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Synonyms: malignant hyperpyrexia, malignant hyperthermia susceptibility, MHS, hyperthermia of anaesthesia, King syndrome, King-Denborough syndrome
This is a rapid rise in temperature usually triggered by an anaesthetic and is potentially lethal.It is an inherited myopathy 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.
Potent inhalation anaesthetic agents are the main triggers. Other agents such as desflurane, sevoflurane, and isoflurane can cause florid malignant hyperthermia (MH) reactions in the same way as halothane but are also associated with reactions with the onset delayed for several hours into anaesthesia.
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.
In the early descriptions mortality was very high. Now it is around 10% although with prompt and efficient treatment it should approach zero.
- The incidence of MH is low, but the prevalence can be estimated as up to 1:3,000.
- It is inherited as an autosomal dominant gene of variable penetrance.
- As may be expected with any familial condition, there are geographical clusters.
- 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.
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 MH.
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.
- Diagnosis is made by muscle biopsy.
- 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.
- 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 MH susceptibility.
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.
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.
- 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.
Two names are associated with the syndrome. In 1962 Denborough et al described a family in which 11 of 38 who had received general anaesthetic 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 al 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.
Further reading and references
Wappler F; Anesthesia for patients with a history of malignant hyperthermia. Curr Opin Anaesthesiol. 2010 Jun23(3):417-22. doi: 10.1097/ACO.0b013e328337ffe0.
Carpenter D, Robinson RL, Quinnell RJ, et al; Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth. 2009 Oct103(4):538-48. Epub 2009 Jul 31.
Hopkins PM; Malignant hyperthermia: pharmacology of triggering. Br J Anaesth. 2011 Jul107(1):48-56. doi: 10.1093/bja/aer132. Epub 2011 May 30.
Hirshey Dirksen SJ, Larach MG, Rosenberg H, et al; Special article: Future directions in malignant hyperthermia research and patient care. Anesth Analg. 2011 Nov113(5):1108-19. doi: 10.1213/ANE.0b013e318222af2e. Epub 2011 Jun 27.
Parness J, Bandschapp O, Girard T; The myotonias and susceptibility to malignant hyperthermia. Anesth Analg. 2009 Oct109(4):1054-64.
Malignant Hyperthermia, Susceptibility to, 1; Online Mendelian Inheritance in Man (OMIM)
Schneiderbanger D, Johannsen S, Roewer N, et al; Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag. 2014 May 1410:355-62. doi: 10.2147/TCRM.S47632. eCollection 2014.
Bandschapp O, Girard T; Malignant hyperthermia. Swiss Med Wkly. 2012 Jul 31142:w13652. doi: 10.4414/smw.2012.13652.
Stowell KM; DNA testing for malignant hyperthermia: the reality and the dream. Anesth Analg. 2014 Feb118(2):397-406. doi: 10.1213/ANE.0000000000000063.