within 10 min of maternity units. We recommend that hospitals institute alternative strategies (e.g., maintain a small supply of dantrolene on the maternity unit for starting treatment).

Estrogens Protect Calsequestrin-1 Knockout Mice from Lethal Hyperthermic Episodes by Reducing Oxidative Stress in Muscle.

Oxidative stress has been proposed to play a key role in malignant hyperthermia (MH), a syndrome caused by excessive Ca2+ release in skeletal muscle. Incidence of mortality in male calsequestrin-1 knockout (CASQ1-null) mice during exposure to halothane and heat (a syndrome closely resembling human MH) is far greater than that in females. To investigate the possible role of sex hormones in this still unexplained gender difference, we treated male and female CASQ1-null mice for 1 month, respectively, with Premarin (conjugated estrogens) and leuprolide (GnRH analog) and discovered that during exposure to halothane and heat Premarin reduced the mortality rate in males (79-27% and 86-20%), while leuprolide increased the incidence of mortality in females (18-73% and 24-82%). We then evaluated the (a) responsiveness of isolated muscles to temperature and caffeine, (b) sarcoplasmic reticulum (SR) Ca2+ release in single fibers, and (c) oxidative stress and the expression levels of main enzymes involved in the regulation of the redox balance in muscle. Premarin treatment reduced the temperature and caffeine sensitivity of EDL muscles, normalized SR Ca2+ release, and reduced oxidative stress in males, suggesting that female sex hormones may protect mice from lethal hyperthermic episodes by reducing both the SR Ca2+ leak and oxidative stress.

Dantrolene requires Mg2+ to arrest malignant hyperthermia.

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

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.

A report of fulminant malignant hyperthermia in a patient with a novel mutation of the CACNA1S gene.

PURPOSE: To report the identification of a novel mutation in the CACNA1S gene that encodes the alpha-1-subunit (Cav1.1) of the voltage-gated skeletal muscle L-type calcium channel in a patient with malignant hyperthermia. CLINICAL FINDINGS: An otherwise healthy 34-yr-old female developed fulminant malignant hyperthermia (MH) under sevoflurane anesthesia during laparoscopic donor nephrectomy. The first sign was an increase in end-tidal CO(2). Malignant hyperthermia was suspected early, and resuscitative measures, including supportive and specific treatment, were successfully implemented. The patient rejected the open muscle biopsy for the Caffeine-Halothane Contracture Test (CHCT); therefore, only molecular genetic testing was performed. Sequencing of the entire ryanodine receptor type 1 transcript did not reveal any MH causative mutations. However, a novel homozygous mutation, p.Arg1086Ser, was identified in the CACNA1S gene that encoded for the alpha-1-subunit of the skeletal muscle L-type calcium channel (Cav1.1). A CACNA1S mutation, p.Arg1086His, involving the same Arg1086 residue that is mutated in our patient has previously been reported in association with MH in three independent families. CONCLUSION: The homozygous p.Arg1086Ser mutation of CACNA1S, the gene that encodes the alpha-1-subunit of the voltage-gated skeletal muscle L-type calcium channel, is a novel mutation associated with malignant hyperthermia.

[Case of malignant hyperthermia in which treatment was carried out smoothly].

We experienced a case of the abortive malignant hyperthermia (MH) that had developed during operation. The patient was a 14-year-old girl, and plastic surgery was scheduled under general anesthesia. Serum creatine kinase (CK) levels were high with 505 IU x l(-1) at the preoperative examination. General anesthesia was induced with propofol and vecuronium bromide, and maintained with sevoflurane. Suddenly, sinus tachycardia of an uncertain cause and a rapid rise of end-tidal carbon dioxide (Et(CO2)) concentration were noticed. Since we suspected MH, we did cooling and hyperventilation and administered dantrolene sodium 2 mg x kg(-1) for the patient. As a result, the highest temperature remained at 37.6 degrees C. Serum CK levels increased most postoperative 18 hours later and it is improved gradually. As sevoflurane, promotes the CICR (calcium-induced calcium release) mechanism, the trigger of this case is probably sevoflurane. As for the symptom that makes us doubt MH first, there is a maked rapid rises of Et(CO2). Therefore, it is important monitor and recognize the first symptom of MH.

Dantrolene stabilizes domain interactions within the ryanodine receptor.

Interdomain interactions between N-terminal and central domains serving as a "domain switch" are believed to be essential to the functional regulation of the skeletal muscle ryanodine receptor-1 Ca(2+) channel. Mutational destabilization of the domain switch in malignant hyperthermia (MH), a genetic sensitivity to volatile anesthetics, causes functional instability of the channel. Dantrolene, a drug used to treat MH, binds to a region within this proposed domain switch. To explore its mechanism of action, the effect of dantrolene on MH-like channel activation by the synthetic domain peptide DP4 or anti-DP4 antibody was examined. A fluorescence probe, methylcoumarin acetate, was covalently attached to the domain switch using DP4 as a delivery vehicle. The magnitude of domain unzipping was determined from the accessibility of methylcoumarin acetate to a macromolecular fluorescence quencher. The Stern-Volmer quenching constant (K(Q)) increased with the addition of DP4 or anti-DP4 antibody. This increase was reversed by dantrolene at both 37 and 22 degrees C and was unaffected by calmodulin. [(3)H]Ryanodine binding to the sarcoplasmic reticulum and activation of sarcoplasmic reticulum Ca(2+) release, both measures of channel activation, were enhanced by DP4. These activities were inhibited by dantrolene at 37 degrees C, yet required the presence of calmodulin at 22 degrees C. These results suggest that the mechanism of action of dantrolene involves stabilization of domain-domain interactions within the domain switch, preventing domain unzipping-induced channel dysfunction. We suggest that temperature and calmodulin primarily affect the coupling between the domain switch and the downstream mechanism of regulation of Ca(2+) channel opening rather than the domain switch itself.

A survey for prevention and treatment of malignant hyperthermia in Taiwan.

BACKGROUND: Malignant hyperthermia (MH) is a hypermetabolic disorder with high mortality. Intravenous administration of dantrolene is the specific treatment. However, the only means to lower mortality rate are early detection and suitable treatment. Therefore, properly monitoring and handy availability of dantrolene are essential to lower the mortality of MH. This study was designed to evaluate the capabilities in prevention and treatment of MH of the hospitals in Taiwan. METHODS: There were 102 certified training hospitals (including medical centers and regional hospitals) in Taiwan selected for this study. A questionnaire was designed to evaluate the capabilities of these hospitals in dealing with prevention and treatment of MH. RESULTS: A total of 66 copies of the questionnaire were returned, which gave a response rate of 64.7%. The results of the survey are as follows: Succinylcholine was frequently used for induction in 92% of the hospitals investigated. For monitoring during general anesthesia, pulse oximeter was routinely used in 66(100%) hospitals, and ETCO2 monitor in 51 (77.3%) hospitals but continuous body temperature was routinely monitored only in 13 (19.7%) hospitals. Six or more vials of dantrolene were stored and available for immediate use in 23 (34.9%) hospitals and the rest of 43 (65.1%) hospitals did not have any stock of dantrolene at all. Of these 43 hospitals, 25 (58.1%) relied on other hospitals to supply dantrolene and the time required to obtain dantrolene from other hospitals was 70.7 +/- 34.7 min. There were 21 cases who sustained MH in 17 (25.8%) hospitals in the past ten years, of whom 15 were resuscitated successfully and 6 died, thus giving a mortality rate of 28.6%. CONCLUSIONS: This study has revealed that in some hospitals in Taiwan intraoperatively (anesthetic) monitoring is inadequate and there is no stockpile of dantrolene for immediate treatment of MH. We recommend that appropriate anesthetic monitoring equipment should be strictly applied and a stock of initial dose of dantrolene (6 vials) should be kept, which are necessary for early diagnosis and treatment of MH.

Malignant hyperthermia: pathophysiology, clinical presentation, and treatment.

Malignant hyperthermia (MH) was first described as an inherited highly lethal disorder in 1960. There has since been significant progress in the clinical management, identification of MH susceptible (MHS) persons, and understanding of the underlying pathophysiology. When patients are known to be MHS prior to surgery, an MH episode can easily be avoided by the use of safe nontriggering anesthetic agents. Current MH mortality is <10%, but many experts believe this can be significantly reduced by improved MH preparedness. MH is triggered in humans by an MH triggering anesthetic agent, which causes the release of calcium from the sarcoplastic reticulum of the skeletal muscle cell at an uncontrolled rate resulting in a hypermetabolic state. Recent molecular genetic studies have shown that MH is related to an abnormal ryanodine receptor that controls the release of calcium from the sarcoplastic reticulum. This article reviews the current understanding of the pathophysiology, diagnosis, clinical presentation, and treatment of MH.

Malignant hyperthermia.

Malignant Hyperthermia (MH) has been a recognized complication of general anesthesia after the first case reports in the 1940's. Since then a great deal has been discovered about the genetics, pathophysiology and treatment of this once fatal syndrome. MH is the only clinical entity specifically related to and caused by anesthetic agents. MH once triggered during anesthesia results in a profound hyper metabolic state with rise in the core temperature, increased carbon dioxide production and oxygen consumption. Death will ensue if specific treatment is not started. The incidence of fulminant MH ranges from 1:62,000 to 1: 84,000 of general anesthesia cases if succinylcholine and inhalation agents are used. Massseter muscle spasm on induction of anesthesia, with an incidence of between 1:16,000 and 1:4,000, may be a predromal indication of the development of MH. Anesthetic agents, which may trigger MH in susceptible individuals, are the depolarizing muscle relaxant, succinyl choline and all the volatile anesthetic gasses. Nitrous oxide, intravenous induction agents, benzodiazepines, opioids, and the non-depolarizing relaxants do not trigger MH. MH susceptibility is associated with certain disorders, such as Duchene muscular dystrophy, and triggering agent should not be used in these patients. Inheritance is an autosomal dominant trait with variable penetrance. The pathogenesis of MH involves the loss of control of intracellular calcium ions in skeletal muscle with resultant protracted spasm and hyper metabolism. Clinically this will progress to hypercarbia, hypoxia, hyperthermia, hyperkalemia and death will result if specific treatment is not started. Management involves immediate discontinuation of the triggering anesthetics, hyperventilation with 100% oxygen and most importantly the definitive treatment with intravenous dantrolene.The importance of instigating the use of dantrolene in cases of MH cannot be overemphasized. MH is now treatable when once it would be fatal before the availability of dantrolene. Unless of an emergent nature, surgery should be canceled following the acute phase of MH. The patient should be admitted to intensive care for at least 24 hours and dantrolene continued as recurrence has been described. It is imperative that the patient and their family are counseled, Medalert bracelets provided and registration with the Malignant Hyperthermia Association of the United States (MHAUS), encouraged. The caffeine/halothane testing of muscle biopsies is currently the most definitive test for malignant hyperthermia susceptibility. The routine use in suspected cases or the immediate family of known cases remains a matter of contention.

Delayed onset of malignant hyperthermia in desflurane anesthesia.

IMPLICATIONS: Animal-experimental studies demonstrate desflurane's trigger effect for malignant hyperthermia (MH). In contrast to other anesthetics, the time interval from exposure to the occurrence of symptoms is much longer with desflurane. This case report focuses on MH induced by desflurane alone.

Malignant hyperthermia: perianesthesia recognition, treatment, and care.

UNLABELLED: Although relatively uncommon, malignant hyperthermia (MH) can be a life-threatening crisis when it occurs intraoperatively or postoperatively. It is imperative that every member of the perianesthesia team knows what to do and works cohesively because it is a true emergency. This article reviews information for perianesthesia nurses, perioperative nurses, and anesthesia providers about agents that trigger MH; early and late symptoms of MH; recommended medications, equipment, and emergency supplies that should be readily available for use; and the recommended protocol for effectively treating MH. OBJECTIVES: -Based on the content of this article, the reader should be able to (1) describe the pathophysiology of malignant hyperthermia (MH); (2) identify the triggering agents of MH; (3) identify patients at risk for MH; (4) describe the early and late signs of MH; (5) state the medication of choice to treat MH; and (6) describe perianesthesia and/or perioperative nursing interventions for treating an MH patient.

Malignant hyperthermia.

A specific inherited muscle membrane disorder predisposes to a variety of clinical problems. The most common is malignant hyperthermia (MH), a dangerous hypermetabolic state after anaesthesia with suxamethonium and/or volatile halogenated anaesthetic agents. MH may also be triggered in susceptible individuals by severe exercise in hot conditions, infections, neuroleptic drugs, and overheating in infants. Inbred pigs have provided a helpful model, and experiments on these animals and in MH-susceptible patients have shown that the essential biochemical abnormality is an increase in calcium ions in the muscle cells. This knowledge has led to a specific muscle test to identify susceptibility to MH and to a specific treatment, dantrolene; and as a result the case-fatality rate in MH has fallen from 70% in the 1970s to 5% today. In pigs susceptibility to MH is caused by a single mutation in the ryanodine receptor (RYR) in skeletal muscle. In man the genetics is more complex and three clinical myopathies that predispose to MH have been defined. By far the most common is inherited as a mendelian dominant characteristic and at present mutations in the human RYR account for no more than 20% of susceptible families.

Malignant hyperthermia.

Malignant hyperthermia is a rare autosomal dominant trait that predisposes affected individuals to great danger when exposed to certain anaesthetic triggering agents (such as potent volatile anaesthetics and succinylcholine). A sudden hypermetabolic reaction in skeletal muscle leading to hyperthermia and massive rhabdomyolysis can occur. The ultimate treatment is dantrolene sodium a nonspecific muscle relaxant. Certain precautions should be taken before anaesthesia of patients known to be susceptible to malignant hyperthermia. These include the prohibition of the use of triggering agents, monitoring of central body temperature and expired CO2, and immediate availability of dantrolene. In addition, careful cleansing of the anaesthesia machine of vapours of halogenated agents is recommended. If these measures are taken, the chances of an MH episode are greatly reduced. When malignant hyperthermia-does occur in the operating room, prompt recognition and treatment usually prevent a potentially fatal outcome. The most reliable test to establish susceptibility to malignant hyperthermia is currently the in vitro caffeine-halothane contracture test. It is hoped that in the future a genetic test will be available.