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Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence vs. Conjecture

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ALetter to the Editor to this article was published on 09 October 2021

ALetter to the Editor to this article was published on 09 October 2021

Abstract

Exertional heat stroke (EHS) and malignant hyperthermia (MH) are life-threatening conditions, triggered by different environmental stimuli that share several clinical symptoms and pathophysiological features. EHS manifests during physical activity normally, but not always, in hot and humid environments. MH manifests during exposure to haloalkane anesthetics or succinylcholine, which leads to a rapid, unregulated release of calcium (Ca2+) within the skeletal muscles inducing a positive-feedback loop within the excitation–contraction coupling mechanism that culminates in heat stroke-like symptoms, if not rapidly recognized and treated. Rare cases of awake MH, independent of anesthesia exposure, occur during exercise and heat stress. It has been suggested that EHS and MH are mediated by similar mechanisms, including mutations in Ca2+ regulatory channels within the skeletal muscle. Rapid cooling, which is the most effective treatment for EHS, is ineffective as an MH treatment; rather, a ryanodine receptor antagonist drug, dantrolene sodium (DS), is administered to the victim to prevent further muscle contractions and hyperthermia. Whether DS can be an effective treatment for EHS victims remains uncertain. In the last decade, multiple reports have suggested a number of mechanistic links between EHS and MH. Here, we discuss aspects related to the pathophysiology, incidence, diagnosis and treatment. Furthermore, we present evidence regarding potential overlapping mechanisms between EHS and MH and explore current knowledge to establish what is supported by evidence or a lack thereof (i.e. conjecture).

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Article03 February 2022

References

  1. Tobin JR. Malignant hyperthermia and apparent heat stroke. JAMA. 2001;286:168.

    Article CAS PubMed  Google Scholar 

  2. Leon LR, Bouchama A. Heat stroke. Compr Physiol. 2015;5:611–47.

    Article PubMed  Google Scholar 

  3. Sawka MN, Leon LR, Montain SJ, Sonna LA. Integrated physiological mechanisms of exercise performance, adaptation, and maladaptation to heat stress. Compr Physiol. 2011;1:1883–928.

    Article PubMed  Google Scholar 

  4. Roberts WO. Exertional heat stroke during a cool weather marathon: a case study. Med Sci Sports Exerc. 2006;38:1197–203.

    Article PubMed  Google Scholar 

  5. Ellinas H, Albrecht MA. Malignant hyperthermia update. Anesthesiol Clin. 2020;38:165–81.

    Article PubMed  Google Scholar 

  6. Appiah-Ankam J, Hunter JM. Pharmacology of neuromuscular blocking drugs. Contin Educ Anaesth Crit Care Pain. 2004;4:2–7.

    Article  Google Scholar 

  7. Jardon OM. Physiologic stress, heat stroke, malignant hyperthermia—a perspective. Mil Med. 1982;147:8–14.

    Article CAS PubMed  Google Scholar 

  8. Lavezzi WA, Capacchione JF, Muldoon SM, Sambuughin N, Bina S, Steele D, et al. Death in the emergency department: an unrecognized awake malignant hyperthermia-like reaction in a six-year-old. Anesth Analg. 2013;116:420.

    Article PubMed  Google Scholar 

  9. Figarella-Branger D, Kozak-Ribbens G, Rodet L, Aubert M, Borsarelli J, Cozzone PJ, et al. Pathological findings in 165 patients explored for malignant hyperthermia susceptibility. Neuromuscul Disord. 1993;3:553–6.

    Article CAS PubMed  Google Scholar 

  10. Ogletree JW, Antognini JF, Gronert GA. Postexercise muscle cramping associated with positive malignant hyperthermia contracture testing. Am J Sports Med. 1996;24:49–51.

    Article CAS PubMed  Google Scholar 

  11. Gronert GA, Thompson RL, Onofrio BM. Human malignant hyperthermia: awake episodes and correction by Dantrolene. Anesth Analg. 1980;59:377.

    Article CAS PubMed  Google Scholar 

  12. Fink E, Brandom BW, Torp KD. Heatstroke in the super-sized athlete. Pediatr Emerg Care. 2006;22:510.

    Article PubMed  Google Scholar 

  13. Poussel M, Guerci P, Kaminsky P, Heymonet M, Roux-Buisson N, Faure J, et al. Exertional heat stroke and susceptibility to malignant hyperthermia in an athlete: evidence for a link? J Athl Train. 2015;50:1212–4.

    Article PubMed PubMed Central  Google Scholar 

  14. Hopkins PM, Ellis FR, Halsall PJ. Evidence for related myopathies in exertional heat stroke and malignant hyperthermia. Lancet. 1991;338:1491–2.

    Article CAS PubMed  Google Scholar 

  15. Capacchione JF, Muldoon SM. The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia. Anesth Analg. 2009;109:1065.

    Article PubMed  Google Scholar 

  16. Muldoon S, Deuster P, Voelkel M, Capacchione J, Bunger R. Exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia: is there a link? Curr Sports Med Rep. 2008;7:74.

    Article PubMed  Google Scholar 

  17. Muldoon S, Deuster P, Brandom B, Bunger R. Is there a link between malignant hyperthermia and exertional heat illness? Exerc Sport Sci Rev. 2004;32:174.

    Article PubMed  Google Scholar 

  18. Laitano O, Leon LR, Roberts WO, Sawka MN. Controversies in exertional heat stroke diagnosis, prevention, and treatment. J Appl Physiol. 2019;127:1338–48.

    Article CAS PubMed  Google Scholar 

  19. Sagui E, Montigon C, Abriat A, Jouvion A, Duron-Martinaud S, Canini F, et al. Is there a link between exertional heat stroke and susceptibility to malignant hyperthermia? PLoS ONE. 2015;10:e0135496.

    Article PubMed PubMed Central CAS  Google Scholar 

  20. Nybo L, Rasmussen P, Sawka MN. Performance in the heat-physiological factors of importance for hyperthermia-induced fatigue. Compr Physiol. 2014;4:657–89.

    Article PubMed  Google Scholar 

  21. González-Alonso J, Crandall CG, Johnson JM. The cardiovascular challenge of exercising in the heat. J Physiol (Lond). 2008;586:45–53.

    Article CAS  Google Scholar 

  22. Casa DJ, DeMartini JK, Bergeron MF, Csillan D, Eichner ER, Lopez RM, et al. National athletic trainers’ association position statement: exertional heat illnesses. J Athl Train. 2015;50:986–1000.

    Article PubMed PubMed Central  Google Scholar 

  23. Binkley HM, Beckett J, Casa DJ, Kleiner DM, Plummer PE. National athletic trainers’ association position statement: exertional heat illnesses. J Athl Train. 2002;37:329–43.

    PubMed PubMed Central  Google Scholar 

  24. Smith JE. Cooling methods used in the treatment of exertional heat illness. Br J Sports Med. 2005;39:503–7.

    Article CAS PubMed PubMed Central  Google Scholar 

  25. Larach MG, Rosenberg H, Larach DR, Broennle AM. Prediction of malignant hyperthermia susceptibility by clinical signs. Anesthesiology. 1987;66:547–50.

    Article CAS PubMed  Google Scholar 

  26. Glahn KPE, Ellis FR, Halsall PJ, Müller CR, Snoeck MMJ, 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.

    Article CAS PubMed  Google Scholar 

  27. Campbell IT, Ellis FR, Evans RT. Metabolic rate and blood hormone and metabolite levels of individuals susceptible to malignant hyperpyrexia at rest and in response to food and mild exercise. Anesthesiology. 1981;55:46–52.

    Article CAS PubMed  Google Scholar 

  28. Leon LR, Gordon CJ, Helwig BG, Rufolo DM, Blaha MD. Thermoregulatory, behavioral, and metabolic responses to heatstroke in a conscious mouse model. Am J Physiol Regul Integr Comp Physiol. 2010;299:R241–248.

    Article CAS PubMed  Google Scholar 

  29. King MA, Ward MD, Mayer TA, Plamper ML, Madsen CM, Cheuvront SN, et al. Influence of prior illness on exertional heat stroke presentation and outcome. PLoS ONE. 2019;14:e0221329.

    Article CAS PubMed PubMed Central  Google Scholar 

  30. Roberts WO, Dorman JC, Bergeron MF. Recurrent heat stroke in a runner: race simulation testing for return to activity. Med Sci Sports Exerc. 2016;48:785–9.

    Article PubMed  Google Scholar 

  31. Howe AS, Boden BP. Heat-related illness in athletes. Am J Sports Med. 2007;35:1384–95.

    Article PubMed  Google Scholar 

  32. Knight N, Parkin J, Smith R, Kipps C. The incidence of exertional heat stroke during mass-participation triathlon races: optimising athlete safety. Br J Sports Med. 2017;51:344–5.

    Article  Google Scholar 

  33. Rosero EB, Adesanya AO, Timaran CH, Joshi GP. Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology. 2009;110:89–94.

    Article PubMed  Google Scholar 

  34. Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524368/

  35. Wappler F. Anesthesia for patients with a history of malignant hyperthermia. Curr Opin Anaesthesiol. 2010;23:417–22.

    Article PubMed  Google Scholar 

  36. Monnier N, Krivosic-Horber R, Payen J-F, 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.

    Article CAS PubMed  Google Scholar 

  37. Bachand M, Vachon N, Boisvert M, Mayer FM, Chartrand D. Clinical reassessment of malignant hyperthermia in Abitibi-Témiscamingue. Can J Anaesth. 1997;44:696–701.

    Article CAS PubMed  Google Scholar 

  38. 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.

    Article PubMed  Google Scholar 

  39. Harmer AR, Ruell PA, Hunter SK, McKenna MJ, Thom JM, Chisholm DJ, et al. Effects of type 1 diabetes, sprint training and sex on skeletal muscle sarcoplasmic reticulum Ca2+ uptake and Ca2+-ATPase activity. J Physiol (Lond). 2014;592:523–35.

    Article CAS  Google Scholar 

  40. Dhaese HL, Martens PR, Müller NH, Casier IM, Mulier JPJ, Heytens L. The use of emergency medical cooling system pads in the treatment of malignant hyperthermia. Eur J Anaesthesiol. 2010;27:83–5.

    Article CAS PubMed  Google Scholar 

  41. Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth. 1975;47:62–5.

    Article CAS PubMed  Google Scholar 

  42. Fiszer D, Shaw M-A, Fisher NA, Carr IM, Gupta PK, Watkins EJ, et al. Next-generation sequencing of RYR1 and CACNA1S in malignant hyperthermia and exertional heat illness. Anesthesiology. 2015;122:1033–46.

    Article CAS  Google Scholar 

  43. Mungunsukh O, Deuster P, Muldoon S, O’Connor F, Sambuughin N. Estimating prevalence of malignant hyperthermia susceptibility through population genomics data. Br J Anaesth. 2019;123:e461–e463463.

    Article PubMed  Google Scholar 

  44. Riazi S, Kraeva N, Hopkins PM. Malignant hyperthermia in the post-genomics era: new perspectives on an old concept. Anesthesiology. 2018;128:168–80.

    Article PubMed  Google Scholar 

  45. Protasi F, Paolini C, Dainese M. Calsequestrin-1: a new candidate gene for malignant hyperthermia and exertional/environmental heat stroke. J Physiol (Lond). 2009;587:3095–100.

    Article CAS  Google Scholar 

  46. Lydiatt JS, Hill GE. Treatment of heat stroke with dantrolene. JAMA. 1981;246:41–2.

    Article CAS PubMed  Google Scholar 

  47. Tayeb OS, Marzouki ZM. Effect of dantrolene pretreatment on heat stroke in sheep. Pharmacol Res. 1990;22:565–72.

    Article CAS PubMed  Google Scholar 

  48. Channa AB, Seraj MA, Saddique AA, Kadiwal GH, Shaikh MH, Samarkandi AH. Is dantrolene effective in heat stroke patients? Crit Care Med. 1990;18:290–2.

    Article CAS PubMed  Google Scholar 

  49. Bouchama A, Cafege A, Devol EB, Labdi O, El-Assil K, Seraj M. Ineffectiveness of dantrolene sodium in the treatment of heatstroke. Crit Care Med. 1991;19:176–80.

    Article CAS PubMed  Google Scholar 

  50. Moran D, Epstein Y, Wiener M, Horowitz M. Dantrolene and recovery from heat stroke. Aviat Space Environ Med. 1999;70:987–9.

    CAS PubMed  Google Scholar 

  51. Kalow W, Britt BA, Terreau ME, Haist C. Metabolic error of muscle metabolism after recovery from malignant hyperthermia. Lancet. 1970;2:895–8.

    Article CAS PubMed  Google Scholar 

  52. Ellis FR, Harriman DG, Keaney NP, Kyei-Mensah K, Tyrrell JH. Halothane-induced muscle contracture as a cause of hyperpyrexia. Br J Anaesth. 1971;43:721–2.

    CAS PubMed  Google Scholar 

  53. Kalow W, Britt BA, Richter A. The caffeine test of isolated human muscle in relation to malignant hyperthermia. Can Anaesth Soc J. 1977;24:678–94.

    Article CAS PubMed  Google Scholar 

  54. Bendahan D, Guis S, Monnier N, Kozak-Ribbens G, Lunardi J, Ghattas B, et al. Comparative analysis of in vitro contracture tests with ryanodine and a combination of ryanodine with either halothane or caffeine: a comparative investigation in malignant hyperthermia. Acta Anaesthesiol Scand. 2004;48:1019–27.

    Article CAS PubMed  Google Scholar 

  55. The European Malignant Hyperpyrexia Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. Br J Anaesth. 1984;56:1267–9.

    Article  Google Scholar 

  56. Zullo A, Textor M, Elischer P, Mall S, Alt A, Klingler W, et al. Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia-susceptible muscle. J Gen Physiol. 2018;150:111–25.

    Article CAS PubMed PubMed Central  Google Scholar 

  57. Klein MG, Simon BJ, Schneider MF. Effects of caffeine on calcium release from the sarcoplasmic reticulum in frog skeletal muscle fibres. J Physiol (Lond). 1990;425:599–626.

    Article CAS  Google Scholar 

  58. Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KPE, Ellis FR, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115:531–9.

    Article CAS PubMed  Google Scholar 

  59. 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.

    Article CAS PubMed  Google Scholar 

  60. 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;88:579–88.

    Article CAS PubMed  Google Scholar 

  61. Kindler CH, Girard T, Gong D, Urwyler A. The differential effect of halothane and 1,2-dichlorohexafluorocyclobutane on in vitro muscle contractures of patients susceptible to malignant hyperthermia. Anesth Analg. 2002;94:1028–33.

    Article CAS PubMed  Google Scholar 

  62. Heytens L, Martin JJ, Van de Kelft E, Bossaert LL. In vitro contracture tests in patients with various neuromuscular diseases. Br J Anaesth. 1992;68:72–5.

    Article CAS PubMed  Google Scholar 

  63. Oku S, Mukaida K, Nosaka S, Sai Y, Maehara Y, Yuge O. Comparison of the in vitro caffeine-halothane contracture test with the Ca-induced Ca release rate test in patients suspected of having malignant hyperthermia susceptibility. J Anesth. 2000;14:6–13.

    Article CAS PubMed  Google Scholar 

  64. 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.

    Article CAS PubMed  Google Scholar 

  65. Wappler F, Roewer N, Kochling A, Scholz J, Loscher W, Steinfath M, et al. Effects of the Serotonin2Receptor agonist DOI on skeletal muscle specimens from malignant hyperthermia-susceptible patients. Anesthesiology. 1996;84:1280–7.

    Article CAS  Google Scholar 

  66. Lee MA, McGlinch EB, McGlinch MC, Capacchione JF. Malignant hyperthermia susceptibility and fitness for duty. Mil Med. 2017;182:e1854–e18571857.

    Article PubMed  Google Scholar 

  67. Rosenberg H, Davis M, James D, Pollock N, Stowell K. Malignant hyperthermia. Orphanet J Rare Dis. 2007;2:21.

    Article PubMed PubMed Central  Google Scholar 

  68. Zvaritch E, Gillies R, Kraeva N, Richer M, Jungbluth H, Riazi S. Fatal awake malignant hyperthermia episodes in a family with malignant hyperthermia susceptibility: a case series. Can J Anaesth. 2019;66:540–5.

    Article PubMed  Google Scholar 

  69. Hunter SL, Rosenberg H, Tuttle GH, DeWalt JL, Smodic R, Martin J. Malignant hyperthermia in a college football player. Phys Sportsmed. 1987;15:77–81.

    Article  Google Scholar 

  70. Pamukcoglu T. Sudden death due to malignant hyperthermia. Am J Forensic Med Pathol. 1988;9:161–2.

    Article CAS PubMed  Google Scholar 

  71. Kozak-Ribbens G, Bendahan D, Rodet L, Confort-Gouny S, Miri A, Talmant A, et al. Metabolic events with spontaneous malignant hyperthermia crisis in an anaesthetized pig. Can J Anaesth. 1997;44:757–64.

    Article CAS PubMed  Google Scholar 

  72. Gatz EE, Wingard DW. Malignant hyperthermia. Nebr Med J. 1973;58:434–7.

    CAS PubMed  Google Scholar 

  73. 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.

    Article CAS  Google Scholar 

  74. Ellis KO, Castellion AW, Honkomp LJ, Wessels FL, Carpenter JE, Halliday RP. Dantrolene, a direct acting skeletal muscle relaxant. J Pharm Sci. 1973;62:948–51.

    Article CAS PubMed  Google Scholar 

  75. Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene–a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004;59:364–73.

    Article CAS PubMed  Google Scholar 

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Acknowledgements

We thank Mr. Lucas de Carvalho for technical contributions with the illustration.

Disclaimers

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Army or the Department of Defense. Any citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement of approval of the products or services of these organizations.

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Authors and Affiliations

  1. Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, 1864 Stadium Road, Room 100, Gainesville, FL, USA

    Orlando Laitano & Kevin O. Murray

  2. Thermal and Mountain Medicine Division, US Army Research Institute for Environmental Medicine, Natick, MA, USA

    Lisa R. Leon

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  1. Orlando Laitano

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  2. Kevin O. Murray

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  3. Lisa R. Leon

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Correspondence toOrlando Laitano.

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Conflict of Interest

Orlando Laitano (OL), Kevin O. Murray (KOM) and Lisa R. Leon (LRL) declare that they have no conflicts of interest relevant to the content of this review.

Authorship Contributions

OL and LRL outlined and wrote the first draft of the manuscript. KOM analyzed, interpreted the literature and wrote the section on IVCT. OL, KOM and LRL revised the original manuscript. All authors read and approved the final version of the manuscript.

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Laitano, O., Murray, K.O. & Leon, L.R. Overlapping Mechanisms of Exertional Heat Stroke and Malignant Hyperthermia: Evidence vs. Conjecture.Sports Med50, 1581–1592 (2020). https://doi.org/10.1007/s40279-020-01318-4

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