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

This is a rapid rise in temperature usually triggered by an anaesthetic. It is an inherited myopathy is due to a genetic mutation. Linkage studies show that in the majority of families the defect is in the ryanodine receptor gene (RYR1) at chromosome 19q13.1.^1,2 Other genes have been identified and their OMIM listing is included in the Internet and further reading section at the end.

Pathophysiology

A sustained increase in intramyoplasmic calcium ions via release from sarcoplasmic reticulum and, possibly, entry from the extracellular milieu, leads to hypermetabolism, muscle rigidity and rhabdomyolysis.³

In the early descriptions mortality was very high. Now it is around 10% although with prompt and efficient treatment it should approach zero.

Epidemiology

• Malignant hyperpyrexia in response to general anaesthetic (GA) has been cited as 1 in 15,000 administrations to children and 1 in 50,000 to 100,000 in adults.^4,5,6
• One study of surgical patients treated in New York State hospitals found an incidence of 1 per 100,000. The risk in males is significantly higher than in females.
• An American nationwide study comparing patients discharged with a diagnosis of malignant hyperthermia in 2000 and 2005, found that the number of cases had increased from 372 to 521.⁷
• It is inherited as an autosomal dominant gene of variable penetrance.
• 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 congenita⁸ and both Duchenne's muscular dystrophy and Becker's muscular dystrophy.⁹
• There may be strabismus, myalgias on exercise, tendency to fever, myoglobinuria, muscular disease and intolerance of caffeine. Children having surgery for strabismus are 2.8 times as likely to have the diagnosis.
• Susceptibility to heat stroke may suggest the condition before it presents at anaesthesia.⁴
• Up to half of suffers have had a previous GA and no adverse events.¹⁰
• Severe rhabdomyolysis may occur after a viral infection. It presents with severe swelling of the calves.¹⁰ Creatine kinase (CK) is grossly elevated and acute renal failure occurs.
• It has also been noted that babies dying of sudden infant death syndrome often have very high temperature and this too may be a feature.¹¹
• A patient with chronic myopathy beginning at age 2, with marked muscle weakness, elevated serum CK and a distinct enlargement and increase of muscle mitochondria on biopsy has been described.¹² Both parents had the condition and so this probably represented a homozygous form.
• 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.

Associated diseases

The association with other neuromuscular diseases has been noted above.

Other important precipitants are neuroleptic drugs and alcohol. A malignant neuroleptic syndrome is described that seems remarkably similar to malignant hyperthermia although authors writing about one do not often mention the other.

• Both are characterised by muscle spasms, evidence of severe rhabdomyolysis and both respond to dantrolene.
• The neuroleptics that are implicated include monoamine oxidase inhibitors (MAOIs), especially if combined with other agents such as tricyclic antidepressants, toxic levels of lithium, amfetamines including ecstasy (MDMA), methyfenidate and cocaine.
• Some authors do note similarities¹³ and they have been compared and contrasted.¹⁴
• An OMIM search for malignant neuroleptic syndrome brings up nothing of that name but it does produce MHS1.
• It is suggested that they are clinically similar but pharmacologically distinct.¹⁵

Presentation

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, hypercapnia and a metabolic acidosis.
• Temperature may rise above 40° but normothermia does not exclude the condition.¹⁶ 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.

Diagnosis

• Diagnosis is made by muscle biopsy, usually from the vastus lateralis. Both the European and the American MH groups have a protocol.¹⁷
• 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.¹⁸
• The in vitro test has been validated as highly sensitive and specific, even in low-risk groups.¹⁹ It is 85% specific and 100% sensitive.
• Gene typing can add to the accuracy of the diagnosis.^20,21
• CK is elevated in 70% of susceptible patients.

Differential diagnosis

This includes pheochromocytoma, 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
• Some people give danrolene with premedication but the value of this is unknown

Management

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
• Deepen anaesthesia with opioids, benzodiazepines, barbiturates or propofol
• Adjust ventilation according to blood gas analysis and end expiratory pCO₂
• Check blood gases, electrolytes, CK, myoglobin and lactate (via an arterial catheter) immediately, after 30 minutes, 4 hours, 12 hours and 24 hours
• 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
• Give dantrolene 2.5 mg/kg iv as a bolus

If a fulminant malignant hyperpyrexia crisis occurs:

• Stop inhalational anaesthetic, give 100% oxygen and deepen anaesthesia with other agents as above
• Give a bolus of iv dantrolene at a dose of 2.5 mg per kg body weight and repeat at a dose of 2 mg per kg every 5 minutes until hypermetabolism stops as shown by a normal end expiratory pCO₂
• Then give dantrolene at 10 mg per kg over the next 24 hours
• Sodium bicarbonate may be given according to blood gas analysis
• Arrhythmia may be treated with beta blocker or lidocaine
• Stop surgery as soon as possible
• Cool the patient, e.g. ice water through a nasogastric tube
• Intensive monitoring including arterial catheter, central venous catheter, Swan-Ganz catheter, urinary catheter
• Forced diuresis to help protect kidneys
• Check renal function, check myoglobinuria, coagulation screen, temperature, electrolytes and CK

History

Two names are associated with the syndrome. In 1962 Denborough et al²² described a family in which 11 of 38 who had received GA developed explosive hyperthermia and died. The relationships suggested an autosomal dominant means of inheritance. In 1970 he reported that MH was often associated with hypertonicity of the voluntary muscles and elevation of serum CK, phosphate and potassium, indicating severe muscle damage. Severe lactic acidosis also occurred. In 1972 King et al²³ reported elevated levels of serum CK and clinical findings of a dominantly inherited myopathy. He called it Evans' syndrome, as Evans was the name of the family that Denborough had reported.

Document references

1. Brandom BW; Genetics of malignant hyperthermia. ScientificWorldJournal. 2006 Dec 28;6:1722-30. [abstract]
2. Carpenter D, Robinson RL, Quinnell RJ, et al; Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth. 2009 Oct;103(4):538-48. Epub 2009 Jul 31. [abstract]
3. Parness J, Bandschapp O, Girard T; The myotonias and susceptibility to malignant hyperthermia. Anesth Analg. 2009 Oct;109(4):1054-64. [abstract]
4. Nelson TE, Flewellen EH; Current concepts. The malignant hyperthermia syndrome. N Engl J Med. 1983 Aug 18;309(7):416-8.
5. Brady JE, Sun LS, Rosenberg H, et al; Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001-2005. Anesth Analg. 2009 Oct;109(4):1162-6. [abstract]
6. Hopkins PM, Ellis FR, Halsall PJ; Evidence for related myopathies in exertional heat stroke and malignant hyperthermia. Lancet. 1991 Dec 14;338(8781):1491-2. [abstract]
7. Rosero EB, Adesanya AO, Timaran CH, et al; Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology. 2009 Jan;110(1):89-94. [abstract]
8. Heiman-Patterson T, Martino C, Rosenberg H, et al; Malignant hyperthermia in myotonia congenita. Neurology. 1988 May;38(5):810-2. [abstract]
9. Heiman-Patterson TD, Natter HM, Rosenberg HR, et al; Malignant hyperthermia susceptibility in X-linked muscle dystrophies. Pediatr Neurol. 1986 Nov-Dec;2(6):356-8. [abstract]
10. Denborough MA, McLean A, Morgan G, et al; Fatal inherited rhabdomyolysis and malignant hyperthermia. Lancet. 1994 Jan 22;343(8891):236-7.
11. Denborough MA, Galloway GJ, Hopkinson KC; Malignant hyperpyrexia and sudden infant death. Lancet. 1982 Nov 13;2(8307):1068-9.
12. Deufel T, Muller-Felber W, Pongratz DE, et al; Chronic myopathy in a patient suspected of carrying two malignant hyperthermia susceptibility (MHS) mutations. Neuromuscul Disord. 1992;2(5-6):389-96. [abstract]
13. Bertorini TE; Myoglobinuria, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome. Neurol Clin. 1997 Aug;15(3):649-71. [abstract]
14. Heiman-Patterson TD; Neuroleptic malignant syndrome and malignant hyperthermia. Important issues for the medical consultant. Med Clin North Am. 1993 Mar;77(2):477-92. [abstract]
15. Keck PE Jr, Caroff SN, McElroy SL; Neuroleptic malignant syndrome and malignant hyperthermia: end of a controversy? J Neuropsychiatry Clin Neurosci. 1995 Spring;7(2):135-44. [abstract]
16. Hogan K; To fire the train: a second malignant-hyperthermia gene. Am J Hum Genet. 1997 Jun;60(6):1303-8.
17. No authors listed; A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. The European Malignant Hyperpyrexia Group. Br J Anaesth. 1984 Nov;56(11):1267-9. [abstract]
18. Ording H, Bendixen D; Sources of variability in halothane and caffeine contracture tests for susceptibility to malignant hyperthermia. Eur J Anaesthesiol. 1992 Sep;9(5):367-76. [abstract]
19. 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 Sep;41(8):955-66. [abstract]
20. Ruffert H, Olthoff D, Deutrich C, et al; In vitro contracture test and gene typing in diagnosing malignant hyperthermia. Each as an appropriate complement to the other method. Anaesthesist. 2000 Feb;49(2):113-20. [abstract]
21. Rosenberg H, Davis M, James D, et al; Malignant hyperthermia. Orphanet J Rare Dis. 2007 Apr 24;2:21. [abstract]
22. DENBOROUGH MA, FORSTER JF, LOVELL RR, et al; Anaesthetic deaths in a family. Br J Anaesth. 1962 Jun;34:395-6.
23. King JO, Denborough MA, Zapf PW; Inheritance of malignant hyperpyrexia. Lancet. 1972 Feb 12;1(7746):365-70.

Internet and further reading

• Malignant Hyperthermia, MedStudents; A Brazilian site in English aimed at medical students. Simple and helpful
• British Malignant Hyperthermia Association
• Tonkonogy J; Malignant Neuroleptic Syndrome; emedicine. 2009.
• OMIM 145600; MHS1
• OMIM 154275; Malignant hyperthermia, susceptibility 2
• OMIM 154276; MHS3
• OMIM600467; MHS4
• OMIM 601887; MHS5
• OMIM60188; MSH6

Acknowledgements