Malignant Hyperthermia

Malignant hyperthermia is a rare, inherited pharmacogenetic disorder of skeletal muscle in which exposure to potent volatile anaesthetics or the depolarising muscle relaxant succinylcholine triggers an uncontrolled rise in intracellular calcium, producing a hypermetabolic crisis. Without recognition and treatment it can be rapidly fatal, which is why it is a defining emergency of anaesthetic practice.

Definition

Malignant hyperthermia is a hereditary disorder of skeletal-muscle calcium homeostasis in which susceptible individuals respond to potent inhalational anaesthetics or succinylcholine with a potentially fatal hypermetabolic reaction characterised by sustained muscle contracture, rising carbon dioxide production, hyperthermia, and metabolic acidosis.

Scope

This entry covers the genetics, the underlying defect in skeletal-muscle calcium regulation, the triggering agents, the clinical pattern of the hypermetabolic crisis, and how susceptibility is identified and registered. It treats malignant hyperthermia as a clinical entity and reference topic; it does not provide dosing or step-by-step management instructions, which belong to current emergency guidelines.

Core questions

• What molecular defect makes skeletal muscle susceptible to a malignant hyperthermia crisis?
• Which anaesthetic agents are recognised triggers, and which are considered safe in susceptible patients?
• How is malignant hyperthermia susceptibility diagnosed and confirmed?
• How has mortality from malignant hyperthermia changed since the introduction of a specific treatment?

Key concepts

• Ryanodine receptor 1 (RYR1) and calcium release
• Excitation-contraction coupling defect
• Triggering agents (volatile anaesthetics, succinylcholine)
• Hypermetabolic crisis
• In vitro contracture / caffeine-halothane testing
• Malignant hyperthermia susceptibility and registries
• Dantrolene as specific therapy

Mechanisms

Susceptibility most commonly arises from variants in the gene encoding the type 1 ryanodine receptor (RYR1), the skeletal-muscle calcium-release channel of the sarcoplasmic reticulum, with a smaller proportion linked to the dihydropyridine receptor subunit CACNA1S. In susceptible muscle, triggering agents cause abnormal, sustained calcium release; the resulting continuous muscle activity drives a hypermetabolic state with greatly increased oxygen consumption and carbon dioxide production, heat generation, acidosis, rhabdomyolysis, and hyperkalaemia. Inheritance is generally autosomal dominant with variable penetrance, so a normal previous anaesthetic does not exclude susceptibility (Rosenberg et al., 2015; Rosenberg et al., 2007).

Clinical relevance

Malignant hyperthermia is a paradigm of pharmacogenetic risk in anaesthesia and a core item in preoperative history-taking, because family or personal history can flag susceptibility before exposure. The availability of a specific antidote transformed it from a frequently fatal event into a usually survivable one, illustrating how mechanism-targeted therapy changes outcome. This entry explains the disorder and how susceptibility is identified; it is not a guide to managing an acute episode, for which current emergency protocols should be consulted.

Epidemiology

Clinical malignant hyperthermia reactions are rare, reported in a small fraction of anaesthetics, though the prevalence of underlying genetic susceptibility is higher than the rate of overt crises because of variable penetrance and incomplete trigger exposure. Registry data document a marked fall in mortality following the adoption of specific treatment and improved monitoring, while also showing that arrests and deaths still occur, often associated with delays in recognition (Larach et al., 2008; Rosenberg et al., 2015).

History

The syndrome was brought to wide attention in the 1960s after reports of anaesthetic deaths clustering in families, including a frequently cited Australian pedigree. Investigators subsequently localised the defect to skeletal-muscle calcium handling, identified RYR1 as the principal susceptibility gene, and developed in vitro contracture testing for diagnosis. The introduction of dantrolene as a specific therapy and the establishment of national registries and hotlines turned malignant hyperthermia into a model of organised rare-disease and crisis management (Rosenberg et al., 2007; Rosenberg et al., 2015).

Debates

How should ambulatory and trigger-free settings handle susceptible patients?

Whether and how malignant hyperthermia-susceptible patients can be safely anaesthetised in ambulatory surgery centres, including the resources and antidote stocking required, is addressed by formal position statements rather than settled by a single trial.

How reliably does genetic testing identify susceptibility?

Because many RYR1 variants exist and penetrance is variable, genetic testing complements but does not fully replace in vitro contracture testing, and the relationship between specific variants and clinical risk remains an active area.

Seminal works

• rosenberg-2007
• rosenberg-2015
• larach-mhaus-history

Frequently asked questions

What triggers a malignant hyperthermia crisis?

In susceptible individuals, potent volatile (inhalational) anaesthetics and the depolarising muscle relaxant succinylcholine are the recognised triggers; many other anaesthetic techniques are considered non-triggering.

Is malignant hyperthermia inherited?

Yes. It is usually inherited in an autosomal dominant pattern, most often linked to variants in the RYR1 gene, although penetrance is variable, so a previously uneventful anaesthetic does not rule out susceptibility.