Malignant Hyperpyrexia

Synonyms: Malignant Hyperthermia Susceptibility, MHS, Hyperthermia of Anaesthesia, Malignant Hyperpyrexia, MH, King Syndrome, King-Denborough Syndrome.

This inherited myopathy is due to a genetic mutation. There are several loci that have been identified. The commonest is called MHS1¹ (malignant hyperthermia syndrome or susceptibility) and is at gene map locus 19q13.1. The others are numbered from MHS2 to MHS6 and their OMIM listing is included in the Internet and further reading section at the end.

The syndrome is thought to be due to a reduced reuptake of calcium by the sarcoplasmic reticulum necessary for termination of muscle contraction. This causes sustained muscle contraction, resulting in the clinical picture.

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

• Malignant hyperthermia in response to general anaesthetic has been cited as 1 in 15,000 administrations to children and 1 in 50,000 to 100,000 in adults.²
• The international incidence of malignant hyperthermia has been estimated at 1 in 50,000 anaesthetics.³
• It is inherited as an autosomal dominant 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 congenita⁴ and both Duchenne muscular dystrophy and Becker muscular dystrophy.⁵
• 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.²
• Up to half of suffers have had a previous GA and no adverse events.⁶
• Severe rhabdomyolysis may occur after a viral infection. It presents with severe swelling of the calves.⁶ 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.⁷
• A patient with chronic myopathy beginning at age 2, with marked muscle weakness, elevated serum creatine kinase, and a distinct enlargement and increase of muscle mitochondria on biopsy has been described.⁸ 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 thiopentone.

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 creatine kinase. If in doubt, use a trigger-free anaesthesic. 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 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 MAOIs, especially if combined with other agents such as tricyclic antidepressants, toxic levels of lithium, amphetamines including ecstasy (MDMA), methyphenidate and cocaine.
• Some authors do note similarities⁹ and they have been compared and contrasted.¹⁰
• 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.¹¹

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.¹² 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.

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, creatine kinase, 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 no triggers
• Give dantrolene 2.5 mg/kg intravenous 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 2.5mg per kg body weight and repeat at a dose of 2mg per kg every 5 minutes until hypermetabolism stops as shown by a normal end expiratory pCO₂
• Then give dantrolene at 10mg 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 lignocaine
• Stop surgery as soon as possible
• Cool the patient, eg 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 creatine kinase

• Diagnosis is made by muscle biopsy, usually from the vastus lateralis. Both the European and the American MH groups have a protocol.¹³
• 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.¹⁴
• The in vitro test has been validated as highly sensitive and specific, even in low risk groups.¹⁵ It is 85% specific and 100% sensitive.
• Gene typing can add to the accuracy of the diagnosis.¹⁶
• Creatine phosphokinase is elevated in 70% of susceptible patients.

This includes pheochromocytoma, hyperthyroid crisis and malignant neuroleptic syndrome.

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

Two names are associated with the syndrome. In 1962 Denborough et al¹⁷ described a family in which 11 of 38 who had received general anaesthesia developed explosive hyperthermia and died. The relationships suggested an autosomal dominant. In 1970 he reported that malignant hyperpyrexia was often associated with hypertonicity of the voluntary muscles and elevation of serum creatine phosphokinase (CK), phosphate, and potassium, indicating severe muscle damage. Severe lactic acidosis also occurred. In 1972 King et al¹⁸ 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.