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Malignant hyperthermia

Medical Professionals

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Synonyms: malignant hyperpyrexia, malignant hyperthermia susceptibility, MHS, hyperthermia of anaesthesia, King syndrome, King-Denborough syndrome

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What is malignant hyperthermia?

Malignant Hyperthermia is a life-threatening pharmacogenetic disorder which results from exposure to volatile anaesthetic agents and depolarising muscle relaxants. It manifests as a hypermetabolic response resulting in tachycardia, tachypnoea, hyperthermia, hypercapnia, acidosis, muscle rigidity and rhabdomyolysis.1

Volatile anaesthetic gases that may trigger malignant hyperthermia include halothane, sevoflurane, desflurane, isoflurane, and the depolarising muscle relaxant succinylcholine may also be responsible. It also very rarely presents as a response to stressors such as vigorous exercise and heat.2


An uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation, leads to the pathophysiological changes.

In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for malignant hyperthermia.

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How common is malignant hyperthermia? (Epidemiology)

  • The incidence ranges from 1 in 10,000 to 1 in 250,000 anaesthetics. However, the prevalence of the genetic abnormalities may be as high as 1 in 400 individuals.2

  • It is inherited as an autosomal dominant gene of variable penetrance.3

  • As may be expected with any familial condition, there are geographical clusters.

Risk factors

  • Usually there is nothing in the past medical history to suggest the diagnosis although it has been associated with myotonia congenita and both Duchenne muscular dystrophy and Becker's muscular dystrophy.

  • A number of anaesthetics may trigger the condition, especially halothane and related compounds. Suxamethonium, used as a neuromuscular blocking agent to induce paralysis, is also implicated. The safety of tubocurarine and phenothiazines is uncertain. Non-depolarising neuromuscular blockers such as pancuronium are safe. So is nitrous oxide and barbiturates including thiopental.

Before an anaesthetic ask about unclear complications from previous anaesthesia, muscle disorders in the family, myalgia, muscle cramps and dark urine.

If there is suspicion, check CK. If in doubt, use a trigger-free anaesthetic. The condition may present as unexplained persistent elevation of CK.

Diseases associated with malignant hyperthermia

The association with other neuromuscular diseases has been noted above.

Other important precipitants are neuroleptic drugs and alcohol. A neuroleptic malignant syndrome is described that seems similar to malignant hyperthermia.

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Malignant hyperthermia symptoms (presentation)2 4

The onset is insidious and rapid, with the preclinical stage characterised by rigidity of the masseter muscle, a high level of end-tidal carbon dioxide, and a sharp and persistent increase in body temperature.5

The classic signs include hyperthermia, tachycardia, tachypnoea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response.

Onset may be during or within a few hours after anaesthesia.

  • Spasm of the masseter muscle is often first noted.

  • There is muscular rigidity despite a paralysing agent. If breathing is still spontaneous there is tachypnoea.

  • There is tachycardia and the skin is flushed.

  • There is hypoxia, hypercapnoea and a metabolic acidosis.

  • Temperature may rise above 40° but normothermia does not exclude the condition. A rise in temperature tends to be a late feature.

  • There is myoglobinuria.

  • Specific early changes are a rise of the end expiratory CO2 together with the metabolic acidosis.

  • Later signs include complex arrhythmias, cyanosis, hypoxia, hypotension, electrolyte abnormalities, rhabdomyolysis and severe hyperthermia. Hyperthermia is a late sign.

  • Rhabdomyolysis is a sign of the severity of the condition.

Diagnosing malignant hyperthermia4

  • Diagnosis is made by muscle biopsy.6 It involves an in vitro contracture test using a small segment of skeletal muscle. Caffeine, halothane, succinylcholine and increased potassium induce exaggerated contractions. The tests show enormous variability and each laboratory must standardise and validate its procedures.

  • An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue.2

  • DNA analysis has been of increasing importance. Only a small blood sample is required to screen for an RYR1 mutation. However, DNA testing cannot be used as the sole test for malignant hyperthermia susceptibility.7

Differential diagnosis

This includes phaeochromocytoma, hyperthyroid crisis and malignant neuroleptic syndrome.

Anaesthesia in the diagnosed patient

Anaesthesia can be safely given if the diagnosis is known in advance.

  • All the at-risk drugs must be avoided and alternatives used.

  • Check CK both before and after surgery.

  • Put the patient first on the list and flush the apparatus through with oxygen for 10 minutes before using.

Malignant hyperthermia treatment and management1 4

The principles of management of a malignant hyperthermia reaction are to immediately reverse the reaction and treat the consequences of the reaction. Three approaches to reversing the malignant hyperthermia process should be applied together:8

  • Eliminate the trigger agent.

  • Give intravenous dantrolene.

  • Start active body cooling.

Call for help, as management can be difficult and complex for one person.

  • Switch from volatile anaesthetics to alternative forms of anaesthesia.

  • Give 100% oxygen and adjust ventilation according to blood gas analysis and end expiratory pCO2.

  • Deepen anaesthesia with opioids, benzodiazepines, barbiturates or propofol.

  • Monitor blood gases, electrolytes, CK, myoglobin and lactate.

  • Stop surgery if it is elective and if there are signs of masseter spasm or a fulminant crisis.

  • Continue surgery, if there is no hyperkalaemia, no acidosis and there are no triggers.

  • Dantrolene sodium is effective in management, and should be available whenever general anaesthesia is administered. Intravenous dantrolene should be given but prophylactic administration of dantrolene is now regarded as obsolete.

If a fulminant malignant hyperpyrexia crisis occurs:

  • Sodium bicarbonate may be given according to blood gas analysis.

  • Arrhythmia may be treated with a beta-blocker or lidocaine.

  • Stop surgery as soon as possible.

  • Cool the patient - eg, iced water through a nasogastric tube.

  • Intensive monitoring including arterial catheter, central venous catheter, Swan-Ganz catheter, urinary catheter. Monitor renal function, check myoglobinuria, coagulation screen, temperature, electrolytes and CK.

  • Forced diuresis to help protect the kidneys.


Malignant hyperthermia is likely to be fatal if untreated. However, the mortality rate should approach zero with prompt and effective treatment.

Further reading and references

  • British Malignant Hyperthermia Association
  • Ruffert H, Bastian B, Bendixen D, et al; Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021 Jan;126(1):120-130. doi: 10.1016/j.bja.2020.09.029. Epub 2020 Oct 31.
  1. Kaur H, Katyal N, Yelam A, et al; Malignant Hyperthermia. Mo Med. 2019 Mar-Apr;116(2):154-159.
  2. Rosenberg H, Pollock N, Schiemann A, et al; Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015 Aug 4;10:93. doi: 10.1186/s13023-015-0310-1.
  3. Malignant Hyperthermia, Susceptibility to, 1; Online Mendelian Inheritance in Man (OMIM)
  4. Schneiderbanger D, Johannsen S, Roewer N, et al; Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014 May 14;10:355-62. doi: 10.2147/TCRM.S47632. eCollection 2014.
  5. Bin X, Wang B, Tang Z; Malignant Hyperthermia: A Killer If Ignored. J Perianesth Nurs. 2022 Aug;37(4):435-444. doi: 10.1016/j.jopan.2021.08.018. Epub 2022 Apr 10.
  6. Bandschapp O, Girard T; Malignant hyperthermia. Swiss Med Wkly. 2012 Jul 31;142:w13652. doi: 10.4414/smw.2012.13652.
  7. Stowell KM; DNA testing for malignant hyperthermia: the reality and the dream. Anesth Analg. 2014 Feb;118(2):397-406. doi: 10.1213/ANE.0000000000000063.
  8. Hopkins PM, Girard T, Dalay S, et al; Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists. Anaesthesia. 2021 May;76(5):655-664. doi: 10.1111/anae.15317. Epub 2021 Jan 5.

Article history

The information on this page is written and peer reviewed by qualified clinicians.

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