Malignant Hyperthermia

Chapter 45

Malignant Hyperthermia: An Inherited Disorder of Muscle Calcium Metabolism Werner Klingler and Frank Lehmann-Horn

MALIGNANT HYPERTHERMIA—DEATHS IN GENERAL ANESTHESIA The name malignant hyperthermia (MH) is derived from the clinical observations of Denborough and Lovell, who analyzed the unexplained deaths of previously asymptomatic patients undergoing general anesthesia in 1960.1 These patients exhibited symptoms of muscle rigidity and rapidly rising, irrepressible core body temperature; hence the term MH. Within 2 years, Denborough and colleagues realized that young age and blood relationship is a risk factor for the development of the syndrome.2 An autosomal dominant mode of inheritance was later identified in 1990.3,4 In due course, more sophisticated anesthesiological equipment allowed the analysis of signs and symptoms of MH crises in more detail (Table 45.1), the main features of which are rigidity of skeletal muscle, severe acidosis, and inadequate increase in body temperature (Figure 45.1). The majority of reported MH crises indicate that the phenomenon is pharmacologically provoked; crises are triggered by the volatile anesthetic halothane and the depolarizing muscle-relaxant succinylcholine. This predominance is most likely due to the fact that these drugs were common for many years—and still are in economically poorer countries—and that they were not only used frequently, but also regularly in combination. With the exception of xenon and nitrous oxide, MH crises have been observed with all volatile anesthetics (i.e. halothane, sevoflurane, enflurane, isoflurane, and desflurane).7,8 The preservative 4-chloro-m-cresol (4-CmC) was found to trigger MH and was consequently removed from succinylcholine preparations and other muscle relaxants in the 1980s. 4-CmC is still used as preservative (e.g. for insulin formulations); however, the enclosed dosages are two orders of magnitude below clinical relevance in terms of MHtriggering effects. Hence, modern 4-CmC containing

pharmacological formulations can be used safely in MHdisposed individuals.9

MUSCULAR HYPERMETABOLISM BY RAMPANT CA21 In predisposed individuals, application of MH triggers leads to excessive release of Ca21 in skeletal muscle cells. Here, Ca21 is accumulated in intracellular Ca21 stores within the sarcoplasmic reticulum (SR). Ca21 release is regulated by a complex of four dihydropyridinereceptors (DHPR) and the homotetrameric ryanodine receptor type 1 (RyR1), arranged in clusters along the triadic junction between the transverse tubular system and the SR. The voltage sensitive DHPR activates RyR1 predominantly by direct (mechanical) protein-protein interaction and secondarily by promotion of Ca21-induced Ca21 release (CICR). Volatile anesthetics are direct and potent agonists on RyR1, which is the largest known ion channel (.2MDa, roughly 5000 amino acids) allowing high ion flux and increase in cytoplasmic Ca21 concentration by several orders of magnitude within milliseconds.10 Ca21 unmasks actin and leads to force generation by myosin-ATPase. Rampant Ca21 release in MH muscle leads to generalized muscle rigidity, consumption of energy carriers, and stimulation of glycolysis and respiratory enzymes. Accumulation of acidic metabolites, ATP exhaustion, and Ca21 overload finally result in loss of cellular integrity and rhabdomyolysis (Figure 45.1). Clinically, a severe hypermetabolism can be observed including tachypnea, tachycardia, hypoxemia, and rapid increase in end-tidal CO2 concentrations. Anesthesiologists refer to hot soda lime, which is the CO2-absorbing component in the breathing circuit of the anesthesia machine. Due to the rigidity of respiratory muscles, blood gas analysis yields a combined

B.T. Darras, H. Royden Jones, Jr., M.M. Ryan & D.C. De Vivo (Eds): Neuromuscular Disorders of Infancy, Childhood and Adolescence, Second edition. DOI: http://dx.doi.org/10.1016/B978-0-12-417044-5.00045-7 © 2015 Elsevier Inc. All rights reserved.

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TABLE 45.1 Symptoms and Treatment of a Clinical MH Episode Malignant Hyperthermia Early signs: G increasing ETCO 2 G tachycardia G tachypnea G mixed acidosis G masseter spasm/trismus

Signs that may appear later: G hyperthermia G muscle rigidity G myoglobinuria G cardiac arrest

Call for Help Start preparing Dantrolene Differential diagnoses: G inadequate anesthesia or analgesia G insufflation of CO 2 G hypoventilation G tourniquet ischemia G used soda lime G infection, sepsis, external overheating G hypoxemia G pheochromocytoma G thyroid storm Treatment: G stop MH triggers G increase fresh gas flow to 10 L/min (no change of system) G convert to total intravenous anesthesia G hyperventilation FiO 100% 2 G preparation of dantrolene 2.5 mg/kg IV bolus (help necessary!) G rapid administration of dantrolene up to 10 mg/kg until patient stable G buffer metabolic acidosis / hyperkalemia G physical cooling G treat cardiac arrhythmia according to advanced life support guidelines G intensive care unit, aim at urine output of 2 mL/kg/h, G blood gas analysis, blood count, liver enzymes, creatine kinase, myoglobin, lactic acid, coagulation G continue dantrolene 1 mg/kg every 4 6 hours until patient stable for a maximum of 24 36 hours There is no specific sign for MH. The time course varies significantly. Administration of calcium antagonists can potentiate hyperkalemia. Modified after Harrison et al. (2013).5

metabolic and respiratory acidosis (i.e. mixed acidosis). Laboratory investigations further show increasing K1 and creatine phosphokinase levels originating from rhabdomyolysis. The course of an MH crisis may be complicated by renal failure and myoglobinuria, which can appear as “colacolored” urine, and/or disseminated intravascular coagulation. Cardiac arrhythmia is a phenomenon in MH mainly due to an increase in serum K1.11 13 Membrane depolarization by succinylcholine can boost and rarely induce an MH reaction by stimulation of DHPR and nonspecific Ca21 influx. Nondepolarizing muscle relaxants can be used safely in MH-predisposed individuals. Moreover, precurarization (i.e. pretreatment

FIGURE 45.1 Pathophysiology of malignant hyperthermia (MH). Cartoon of the key structures of excitation-contraction coupling in the transverse tubule (T-tubule) of skeletal muscle. The dihydropyridine receptor (DHPR) is linked to the ryanodine receptor (RyR1), which is the calcium release channel situated in the membrane of the sarcoplasmic reticulum (SR). The cardinal symptoms of MH are explained by excessive calcium release, and stimulated glycolysis and respiratory chain. Reprinted with permission from Lehmann-Horn et al. (2011).6

with nondepolarizing muscle relaxants) may attenuate or even prevent clinical MH reactions.14,15 There is no specific symptom pathognomonic for MH because clinical features and time course of MH crises vary markedly.13,14 In 1994, Larach and colleagues developed a mathematical scoring model to estimate the likelihood of a clinical MH event. Five main processes are assessed: muscle rigidity, muscle breakdown (i.e. rise of the muscle enzyme creatine phosphokinase above 10,000 units/L), acidosis, inadequate increase in body temperature, and the beneficial effect of the specific antidote dantrolene, which also contains mannitol to prevent renal failure.11 Treatment of an MH crisis is based on interruption of the positive feedback loop of self-sustaining myoplasmic hypermetabolism. Dantrolene significantly reduces myoplasmic Ca21 overload by various mechanisms, and should be administered immediately after stopping the trigger anesthetics. A clinical MH event can be suspected upon observation of beneficial effects of dantrolene (i.e. reversal of hypermetabolism). Regarding hypermetabolism and hyperthermia, most interestingly, RyR1 has been identified in B-lymphocytes, where it plays a role in the regulation of specific immune response. In B cells RyR1-liberated Ca21 promotes the release of interleukin 1β (IL-1β), which is an endogenous

Chapter | 45 Malignant Hyperthermia: An Inherited Disorder of Muscle Calcium Metabolism

pyrogen. B-lymphocytes from MH patients show an elevated cellular metabolism and increased IL-1β release after pharmacological challenge with MH-triggering drugs. Action of endogenous pyrogens may explain recrudescence of MH hypermetabolism and even delayed onset, which has been described several hours after anesthesia.16 18

ANESTHESIA-RELATED MUSCLE SPASMS Localized muscle stiffness can present as jaw stiffness (trismus), which may be a threatening condition during induction of general anesthesia because ventilation and endotracheal intubation can be hindered. Anesthesiarelated muscle spasm is a nonspecific sign for neuromuscular dysregulation and occurs predominantly in pediatric patients. Independent of underlying disease, masseter spasm is observed in roughly 0.3% of children after administration of the depolarizing muscle relaxant succinylcholine.19 Compared to other muscles, the masseter has an atypical composition that may explain, in part, the increased sensitivity to succinylcholine. Specific features of the masseter muscles include a highly variable and heterogeneous distribution of myosin isoenzymes, the expression of neonatal and alpha-cardiac myosin heavy chain, and the existence of small motor units.20 In other words, jaw muscles contain a comparatively high number of motor endplates, where succinylcholine is an agonist on nicotinic acetylcholine receptors (nAChR). nAChR are nonspecific cation channels that depolarize the muscle membrane by influx of Na1 and, notably, Ca21.14 Membrane depolarization initiates excitation-contraction coupling (i.e. Ca21-release from SR). There are hints that in patients with neuromuscular disorders, most notably MH, the incidence of clinically relevant succinylcholineinduced masseter spasm may be increased.21,22 Anesthesia-related localized and generalized muscle spasm is a phenomenon also seen in other conditions, and may complicate artificial ventilation. In disorders of neuromuscular transmission (e.g. denervation, immobilized patients, paralyzed patients, and myasthenia gravis), reference is made to the pathological upregulation of nAChR and expression of abundant extrajunctional nAChR. Enhanced excitability of muscle membranes is also found in inherited channelopathies, such as chloride channel myotonia (myotonia congenita, Thomsen and Becker types) and sodium channel myotonia (paramyotonia). Clinically, the symptoms can mimic an MH event.23

AWAKE EPISODES Outside general anesthesia, individuals carrying the trait for MH are usually asymptomatic. Some patients complain about exercise-dependent myalgias, predominantly

915

in gross muscle such as the thigh. Other observations include heat intolerance and inadequate temperature increase after physical exercise. Case reports describe clinical crises after heavy physical exercise and in febrile conditions.24,25 Even if there are not enough data for statistical evaluation of incidence, children are obviously more prone to awake MH episodes. Case reports often refer to children, adolescents, or young adults. Crises have been described in hot surroundings, such as a car interior, or during infections with fever.26 28 Awake MH episodes are also found in animal models for MH. Most extensively studied is porcine MH, where stress-induced rhabdomyolysis reduces meat quality. The syndrome was named “porcine stress syndrome” and a homozygote mutation in RyR1 was identified. The mode of inheritance is recessive in porcine stress syndrome and dominant in the horse and mouse MH model. In all animal models, nonanesthetic MH crises occur frequently and can be triggered reproducibly by heat or physical exertion. In affected quarter horses, rhabdomyolysis can occur without evident hyperthermia.29 31

MH AND CHILDHOOD The incidence of clinical MH crises as well as awake episodes is more frequent in children (Figure 45.2). Roughly half of the crises occur in children younger than 12.8 Several reasons may account for this observation. Children have fewer developed compensatory mechanisms for

FIGURE 45.2 Age dependence and male predominance. The graph shows age and gender distribution of 200 clinical MH crises evaluated in a European multicenter study. All events were later diagnosed to be proven malignant hyperthermia events by in vitro contracture testing on surgically dissected muscle biopsies. Patients were 70% male; 50% of crises occurred in patients younger than 12 years old. 1% of the crises were triggered by succinylcholine, 18% by volatile anesthetics, and 81% by a combination of both. Figure modified and adapted from: Klingler et al. (2014).8

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increased body temperature. Heat tolerance and dissipation is reduced. Generally, children have a higher metabolic rate in skeletal muscle than adults; CPK levels show an age-dependent decline. Fiber type composition is different in children and adults with a shift to fiber type II with increasing age. In other words, children exhibit a relatively high portion of oxidative type I fibers (slow twitching). In the in vitro contracture test (IVCT), type I fibers are more sensitive to pharmacological triggers.32,33 Indeed, other factors of development such as influence of growth hormones and temperature regulation in the central nervous system may contribute to the enhanced vulnerability of skeletal muscle in childhood. Epidemiological observations in children show that MH-predisposition is associated with anomalies of the musculoskeletal system and connective tissue. Specific diagnoses overrepresented in the MH-predisposed population are various forms of myopathies, strabismus, and scoliosis.34

FUNCTIONAL DIAGNOSTICS—IN VITRO CONTRACTURE TEST The in vitro contracture test (IVCT) is a robust method to diagnose predisposition to MH. The classification yields MH susceptibility (MHS) or an MH negative (MHN) result. IVCT requires a surgical muscle biopsy at a specialized MH unit. A minimum of four muscle bundles of roughly 20 mm length and 300 mg weight are dissected from human vastus lateralis muscle. To avoid pharmacological interferences, regional or spinal anesthesia is preferred over local anesthesia. The IVCT is a functional test on fresh muscle tissue, so muscle bundles need to be investigated freshly within a maximum of 5 hours;

Force [mN]

70

dispatch of specimens to a distant laboratory is impossible. Muscle bundles are suspended and pre-stretched in an organ bath containing physiological Krebs-Ringer solution, pH and temperature are controlled, and the muscle tissue is continuously bubbled with 95% O2 and 5% CO2. Force is measured with a highly sensitive force transducer.14,23 The generated contracture force is used as an indirect marker for myoplasmic Ca21 concentration. Halothane and caffeine, the pharmacological trigger substances, are added to the organ bath in respectively cumulative bolus doses (Figure 45.3). Protocol variants differ depending on the recommendations of the respective North American and European Malignant Hyperthermia Groups. Nonetheless, there is a high concordance between the protocol variants. In Japan, skinned muscle fibers are investigated. In MHS muscle, pharmacologically induced CICR is significantly increased. Although caffeine in the millimolar range is a potent in vitro trigger for MH, this is not the case in vivo because concentrations differ greatly.14,35 At the earliest, IVCT is recommended 3 months after a clinical MH episode. To obtain valid results, recovery of muscle tissue from (partial) rhabdomyolysis and full elimination of pharmaceuticals, most notably dantrolene, is indispensable. Many MH test centers only accept children older than roughly 8 to 10 years because of the required size of the muscle biopsy.14

GENETIC DIAGNOSTICS Estimations for the incidence of clinical MH events range from 1:30,000 in children up to 1:300,000 in adults. Genetic analyses show an autosomal dominant mode of inheritance with an unknown frequency of asymptomatic

Abnormal muscle contracture malignant hyperthermia susceptible

60 Threshold at 1% halothane 50

40

1% 2% 3% Cumulative halothane 20

30

40

50

60

4% 70

Time [min] FIGURE 45.3 In vitro contracture test (IVCT), original trace. The diagram shows a time versus force diagram of a dissected muscle bundle in an organ bath. The initial pre-stretch is necessary for alignment of contractile proteins. Halothane is added in cumulative doses. The bundle shows a baseline force increase of more than 2 mN at 2% halothane. This response is a pathologic contracture and indicates MH-predisposition.

Chapter | 45 Malignant Hyperthermia: An Inherited Disorder of Muscle Calcium Metabolism

carriers. Since the discovery of the link between MH susceptibility and the gene encoding RyR1, research efforts have identified more than 300 RyR1 mutations as of 2014. An association with MH is suggested for the majority of these mutations,3,14,36 many of which are clustered in three hotspot regions of the protein (Figure 45.4). However, causality has only been proven for roughly 10% of these mutations. Certain diagnosis is possible by genetic means according to the guidelines for genetic detection of susceptibility to MH agreed upon by the European Malignant Hyperthermia Group (EMHG).37,38 The RyR1 gene contains 106 exons; therefore, the search for genetic alterations is laborious and it is difficult to differentiate between polymorphism and functionally relevant mutation. Mutations in DHPR have been identified in singular families.36,39 RyR1 is predominantly expressed in skeletal muscle; the level of expression is independent of MH disposition. Isoforms are found in cardiac muscle (RyR2) as well as in the central nervous system (RyR3). Mutations in RyR2 have been linked to ventricular arrhythmia, but general anesthesia including volatile anesthetics and succinylcholine has been described as uneventful.40

Ryanodine receptor type 1 (RyR1)

N

248

35

163

614 552

522

341

403

Central core disease 2454

Multiminicore disease

Genetic knowledge of MH is still incomplete and does not explain some of the specifics seen in MH, such as age dependence and male preponderance (Figure 45.2). Thus, epigenetic factors seem to contribute to the syndrome and complicate the genetic diagnosis.31,41,42

CREATINE PHOSPHOKINASE Creatine phosphokinase (CPK) is an important enzyme of skeletal muscle energy metabolism, which is usually present only in small concentrations in blood. Recurrent elevated CPK levels in asymptomatic patients can hint toward a subclinical myopathy. In MH-susceptible individuals, CPK is often slightly elevated or in the upper normal range. However, CPK is vulnerable to a number of conditions such as hypo- and hyperthyroidism, soft tissue trauma, medical injections, or strenuous muscle exercise. Therefore, it is advisable to determine CPK several times in intervals of roughly 3 months, in several siblings of the family under suspicion of susceptibility, after sports abstention of roughly 2 weeks, and after exclusion of potential interferences. For evaluation, divergent laboratory methods (meanwhile mostly temperature corrected) and especially the specific age-dependent reference values in children need to be considered. In isolated familial chronic CPK-elevation, an MH diagnostic muscle biopsy is indicated.14

HISTOLOGICAL FINDINGS AND CORE FORMATION

MHS, causality? MHS, causative

917

2163 2168 2434

2458 2435 2508

2206 2375 2371

2350

2428

Cytosol 4796

4664

4826

M1

M2

M3

SR lumen

C

4838

M4

4861 4898

FIGURE 45.4 Ryanodine receptor type 1. The ryanodine receptor type 1 (RyR1), shown here, is a homotetramer composed of more than 5000 amino acids. RyR1 is the largest known human ion channel and is even visible by optical microscopy. RyR1 has four transmembrane domains and serves as the Ca21 release channel in the sarcoplasmic reticulum (SR). The sketch shows a selection of mutations associated to malignant hyperthermia. Mutations in RyR1 are clustered in three hotspot regions. Region 1 is found between amino acids 35 and 614, region 2 between 2163 and 2458, and region 3 between 4664 and 5020. Positions of proven causative mutations are quoted.

Histological examinations in muscle tissue from MH patients show normal findings or mild myopathic changes; therefore, diagnosis of MH is not possible by histological methods. Most commonly, MH muscle exhibits atypical, hypertrophic fibers and type I fiber predominance. The changes are usually disseminated and sometimes accompanied by internal nuclei and myofibrillar necrosis.43 In some cases, histological examinations may find cores, which are amorphous regions that lack mitochondria and oxidative enzyme activity. There is a strong link or even overlap between MH and core diseases, most notably central core disease (CCD), which presents with muscle weakness of variable degree. Common features are floppy infant syndrome, skeletal anomalies, delayed motor milestones, and generalized muscle hypotonia during adolescence. In adulthood, CCD usually is nonprogressive and functional improvement can occur. Roughly 40% of affected patients are considered asymptomatic in adulthood. Histologically, CCD is characterized by central cores in the muscle fibers (Figure 45.5). A potential explanation of core formation is initial mitochondrial damage due to Ca21 overload and swelling. Neighboring organelles become involved and

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FIGURE 45.5 Central core disease histology. The figure shows a typical histological finding in central core disease (NADH reductase staining, magnification factor 400). The muscle fibers contain unstructured central cores and lack of oxidative enzyme activity indicating loss of mitochondria. [Some of our group published a similar version of this figure in Klingler et al. (2009).44]

unstructured areas might result from further progressive damage. Core diseases (multiminicore disease, CCD, nemaline myopathy) show genetic diversity. Presumably, the risk for MH is high when mutations are located in the gene encoding RyR1 (Table 45.2). However, mutations in the C-terminal region of RYR1 lead to “loss of function” of the channel and, in contrast to all other mutations, to reduced Ca21 release. Whether these patients are at risk for clinical MH episodes is unclear.44

ASSOCIATED SYNDROMES AND MH-LIKE EPISODES The specific feature of MH is excessive Ca21 release from the SR leading to pathologic hypermetabolism exhibiting a number of clinical signs and symptoms

(Table 45.1). However, hypermetabolic crises are observed in other neuromuscular disorders, which may resemble an MH event despite completely different pathomechanisms. Indeed, in the premolecular era, clinical association with MH was postulated for several neuromuscular diseases and later discarded. For example, an association with MH has been excluded for myotonia congenita (Thomsen and Becker types). In myotonic crises, which may mimic MH-like muscle rigidity, causative therapy is based on inhibition of Na1 conductance in order to reduce electrical membrane excitability. Furthermore, K1 in the upper normal range seems to have antimyotonic effects.23 Volatile anesthetics have not only been used safely in patients suffering from myotonia congenita, but also in mitochondrial myopathy. Mitochondrial disorders have an estimated incidence of 1 in 4000, show a maternal inheritance, and present with various degrees of muscle weakness, cardiomyopathy, and predisposition to epileptic seizures. The most common maternally inherited disorder is the mutation of the mitochondrial tRNA at nucleotide position 3243, which leads to MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes). A further mitochondrial disorder depends on nucleotide exchanges within the mitochondrial tRNA and leads to myoclonic epilepsy with ragged red fibers (MERRF) in the muscle biopsy. Other mitochondrial disorders include Leber hereditary optic neuropathy (LHON) and Kearns-Sayre syndrome, for which MH-like events have been described. In contrast to the situation in most other neuromuscular diseases, the use of propofol, most notably for long-term sedation, may be hazardous in patients suffering from mitochondrial myopathies due to the inhibition of oxidative phosphorylation, β-oxidation, and the enzyme carnitine palmitoyltransferase. The pathomechanism also explains why these patients are prone to the development of a propofol infusion syndrome. Skeletal muscle and cerebral and cardiac function are particularly vulnerable to mitochondrial defects. Tight metabolic monitoring (i.e. electrolytes, glucose, lactate, pH) is essential in the perioperative period and metabolism should be supported by the administration of substrates such as glucose or amino acids.14,45,46 It is certain that there is an increased susceptibility to MH in patients with core diseases and nemaline myopathy, and it is likely that this is also the case in King-Denborough syndrome.44 In other myopathies, such as the nondystrophic myotonias, the periodic paralyses, myotonic dystrophy, and the dystrophin-deficient muscular dystrophies, hypermetabolic “MH-like” events have been described (Table 45.2), but there is no consistent triggering agent and it seems likely that the molecular mechanisms responsible differ from those of MH susceptibility.13,14,47 Several authors also recommend the clarification of MH predisposition in individuals

Chapter | 45 Malignant Hyperthermia: An Inherited Disorder of Muscle Calcium Metabolism

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TABLE 45.2 Syndromes Associated with an Increased Risk of Rhabdomyolysis Syndrome

RyR1 Mutations

Malignant hyperthermia Central core disease Nemaline rod myopathy Multiminicore disease King-Denborough syndrome Atypical core diseases Hypokalemic periodic paralysis Congenital neuromuscular disease with uniform type I fibers Samaritan congenital myopathy Malignant neuroleptic syndrome Recurrent heat stroke Statin-induced rhabdomyolysis Exercise-induced rhabdomyolysis Amphetamine-induced rhabdomyolysis Mitochondrial myopathies (MELAS, MERF, LHON, Kearns-Sayre syndrome) Myotonia congenita (Becker and Thomson types) Myasthenia gravis, Lambert-Eaton syndrome Myotonic dystrophy Proximal myotonic myopathy Hyperkalemic periodic paralysis Paramyotonia Metabolic myopathies (glycogenoses, lipid storage disorders) Myoadenylate deaminase deficiency Carnitine palmitoyltransferase II deficiency Noonan syndrome Brody myopathy

.70% .90% some cases some cases some cases some cases some cases some cases some cases rare cases rare cases rare cases rare cases not investigated no no no no no no no no no no no no

Risk for the development of a true MH crisis depends on the involvement of Ca21 metabolism. This is the case for the majority of patients suffering from CCD, multiminicore disease, or nemaline rod myopathy, where mutations in the RyR1 gene have been documented. The table also shows other syndromes that may present with MH-like hypermetabolism. Potential associations with RyR1 mutations are listed. Interestingly, some cases of sudden infant death have been associated with sequence variants in the cardiac isoform of the RyR (RyR2) gene.

suffering from recurrent heat stroke or exercise-induced rhabdomyolysis, since mutations in RyR1 have been found in a significant portion of these patients.48 There is weak evidence that MH-like events can occur in enzymopathies/genetic syndromes.49 Supposedly, multiple factors are involved to create MH-like reactions.

CLINICAL CONSIDERATIONS Fortunately, perioperative hyperthermia is not MH in most cases. Possible causes for elevated body temperature, especially in children, are warm environment, insolation, heat stroke, hypovolemia, bacterial or viral infection, allergy, hyperthyroidism, side effect of drugs, pheochromocytoma, and other endocrinopathies. Furthermore, preoperative fasting leads to metabolic acidosis in children, which may be mistaken as an MH-associated symptom.50 Patient safety is the most prominent concern when dealing with patients with rare diseases. The clinical signs and the emergency management of an MH crisis are summarized in Table 45.1. There is good evidence that checklists improve handling of MH crises independent of

professional experience and specialization.51 Since MH is a potentially life-threatening condition, individuals and siblings at risk should be referred to a rare disease center, equipped with medical emergency bracelets, and advised to inform medical professionals about the condition, most notably in the case of surgical procedures. There are now a multitude of anesthetic drugs at hand that have been proven safe in persons susceptible to MH, allowing the application of regional and general anesthesias in MHS individuals. It is important to note that a person who has passed several general anesthesias without problems may still have MH disposition because an MH crisis is not necessarily triggered in every anesthesia. MH is usually asymptomatic, but it should be mentioned that MHS persons should refrain from extreme physical stress (e.g. long-distance running, triathlon) or exposure to extremely high environmental temperature. The risk for rhabdomyolysis may be increased with drugs altering the sarcolemmal lipid bilayer (e.g. ecstasy, amphetamines, statins, steroids). Further information can be found on the websites of the Malignant Hyperthermia Association of the United States52 and the EMHG.53

920 PART | VII Special Clinical Problems

In neuromuscular disease, the risk for development of an MH event depends on the involvement of Ca21 conducting proteins. Hundreds of genetic variations have been identified in the gene encoding the sarcoplasmic Ca21 release channel RyR1, most with unclear significance concerning channel function. Presumably, “gain-offunction” mutations are associated with an increased risk for MH. From a clinical point of view and for safety reasons, patients suffering from diseases linked to mutations in RyR1 and/or DHPR should be handled as MHS, even if causality is unknown. Increasing knowledge on genetic and pathophysiologic backgrounds helps to distinguish between classical MH and MH-like events. This discrimination is necessary for optimum management of the patient and, if applicable, of the siblings. Besides the risk of development of MH or MH-like hypermetabolism, anesthetic risk is mainly determined by respiratory and cardiac complications in patients suffering from myopathies. Cardiac involvement is very frequent in myopathies, although only 10% of patients show clinical signs. It is noteworthy that the severity of cardiac dysfunction does not correlate with the symptoms of the skeletal muscles and that even patients whose cardiac status was fully compensated, suddenly and unexpectedly died. Smooth muscle dysfunction is supposed to cause the increased blood loss in scoliosis surgery, which for example can be twice as high in Duchenne patients as compared to patients with idiopathic scoliosis.

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9. Iaizzo PA, Johnson BA, Nagao K, Gallagher WJ. 4-chloro-mcresol triggers malignant hyperthermia in susceptible swine at doses greatly exceeding those found in drug preparations. Anesthesiology 1999;90:1723 32. 10. Paolini C, Fessenden JD, Pessah IN, Franzini-Armstrong C. Evidence for conformational coupling between two calcium channels. Proc Natl Acad Sci USA 2004;101:12748 52. 11. Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80:771 9. 12. Jurkat-Rott K, McCarthy T, Lehmann-Horn F. Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000;23:4 17. 13. Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet J Rare Dis 2007;2:21. 14. Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anaesthesia in neuromuscular disorders. Neuromuscul Disord 2005;15:195 206. 15. Hopkins PM. Malignant hyperthermia: pharmacology of triggering. Br J Anaesth 2011;107:48 56. 16. Morrison AG, Serpell MG. Malignant hyperthermia during prolonged surgery for tumour resection. Eur J Anaesthesiol 1998;15:114 17. 17. Girard T, Cavagna D, Padovan E, Spagnoli G, Urwyler A, Zorzato F, et al. B-lymphocytes from malignant hyperthermia-susceptible patients have an increased sensitivity to skeletal muscle ryanodine receptor activators. J Biol Chem 2001;276:48077 82. 18. Zullo A, Klingler W, De Sarno C, Ferrara M, Fortunato G, Perrotta G, et al. Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized Blymphocytes. Hum Mutat 2009;30:E575 90. 19. Littleford JA, Patel LR, Bose D, Cameron CB, McKillop C. Masseter muscle spasm in children: implications of continuing the triggering anesthetic. Anesth Analg 1991;72:151 60. 20. Sciote JJ, Rowlerson AM, Hopper C, Hunt NP. Fibre type classification and myosin isoforms in the human masseter muscle. J Neurol Sci 1994;126:15 24. 21. Rosenberg H, Fletcher JE. Masseter muscle rigidity and malignant hyperthermia susceptibility. Anesth Analg 1986;65:161 4. 22. Christian AS, Ellis FR, Halsall PJ. Is there a relationship between masseteric muscle spasm and malignant hyperpyrexia? Br J Anaesth 1989;62:540 4. 23. Hoppe K, Lehmann-Horn F, Chaiklieng S, Jurkat-Rott K, Adolph O, Klingler W. In vitro muscle contracture investigations on the malignant hyperthermia like episodes in myotonia congenita. Acta Anaesthesiol Scand 2013;57:1017 23. 24. Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, et al. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology 2001;94:95 100. 25. Thomas J, Crowhurst T. Exertional heat stroke, rhabdomyolysis and susceptibility to malignant hyperthermia. Intern Med J 2013;43:1035 8. 26. Nishio H, Sato T, Fukunishi S, Tamura A, Iwata M, Tsuboi K, et al. Identification of malignant hyperthermia-susceptible ryanodine receptor type 1 gene (RYR1) mutations in a child who died in a car after exposure to a high environmental temperature. Leg Med (Tokyo) 2009;11:142 3. 27. Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, et al. Identical de novo mutation in the type 1 ryanodine

Chapter | 45 Malignant Hyperthermia: An Inherited Disorder of Muscle Calcium Metabolism

28.

29.

30.

31.

32.

33.

34.

35.

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