Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 142 No. 3132 (2012)

Malignant hyperthermia

  • Oliver Bandschapp
  • Thierry Girard
Cite this as:
Swiss Med Wkly. 2012;142:w13652


Malignant hyperthermia (MH) is a subclinical myopathy, usually triggered by volatile anaesthetics and depolarising muscle relaxants. Clinical symptoms are variable, and the condition is sometimes difficult to identify. Nevertheless, rapid recognition and specific as well as symptomatic treatment are crucial to avoid a lethal outcome. Molecular genetic investigations have confirmed the skeletal muscle type ryanodine receptor to be the major MH locus with more than 70% of MH families carrying a mutation in this gene. There is no screening method to test for MH, as current tests are invasive (open muscle biopsy) or restricted to MH families with known MH-associated mutations (molecular genetic testing).

The prevalence of the MH trait is unknown, because the clinical penetrance after contact with triggering agents is very variable. More recently, MH mutations have been associated with rhabdomyolysis following statin therapy or with non-pharmacological triggering, such as exertional heat stroke.


  1. Girard T, Ginz H, Urwyler A. Maligne Hyperthermie. Schweiz Med Forum.2004:1192–7.
  2. Denborough M, Lovell R. Anaesthetic deaths in a family. Lancet.1960;2:45.
  3. Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA.2005;293:2918–24.
  4. Denborough M. Malignant hyperthermia. Lancet. 1998;352:1131–6.
  5. Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet J Rare Dis.2007;2:21.
  6. Hopkins PM. Malignant hyperthermia: pharmacology of triggering. Br J Anaesth. 2011;107:48–56.
  7. Klingler W, Rueffert H, Lehmann-Horn F, Girard T, Hopkins PM. Core myopathies and risk of malignant hyperthermia. Anesth Analg.2009;109:1167–73.
  8. Kinder Ross A. Muscular dystrophy versus mitochondrial myopathy: the dilemma of the undiagnosed hypotonic child. Paediatr Anaesth.2007;17:1–6.
  9. Parness J, Bandschapp O, Girard T. The myotonias and susceptibility to malignant hyperthermia. Anesth Analg.2009;109:1054–64.
  10. Ording H. Incidence of malignant hyperthermia in Denmark. Anesth Analg. 1985;64:700–704.
  11. Urwyler A, Hartung E. Die Maligne Hyperthermie. Anaesthesist.1994;43:557–69.
  12. Sumitani M, Uchida K, Yasunaga H, Horiguchi H, Kusakabe Y, Matsuda S, et al. Prevalence of malignant hyperthermia and relationship with anesthetics in Japan: data from the diagnosis procedure combination database. Anesthesiology.2011;114:84–90.
  13. Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001–2005. Anesth Analg.2009;109:1162-–6.
  14. Monnier N, Krivosic-Horber R, Payen JF, Kozak-Ribbens G, Nivoche Y, Adnet P, et al. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology.2002;97:1067–74.
  15. Tautz TJ, Urwyler A, Antognini JF, Riou B. Case scenario: Increased end-tidal carbon dioxide: a diagnostic dilemma. Anesthesiology.2010;112:440–6.
  16. Karan SM, Crowl F, Muldoon SM. Malignant hyperthermia masked by capnographic monitoring. Anesth Analg.1994;78:590–2.
  17. 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.
  18. Schwartz L, Rockoff MA, Koka BV. Masseter spasm with anesthesia: incidence and implications. Anesthesiology.1984;61:772–5.
  19. Lazzell VA, Carr AS, Lerman J, Burrows FA, Creighton RE. The incidence of masseter muscle rigidity after succinylcholine in infants and children. Can J Anaesth.1994;41:475–9.
  20. Ummenhofer WC, Kindler C, Tschaler G, Hampl KF, Drewe J, Urwyler A. Propofol reduces succinylcholine induced increase of masseter muscle tone. Can J Anaesth. 1998;45:417–23.
  21. O'Flynn RP, Shutack JG, Rosenberg H, Fletcher JE. Masseter muscle rigidity and malignant hyperthermia susceptibility in pediatric patients. An update on management and diagnosis. Anesthesiology.1994;80:1228–33.
  22. Glahn KP, Ellis FR, Halsall PJ, Muller CR, Snoeck MM, Urwyler A, et al. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Br J Anaesth.2010;105:417–20.
  23. Inan S, Wei H. The cytoprotective effects of dantrolene: a ryanodine receptor antagonist. Anesth Analg.2010;111:1400–10.
  24. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med.2009;361:62–72.
  25. Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology.2007;106:901–6.
  26. Iaizzo PA, Klein W, Lehmann-Horn F. Fura-2 detected myoplasmic calcium and its correlation with contracture force in skeletal muscle from normal and malignant hyperthermia susceptible pigs. Pflugers Arch.1988;411:648–53.
  27. Girard T, Johr M, Schaefer C, Urwyler A. Perinatal diagnosis of malignant hyperthermia susceptibility. Anesthesiology.2006;104:1353–4.
  28. McCarthy TV, Quane KA, Lynch PJ. Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mutat.2000;15:410–7.
  29. Groom L, Muldoon SM, Tang ZZ, Brandom BW, Bayarsaikhan M, Bina S, et al. Identical de novo mutation in the type 1 ryanodine receptor gene associated with fatal, stress-induced malignant hyperthermia in two unrelated families. Anesthesiology.2011;115:938–45.
  30. Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat.2006;27:977–89.
  31. Vita GM, Olckers A, Jedlicka AE, George AL, Heiman-Patterson T, Rosenberg H, et al. Masseter muscle rigidity associated with glycine1306-to-alanine mutation in the adult muscle sodium channel alpha-subunit gene. Anesthesiology.1995;82:1097–103.
  32. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive l-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet.1997;60:1316–25.
  33. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. The European Malignant Hyperpyrexia Group. Br J Anaesth.1984;56:1267–9.
  34. Ording H, Brancadoro V, Cozzolino S, Ellis FR, Glauber V, Gonano EF, et al. In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group. Acta anaesthesiol Scand. 1997;41:955–66.
  35. Urwyler A, Deufel T, McCarthy T, West S. Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. Br J Anaesth.2001;86:283–7.
  36. Lehmann-Horn F, Klingler W, Jurkat-Rott K. Nonanesthetic malignant hyperthermia. Anesthesiology. 2011;115:915–7.
  37. Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, et al. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science. 1991;253:448–51.
  38. Wappler F, Fiege M, Schulte am Esch J. Pathophysiological role of the serotonin system in malignant hyperthermia. Br J Anaesth.2001;87:794–8.
  39. Gronert GA, Thompson RL, Onofrio BM. Human malignant hyperthermia: awake episodes and correction by dantrolene. Anesth Analg.1980;59:377–8.
  40. Tobin JR, Jason DR, Challa VR, Nelson TE, Sambuughin N. Malignant hyperthermia and apparent heat stroke. JAMA2001;286:168-–9.
  41. Gronert GA, Tobin JR, Muldoon S. Malignant hyperthermia – human stress triggering. Biochim Biophys Acta. 2011;1813:2191–2.
  42. Maclennan DH, Zvaritch E. Response to "malignant hyperthermia - human stress triggering" in reference to original article "mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum". Biochim Biophys Acta. 2011;1813:2193–4.
  43. Kasi PM. Malignant hyperthermia and idiopathic hyperckemia. Case Reports in Medicine. 2011;2011:3.
  44. Malandrini A, Orrico A, Gaudiano C, Gambelli S, Galli L, Berti G, et al. Muscle biopsy and in vitro contracture test in subjects with idiopathic hyperCKemia. Anesthesiology. 2008;109:625–8.
  45. Weglinski MR, Wedel DJ, Engel AG. Malignant hyperthermia testing in patients with persistently increased serum creatine kinase levels. Anesth Analg.1997;84:1038–41.
  46. Ellis FR, Clarke IM, Modgill M, Currie S, Harriman DG. Evaluation of creatinine phosphokinase in screening patients for malignant hyperpyrexia. Br Med J. 1975;3:511–3.
  47. Amaranath L, Lavin TJ, Trusso RA, Boutros AR. Evaluation of creatinine phosphokinase screening as a predictor of malignant hyperthermia. A prospective study. Br J Anaesth.1983;55:531–3.
  48. Paasuke RT, Brownell AK. Serum creatine kinase level as a screening test for susceptibility to malignant hyperthermia. JAMA.1986;255:769–71.
  49. Lingaraju N, Rosenberg H. Unexplained increases in serum creatine kinase levels: its relation to malignant hyperthermia susceptibility. Anesth Analg.1991;72:702–5.
  50. Monnier N, Kozak-Ribbens G, Krivosic-Horber R, Nivoche Y, Qi D, Kraev N, et al. Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. Hum Mutat2005;26:413–25.
  51. Capacchione JF, Sambuughin N, Bina S, Mulligan LP, Lawson TD, Muldoon SM. Exertional rhabdomyolysis and malignant hyperthermia in a patient with ryanodine receptor type 1 gene, l-type calcium channel alpha-1 subunit gene, and calsequestrin-1 gene polymorphisms. Anesthesiology.2010;112:239–44.
  52. 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.
  53. Guis S, Figarella-Branger D, Mattei JP, Nicoli F, Le Fur Y, Kozak-Ribbens G, et al. In vivo and in vitro characterization of skeletal muscle metabolism in patients with statin-induced adverse effects. Arthritis Rheum.2006;55:551–7.
  54. Sato T, Nishio H, Iwata M, Kentotsuboi, Tamura A, Miyazaki T, et al. Postmortem molecular screening for mutations in ryanodine receptor type 1 (ryr1) gene in psychiatric patients suspected of having died of neuroleptic malignant syndrome. Forensic Sci Int.2010;194:77–9.