For Anaesthetists

Information for Anaesthetists

Definition

Malignant Hyperthermia (MH) is an acute pharmacogenetic (autosomal dominant) disorder, which develops during or immediately after the application of general anaesthesia involving volatile agents and/or depolarising muscle relaxants.

The disorder is as a result of a defect in calcium channel regulation in the muscle cell. Volatile anaesthetic agents and depolarising muscle relaxants interact with the calcium channel resulting in the clinical crisis.

The classic MH crisis is caused primarily by excess calcium availability in the skeletal muscle cytoplasm resulting in excess muscle contraction and saturation of calcium reuptake mechanisms leading to extreme hypermetabolism.

The crisis can manifest as excess CO2 production, skeletal muscle rigidity, tachyarrhythmias, unstable haemodynamics, respiratory acidosis, cyanosis, hyperkalaemia, lactic acidosis, fever, and eventually (if untreated) death. MH can present with a few or all of these features.

Malignant hyperthermia was first described as genetically inherited entity in a letter to the editor of the Lancet in 1960 penned by Michael Denborough and Richard Lovell¹ and in a follow up article in 1962 in the British Journal of Anaesthesia².

The family described showed an autosomal dominant pattern of inheritance for this reaction to anaesthesia. The original letter called for others to share experiences with this type of reaction and the term malignant (“deadly, tending to produce death”) hyperpyrexia (“an abnormally high fever”) was coined.

An excellent summary of the history of MH and anaesthesia³ in Australia has been written by Dr Chris Ball. The article is referenced here and is well worth a read.

Proposed mechanism of MH

In normal muscle, an action potential is generated at the motor end plate which electrically stimulates the L type calcium channel (DHPR). This induces a conformational change in the DHPR which in turn causes a conformational change in the skeletal muscle ryanodine receptor (RYR1) so that RYR1 is now more open and calcium is released into the cytoplasm. How much calcium is released in this process is a function of how “open” the RYR1 channel is. This open state is regulated by smaller related proteins at the junctional sarcoplasmic reticulum(SR) membrane (JP-45, calmodulin, FK506, junctin and triadin) and in the lumen of the SR (calsequestrin) as well as by Ca²⁺, Mg²⁺ and ATP. Volatile agents may influence normal RYR1 to increase the probability of it being in the open state but the balance is maintained by compensation within the system.

Muscle contraction is a result of calcium biding to troponin.

Calcium levels in the cytoplasm are quickly restored by active reuptake of calcium into the sarcoplasmic reticulum via the Ca²⁺ ATPase pump (SERCA), where two Ca²⁺ are exchanged for every one ATP molecule. Calcium that is taken back into the SR is then buffered by calsequestrin to restore equilibrium. RYR1 channel opening is inhibited by high calcium concentrations both directly and via calmodulin.

In persons susceptible to MH, it is proposed that structural alterations in calcium regulating proteins upset the delicate balance between calcium release from and reuptake into the SR. In normal circumstances (without exposure to volatile anaesthetic agents) in the vast majority of mutations, this balance is maintained. On exposure to volatile agents however, the system is overwhelmed and calcium continues to be released into the cytoplasm beyond the influence of the regulatory proteins.

Restoration of cytoplasmic calcium concentration is paramount to normal cellular function so the reuptake of calcium increases, and energy consumption rises dramatically (increased oxygen consumption and CO2 production, heat generation). Muscle gets no chance to relax because of continued calcium exposure (rigidity) and as energy consumption overwhelms oxidative capacity, muscle begins to source energy anaerobically. Lactic acid is produced and the toxic environment of low pH and high Ca²⁺ that has been created, results in cell breakdown and release of creatinine kinase.

Differential diagnosis

This is one of the more challenging differential diagnoses because time to treat is critical.

If in doubt consider that:

Dantrolene is a safe drug with the provision of appropriate ventilatory support
Extreme hyperthermia can result in cell death and an unsalvageable situation
Not all symptoms of MH need to be present to make the diagnosis

If you have inappropriate tachycardia, elevated CO2 and hyper or hypotension, rapidly exclude:

Insufficient anaesthesia
Insufficient ventilation or gas flow
Saturated soda lime
Machine malfunction
CO2 from laparoscopic insufflation (note MH has occurred in laparoscopic cases).

If there is ongoing masseter spasm or rigidity and the situation is stable:

It may be worth considering the response to the addition of non-depolarising muscle relaxant
Masseter spasm and rigidity related to MH should not resolve with a non-depolarising muscle relaxant

Also consider the following differentials:

Phaeochromocytoma – extreme fluctuations in arterial blood pressure, hyperthermia, sweating, usually no muscle involvement
Infection, septicaemia – hyperthermia, usually no muscle involvement
Thyroid Storm –hyperthermia, no rigidity but may have rhabdomyolysis
Central anticholinergic syndrome – delayed emergence, hyperthermia and nystagmus, dilated pupils
Serotonergic syndrome – Triggering agent (serotonergic, cocaine, MDMA, ketamine, methylene blue and SSRI), no nystagmus
Neuroleptic malignant syndrome – slow onset hyperthermia (24-72 hours after withdrawal of dopamine agonist)
Mismatched blood transfusion, blood in the fourth cerebral ventricle, drug toxicity and drug allergies may cause isolated hyperthermia

Masseter spasm

True masseter spasm can be the first and sometimes only sign of MH. True masseter spasm is defined as transient inability or extreme difficulty in distracting the mandible from the maxilla. MMR poses a significant risk to patients, as airway management becomes compromised. Masseter spasm is transient, may be accompanied by other signs of MH susceptibility and can occur following suxamethonium or other drugs.

There are two approaches to the patient with true masseter spasm

Discontinue volatile anaesthesia, continue the case with total intravenous anaesthesia and watch for signs of MH. Treat accordingly if signs develop. Refer to an MH diagnostic centre for follow up.
Abandon surgery and treat for MH if any other signs develop. Refer to an MH diagnostic centre for follow up.

The decision to take either of the above approaches may be influenced by the following:

Testing for MH is not usually performed in patients who are less than 30kg or under ten years of age
Testing will not be performed for at least three months after an episode of masseter spasm
Patients need to travel to a testing centre for the biopsy

Disorders associated with MH

Patients with central core disease (CCD) and multiminicore disease (MMD) with gain of function RYR1 defects are at risk of MH. While those with CCD and MMD and a loss of function RYR1 defect should not be at risk of MH, this may not be clear based on symptomatology or genetic testing. The safest position is to treat all CCD and MMD patients as potentially MH susceptible unless they have had a negative IVCT. CCD and MMD are often asymptomatic in childhood.

King-Denborough syndrome is a myopathy with an RYR1 defect and patients should be considered at risk for MH.

Patients who have a history of exertional heat illness (EHI) with no obvious predisposing factors may be at increased risk of MH. This is more likely if they have had repeated episodes in temperate climate and if there is a familial component to the EHI.

A myopathy caused by a defect in the STAC3 gene manifest as muscle weakness with cleft palate also known as “Native American myopathy” has been associated with MH.

Laboratory Diagnosis

All current Australian and New Zealand laboratories follow the guidelines of the European Malignant Hyperthermia Group for In Vitro Contracture Testing and Molecular genetic testing for MH.

Referrals for testing can be made here

Clinical malignant hyperthermia

Please refer to the MH Resource Kit

Treatment of an MH crisis

This is summarised in the MH Resource Kit

Preparing for the MHS patient

This is summarised in the MH Resource Kit

References

1 Denborough M, Lovell, RR. Anaesthetic deaths in a family. Lancet 1960; 2: 45

2 Denborough MA, Forster JF, Lovell RR, Maplestone PA, Villiers JD. Anaesthetic deaths in a family. Br J Anaesth 1962; 34: 395-6

3 Ball C. Unravelling the mystery of malignant hyperthermia. Anaesth Intensive Care 2007; 35 Suppl 1: 26-31