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Editorial Views  |   November 2011
Nonanesthetic Malignant Hyperthermia
Author Notes
  • Department of Neurophysiology, Ulm University, Ulm, Germany.
Article Information
Editorial Views / Patient Safety
Editorial Views   |   November 2011
Nonanesthetic Malignant Hyperthermia
Anesthesiology 11 2011, Vol.115, 915-917. doi:10.1097/ALN.0b013e318232008f
Anesthesiology 11 2011, Vol.115, 915-917. doi:10.1097/ALN.0b013e318232008f
SUSCEPTIBILITY to malignant hyperthermia (MH) is viewed as a pharmacogenetic trait dependent on exposure to inhalational anesthetics.1,2 Outside of the operating room, individuals susceptible to MH are usually asymptomatic. Events that occurred in the absence of anesthetics have been reported over the years and were originally termed awake episodes.3 In this issue of ANESTHESIOLOGY, two cases of nonanesthetic MH-like episodes triggered by either exposure to environmental heat or infection are described.4 These two cases raise the question of how at risk the MH susceptible individuals actually are.
Classic MH is caused by uncontrolled intracellular Ca2+release from the sarcoplasmic reticulum mediated by an overactive Ca2+release channel, the ryanodine receptor 1 (RyR1) (fig. 1).5 A fulminant anesthetic crisis manifests with tachyarrhythmia and sweating initially, hypercapnia, tachypnea, metabolic acidosis, and rapidly increasing temperature followed by muscle rigidity and rhabdomyolysis. Complications include cardiac arrest, heat stroke, and renal failure. Prompt infusion of dantrolene to block RyR1 is mandatory therapy.
Fig. 1. Scheme of the subcellular structures involved in excitation-contraction coupling of skeletal muscle. The dihydropyridine receptor senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor (which releases Ca2+from the sarcoplasmic reticulum [SR], a Ca2+store). Ca2+binds to troponin and activates the so-called contractile machinery. Interstitial and SR-luminal calcium concentrations are in the millimolar range, whereas the myoplasmic Ca2+concentration at rest is in the upper nanomolar to low micromolar range. The large Ca2+gradients are maintained by the SR Ca2+pump and indirectly by the sarcolemmal Na+/K+pump (the Na+gradient drives the Na+/Ca2+exchanger). In classic malignant hyperthermia, uncontrolled Ca2+release from the SR leads to an increased pump activity and heat production, mainly by the adenosine triphosphate-dependent Ca2+reuptake into the SR. To cope with the increased energy consumption, glycogen stores will be depleted for maximal adenosine triphosphate production. The myoplasmic Ca2+overload may also stimulate Ca2+sensitive proteases, liposomal enzymes, and nuclear DNases, potentially resulting in rhabdomyolysis.
Fig. 1. Scheme of the subcellular structures involved in excitation-contraction coupling of skeletal muscle. The dihydropyridine receptor senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor (which releases Ca2+from the sarcoplasmic reticulum [SR], a Ca2+store). Ca2+binds to troponin and activates the so-called contractile machinery. Interstitial and SR-luminal calcium concentrations are in the millimolar range, whereas the myoplasmic Ca2+concentration at rest is in the upper nanomolar to low micromolar range. The large Ca2+gradients are maintained by the SR Ca2+pump and indirectly by the sarcolemmal Na+/K+pump (the Na+gradient drives the Na+/Ca2+exchanger). In classic malignant hyperthermia, uncontrolled Ca2+release from the SR leads to an increased pump activity and heat production, mainly by the adenosine triphosphate-dependent Ca2+reuptake into the SR. To cope with the increased energy consumption, glycogen stores will be depleted for maximal adenosine triphosphate production. The myoplasmic Ca2+overload may also stimulate Ca2+sensitive proteases, liposomal enzymes, and nuclear DNases, potentially resulting in rhabdomyolysis.
Fig. 1. Scheme of the subcellular structures involved in excitation-contraction coupling of skeletal muscle. The dihydropyridine receptor senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor (which releases Ca2+from the sarcoplasmic reticulum [SR], a Ca2+store). Ca2+binds to troponin and activates the so-called contractile machinery. Interstitial and SR-luminal calcium concentrations are in the millimolar range, whereas the myoplasmic Ca2+concentration at rest is in the upper nanomolar to low micromolar range. The large Ca2+gradients are maintained by the SR Ca2+pump and indirectly by the sarcolemmal Na+/K+pump (the Na+gradient drives the Na+/Ca2+exchanger). In classic malignant hyperthermia, uncontrolled Ca2+release from the SR leads to an increased pump activity and heat production, mainly by the adenosine triphosphate-dependent Ca2+reuptake into the SR. To cope with the increased energy consumption, glycogen stores will be depleted for maximal adenosine triphosphate production. The myoplasmic Ca2+overload may also stimulate Ca2+sensitive proteases, liposomal enzymes, and nuclear DNases, potentially resulting in rhabdomyolysis.
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MH susceptibility is inherited in an autosomal dominant fashion in man and horse whereas in swine, it is recessive (table 1). In swine, the disorder is even named for these events, porcine stress syndrome, and the trait has been selectively bred because already heterozygous animals have muscle hypertrophy and therefore more meat. Homozygous pigs develop MH triggered by emotional and physical exertion during long-lasting transport in hot, close confinement. The animals either die spontaneously or their meat shows a very obvious, changed characteristic after slaughter that leads to the detection of the disorder.6 Mating, fighting, heat exposure, and infection trigger episodes that may not display all elements and show delayed or abortive progression. In the very muscular affected quarter horses, nonanesthetic events are frequent in the form of recurrent rhabdomyolysis without evident hyperthermia, spontaneous colic-like episodes, or heat-induced full MH events.7 In one mare with an especially severe phenotype, a concomitant polysaccharide storage myopathy was identified histologically postmortem.
Table 1. Summary of the Current Understanding of Malignant Hyperthermia and Similar Events
Image not available
Table 1. Summary of the Current Understanding of Malignant Hyperthermia and Similar Events
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The two unrelated children reported in this article,4 a boy and a girl, both showed marked hypertrophy and fever-induced MH-like events or recurrent cramping with rigid gait. The boy also had bilateral ptosis and muscle hypotonia indicative of a congenital myopathy, which may have aggravated the phenotype as in the quarter horse. Although both children harbored the same RyR1 variant, p.R3983C, on one allele, the girl had a second mutation, p.D4505H, on the other allele, possibly suggesting an additive effect comparable with the recessive situation in porcine stress syndrome. The notion of an additive effect of RyR1 mutations with other muscle-damaging traits could be supported by a recent report of a fatal heat-induced MH event with heat stroke in a 2-yr-old child harboring two RyR1 mutations, p.R4645Q and p.L4320_R4322dup.8 Furthermore, a recessive RyR1 myopathy has been described recently that displays symmetrical ptosis and muscle hypotonia.9 However, in MH-susceptible Japanese patients, 10% have compound heterozygous RyR1 mutations without any clinical signs of myopathy,10 so that no generally valid conclusion can be drawn.
The causative RyR1 mutations in the MH-susceptible animals (p.R614C homozygous in swine and p.R2454G dominant in horses) are both in hot spots of RyR1 where very frequent human MH susceptibility mutations reside. The mutations in the two children reported in this article (p.R3983C)4 and in another child who died of a nonanesthetic MH (p.R3983H)11 are in a different RyR1 part that contains an S-nitrosylation site.12 Therefore, it is possible that the episodes represent a distinct phenotype. Diagnostic testing may need to be rethought. The in vitro  contracture test is performed on excised muscle exposed to triggering agents, halothane, and caffeine. The standard protocol of the in vitro  contracture test may not be ideal to determine susceptibility to spontaneous MH-like episodes. The in vitro  contracture test performed on a muscle biopsy of the boy reported in this article4 would be considered by Europeans as MH equivocal. In addition, positive in vitro  contracture test results were found in only 24% of 45 individuals with exertional heat stroke,13 and in 83% of 12 patients with exercise-induced rhabdomyolysis.14 Therefore, more appropriate test protocols in vitro  (heat, oxidative stress, and nitrogen species as triggers) or in vivo  (using 31P MRI)15 need to be developed.
Which individuals should be considered at high risk for nonanesthetic MH? As long as no more specific tests for nonanesthetic MH susceptibility are available, we have to consider which individuals require counseling. Although a single RyR1 mutation predisposes to anesthesia-related MH, two mutations on different alleles seem to be required for nonanesthetic MH susceptibility. Alternatively, only one RyR1 mutation (i.e.  , in only 16% of the tetrameric RyR1 complexes, all four RyR1 subunits are impaired) might be sufficient if combined with a second mutation that is associated with a congenital myopathy. Therefore, MH-susceptible individuals presenting with ophthalmoplegia and muscle hypotonia, hypertrophy, or spasms will be at risk for nonanesthetic MH. At least such individuals should avoid excessive heat exposure, exhausting physical exertion, high fever, and all drugs that increase heat production and reduce heat dissipation or have been reported to cause rhabdomyolysis.16 For prevention of nonanesthetic MH, treatment with dantrolene (blocks RyR1) or N  -acetylcysteine (protects against oxidative damage) might be useful. In case of an episode, rapid cooling at home and during transport to the hospital could significantly contribute to RyR1 stabilization. At the hospital, dantrolene should be infused as in a typical MH crisis. Because children have less developed compensation mechanisms for increased body heat and a higher incidence of MH events than adults (1:15,000 vs.  1:100,000),17 their parents should be particularly careful.
Frank Lehmann-Horn is endowed Senior Research Professor for Neurosciences of the nonprofit Hertie-Foundation (Frankfurt, Germany). The Foundation pays, among others, his salary to his university.
References
Rosenberg H, Davis M, James D, Pollock N, Stowell K: Malignant hyperthermia. Orphanet J Rare Dis 2007; 24:21
Hopkins PM: Malignant hyperthermia: Pharmacology of triggering. Br J Anaesth 2011; 107:48–56
Gronert GA, Thompson RL, Onofrio BM: Human malignant hyperthermia: Awake episodes and correction by dantrolene. Anesth Analg 1980; 59:377–8
Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, Lee H-S, Qiu X, Sambuughin N, Dirksen RT: Identical de novo  mutation in the RYR1 gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. ANESTHESIOLOGY 2011; 115:938–45
Betzenhauser MJ, Marks AR: Ryanodine receptor channelopathies. Pflugers Arch 2010; 460:467–80
Harrison GG: Pale, soft exudative pork, porcine stress syndrome and malignant hyperpyrexia: An identity? J S Afr Vet Assoc 1972; 43:57–63
Aleman M, Nieto JE, Magdesian KG: Malignant hyperthermia associated with ryanodine receptor 1 (C7360G) mutation in Quarter Horses. J Vet Intern Med 2009; 23:329–34
Nishio H, Sato T, Fukunishi S, Tamura A, Iwata M, Tsuboi K, Suzuki K: 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
Bevilacqua JA, Monnier N, Bitoun M, Eymard B, Ferreiro A, Monges S, Lubieniecki F, Taratuto AL, Laquerrière A, Claeys KG, Marty I, Fardeau M, Guicheney P, Lunardi J, Romero NB: Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol 2011; 37:271–84
Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, Nonaka I, Noguchi S, Hayashi YK, Nishino I: Central core disease is due to RYR1 mutations in more than 90% of patients. Brain 2006; 129:1470–80
Gener B, Burns JM, Griffin S, Boyer EW: Administration of ondansetron is associated with lethal outcome. Pediatrics 2010; 125:e1514–7
Durham WJ, Aracena-Parks P, Long C, Rossi AE, Goonasekera SA, Boncompagni S, Galvan DL, Gilman CP, Baker MR, Shirokova N, Protasi F, Dirksen R, Hamilton SL: RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell 2008; 133:53–65
Figarella-Branger D, Kozak-Ribbens G, Rodet L, Aubert M, Borsarelli J, Cozzone PJ, Pellissier JF: Pathological findings in 165 patients explored for malignant hyperthermia susceptibility. Neuromuscul Disord 1993; 3:553–6
Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, Matschke J, Schulte Am Esch J: Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. ANESTHESIOLOGY 2001; 94:95–100
Bendahan D, Kozak-Ribbens G, Confort-Gouny S, Ghattas B, Figarella-Branger D, Aubert M, Cozzone PJ: A noninvasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia. Anesth Analg 2001; 93:683–9
Klingler W, Heffron JJ, Jurkat-Rott K, O'sullivan G, Alt A, Schlesinger F, Bufler J, Lehmann-Horn F: 3,4-Methylenedioxymethamphetamine (ecstasy) activates skeletal muscle nicotinic acetylcholine receptors. J Pharmacol Exp Ther 2005; 314:1267–73
Jurkat-Rott K, McCarthy T, Lehmann-Horn F: Genetics and pathogenesis of malignant hyperthermia. Muscle Nerve 2000; 23:4–17
Fig. 1. Scheme of the subcellular structures involved in excitation-contraction coupling of skeletal muscle. The dihydropyridine receptor senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor (which releases Ca2+from the sarcoplasmic reticulum [SR], a Ca2+store). Ca2+binds to troponin and activates the so-called contractile machinery. Interstitial and SR-luminal calcium concentrations are in the millimolar range, whereas the myoplasmic Ca2+concentration at rest is in the upper nanomolar to low micromolar range. The large Ca2+gradients are maintained by the SR Ca2+pump and indirectly by the sarcolemmal Na+/K+pump (the Na+gradient drives the Na+/Ca2+exchanger). In classic malignant hyperthermia, uncontrolled Ca2+release from the SR leads to an increased pump activity and heat production, mainly by the adenosine triphosphate-dependent Ca2+reuptake into the SR. To cope with the increased energy consumption, glycogen stores will be depleted for maximal adenosine triphosphate production. The myoplasmic Ca2+overload may also stimulate Ca2+sensitive proteases, liposomal enzymes, and nuclear DNases, potentially resulting in rhabdomyolysis.
Fig. 1. Scheme of the subcellular structures involved in excitation-contraction coupling of skeletal muscle. The dihydropyridine receptor senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor (which releases Ca2+from the sarcoplasmic reticulum [SR], a Ca2+store). Ca2+binds to troponin and activates the so-called contractile machinery. Interstitial and SR-luminal calcium concentrations are in the millimolar range, whereas the myoplasmic Ca2+concentration at rest is in the upper nanomolar to low micromolar range. The large Ca2+gradients are maintained by the SR Ca2+pump and indirectly by the sarcolemmal Na+/K+pump (the Na+gradient drives the Na+/Ca2+exchanger). In classic malignant hyperthermia, uncontrolled Ca2+release from the SR leads to an increased pump activity and heat production, mainly by the adenosine triphosphate-dependent Ca2+reuptake into the SR. To cope with the increased energy consumption, glycogen stores will be depleted for maximal adenosine triphosphate production. The myoplasmic Ca2+overload may also stimulate Ca2+sensitive proteases, liposomal enzymes, and nuclear DNases, potentially resulting in rhabdomyolysis.
Fig. 1. Scheme of the subcellular structures involved in excitation-contraction coupling of skeletal muscle. The dihydropyridine receptor senses the membrane depolarization, alters its conformation, and activates the ryanodine receptor (which releases Ca2+from the sarcoplasmic reticulum [SR], a Ca2+store). Ca2+binds to troponin and activates the so-called contractile machinery. Interstitial and SR-luminal calcium concentrations are in the millimolar range, whereas the myoplasmic Ca2+concentration at rest is in the upper nanomolar to low micromolar range. The large Ca2+gradients are maintained by the SR Ca2+pump and indirectly by the sarcolemmal Na+/K+pump (the Na+gradient drives the Na+/Ca2+exchanger). In classic malignant hyperthermia, uncontrolled Ca2+release from the SR leads to an increased pump activity and heat production, mainly by the adenosine triphosphate-dependent Ca2+reuptake into the SR. To cope with the increased energy consumption, glycogen stores will be depleted for maximal adenosine triphosphate production. The myoplasmic Ca2+overload may also stimulate Ca2+sensitive proteases, liposomal enzymes, and nuclear DNases, potentially resulting in rhabdomyolysis.
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Table 1. Summary of the Current Understanding of Malignant Hyperthermia and Similar Events
Image not available
Table 1. Summary of the Current Understanding of Malignant Hyperthermia and Similar Events
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