Journal of Acute Care

Register      Login

VOLUME 1 , ISSUE 3 ( September-December, 2022 ) > List of Articles


Malignant Hyperthermia: A Review

David J Berman, Kumar Belani

Keywords : Anesthesiology, Dantrolene, Genetic disease, Hypermetabolic state, Malignant hyperthermia, Ryanodine receptor

Citation Information : Berman DJ, Belani K. Malignant Hyperthermia: A Review. 2022; 1 (3):135-140.

DOI: 10.5005/jp-journals-10089-0043

License: CC BY-NC 4.0

Published Online: 03-05-2023

Copyright Statement:  Copyright © 2022; The Author(s).


Malignant hyperthermia (MH) is a complex pharmacogenetic condition associated with the development of a hypermetabolic state when exposed to specific “triggering” anesthetic medications. These inciting agents include all potent inhalational anesthetics (e.g., halothane, sevoflurane, desflurane, isoflurane) and succinylcholine. While poorly understood, mutations in the ryanodine receptor are thought to play a pathogenic role in this genetic condition: these mutations are typically inherited in an autosomal dominant fashion or may be de novo mutations. The mainstay of treatment for patients with a history or family history of MH is avoidance of these triggering anesthetic agents. If a crisis occurs, discontinuation of the offending agent, prompt expert consultation, and targeted therapy with dantrolene have decreased the mortality of this condition from >70 to <10%. Future directions for MH research include more accurate genetic testing, a better understanding of the disease mechanism, and continued research for the optimal management of MH crises.

  1. Denborough MA, Forster JFA, Lovell RRH, et al. Anaesthetic deaths in a family. Br J Anaesth 1962;34(6):395–396. DOI: 10.1093/bja/34.6.395
  2. Denborough M. Malignant hyperthermia. Lancet 1998;352(9134):1131–1136. DOI: 10.1016/s0140-6736(98)03078-5
  3. MacLennan D, Phillips M. Malignant hyperthermia. Science 1992;256(5058):789–794. DOI: 10.1126/science.257.5066.11-b
  4. Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis 2015;10:93. DOI: 10.1186/s13023-015-0310-1
  5. Litman RS, Griggs SM, Dowling JJ, et al. Malignant hyperthermia susceptibility and related diseases. Anesthesiology 2018;128(1):159–167. DOI: 10.1097/aln.0000000000001877
  6. Larach MG, Brandom BW, Allen GC, et al. 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. Anesth Analg 2014;119(6):1359–1366. DOI: 10.1213/ANE.0000000000000421
  7. Rosero EB, Adesanya AO, Timaran CH, et al. Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology 2009;110(1):89–94. DOI: 10.1097/ALN.0b013e318190bb08
  8. Brady JE, Sun LS, Rosenberg H, et al. Prevalence of malignant hyperthermia due to anesthesia in New York state, 2001–2005. Anesth Analg 2009;109(4):1162–1166. DOI: 10.1213/ane.0b013e3181ac1548
  9. Bendixen D, Skovgaard LT, Ording H. Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test. Acta Anaesthesiol Scand 1997;41(4):480–484. DOI: 10.1111/j.1399-6576.1997.tb04727.x
  10. Larach MG, Gronert GA, Allen GC, et al. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg 2010;110(2):498–507. DOI: 10.1213/ANE.0b013e3181c6b9b2
  11. Moreno CAI, Hu S, Kraeva N, et al. An assessment of penetrance and clinical expression of malignant hyperthermia in individuals carrying diagnostic ryanodine receptor 1 gene mutations. Anesthesiology 2019;131(5):983–991. DOI: 10.1097/ALN.0000000000002813
  12. Gonsalves SG, Dirksen RT, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes. Clin Pharmacol Ther 2019;105(6):1338–1344. DOI: 10.1002/cpt.1319
  13. Davis PJ, Brandom BW. The association of malignant hyperthermia and unusual disease: when you're hot you're hot or maybe not. Anesth Analg 2009;109(4):1001–1003. DOI: 10.1213/ane.0b013e3181b493d4
  14. Carpenter D, Robinson RL, Quinnell RJ, et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth 2009;103(4):538–548. DOI: 10.1093/bja/aep204
  15. Monnier N, Procaccio V, Stieglitz P, et al. 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(6):1316–1325. DOI: 10.1086/515454
  16. Stamm DS, Aylsworth AS, Stajich JM, et al. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. Am J Med Genet A 2008;146A(14):1832–1841. DOI: 10.1002/ajmg.a.32370
  17. Endo Y, Groom L, Celik A, et al. Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility. Nat Commun 2022;13(1):3403. DOI: 10.1038/s41467-022-31088-8
  18. Carpenter D, Ringrose C, Leo V, et al. The role of CACNA1S in predisposition to malignant hyperthermia. BMC Med Genet 2009;10:104. DOI: 10.1186/1471-2350-10-104
  19. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80(4):771–779. DOI: 10.1097/00000542-199404000-00008
  20. Zvaritch E, Gillies R, Kraeva N, et al. Fatal awake malignant hyperthermia episodes in a family with malignant hyperthermia susceptibility: a case series. Can J Anaesth 2019;66(5):540–545. DOI: 10.1007/s12630-019-01320-z
  21. Sambuughin N, Capacchione J, Blokhin A, et al. The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet 2009;76(6):564–568. DOI: 10.1111/j.1399-0004.2009.01251.x
  22. Tobin JR, Jason DR, Challa VR, et al. Malignant hyperthermia and apparent heat stroke. JAMA 2001;286(2):168–169. DOI: 10.1001/jama.286.2.168
  23. Bendahan D, Kozak-Ribbens G, Confort-Gouny S, et al. A noninvasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia. Anesth Analg 2001;93(3):683–689. DOI: 10.1097/00000539-200109000-00030
  24. Köchling A, Wappler F, Winkler G, et al. Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia. Anaesth Intensive Care 1998;26(3):315–318. DOI: 10.1177/0310057x9802600317
  25. Wappler F, Fiege M, Steinfath M, et al. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology 2001;94(1):95–100. DOI: 10.1097/00000542-200101000-00019
  26. Guis S, Bendahan D, Kozak-Ribbens G, et al. Rhabdomyolysis and myalgia associated with anticholesterolemic treatment as potential signs of malignant hyperthermia susceptibility. Arthritis Rheum 2003;49(2):237–238. DOI: 10.1002/art.11013
  27. Krivosic-Horber R, Dépret T, Wagner JM, et al. Malignant hyperthermia susceptibility revealed by increased serum creatine kinase concentrations during statin treatment. Eur J Anaesthesiol 2004;21(7):572–574. DOI: 10.1017/s0265021504227120
  28. Brandom BW, Bina S, Wong CA, et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg 2013;116(5):1078–1086. DOI: 10.1213/ANE.0b013e31828a71ff
  29. Malignant Hyperthermia Association of the United States. Genetic Testing. [cited 2023]. Available from:
  30. Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry. The North American Malignant Hyperthermia Registry of MHAUS. Anesthesiology 1998;88(3):579–588. DOI: 10.1097/00000542-199803000-00006
  31. Ording H, Brancadoro V, Cozzolino S, 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(8):955–966. DOI: 10.1111/j.1399-6576.1997.tb04820.x
  32. Birgenheier N, Stoker R, Westenskow D, et al. Activated charcoal effectively removes inhaled anesthetics from modern anesthesia machines. Anesth Analg 2011;112(6):1363–1370. DOI: 10.1213/ANE.0b013e318213fad7
  33. Preparing the Anesthesia Machine for MHS Patients. [cited 2023]. Available from:
  34. Kim TW, Nemergut ME. Preparation of modern anesthesia workstations for malignant hyperthermia-susceptible patients: a review of past and present practice. Anesthesiology 2011;114(1):205–212. DOI: 10.1097/ALN.0b013e3181ee2cb7
  35. Jones PM, Allen BN, Cherry RA, et al. Association between known or strongly suspected malignant hyperthermia susceptibility and postoperative outcomes: an observational population-based study. Can J Anaesth 2019;66(2):161–181. DOI: 10.1007/s12630-018-1250-8
  36. Should MHS Patients Be Pretreated With Dantrolene? [cited 2023]. Available from:
  37. Parturient with MHS Partner. [cited January 12, 2023]. Available from:
  38. Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology 2007;106(5):901–908. DOI: 10.1097/01.anes.0000265148.86566.68
  39. Managing a Crisis. [cited 2023]. Available from:
  40. Goldhaber-Fiebert SN, Austin N, Sultan E, et al. Stanford Anesthesia Cognitive Aid Program, Emergency Manual: Cognitive Aids for Perioperative Crises; 2021. [cited 2023]. Available from:
  41. Riazi S, Larach MG, Hu C, et al. Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands. Anesth Analg 2014;118(2):381–387. DOI: 10.1213/ANE.0b013e3182937d8b
  42. Litman RS, Smith VI, Larach MG, et al. Consensus statement of the Malignant Hyperthermia Association of the United States on unresolved clinical questions concerning the management of patients with malignant hyperthermia. Anesth Analg 2019;128(4):652–659. DOI: 10.1213/ANE.0000000000004039
  43. Skerritt C, Carton E. Veno-venous extracorporeal membrane oxygenation in the management of malignant hyperthermia. Br J Anaesth 2019;122(6):e82–e83. DOI: 10.1016/j.bja.2019.03.014
  44. Huh H, Jung JS, Park SJ, et al. Successful early application of extracorporeal membrane oxygenation to support cardiopulmonary resuscitation for a patient suffering from severe malignant hyperthermia and cardiac arrest: a case report. Korean J Anesthesiol 2017;70(3):345–349. DOI: 10.4097/kjae.2017.70.3.345
  45. Malignant Hyperthermia Association of the United States. I Am MH-Susceptible: Now What? A Roadmap to Answers. [cited January 12, 2023]. Available from:
  46. MHAUS. Home. [cited January 10, 2023]. Available from:
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.