Malignant hyperthermia

Malignant hyperthermia is a life-threatening condition that occurs in genetically susceptible individuals after exposure to triggering agents (typically volatile anesthetics and/or succinylcholine). It causes uncontrollable skeletal muscle contraction, hypermetabolism, and an increase in body temperature. Malignant hyperthermia susceptibility is primarily autosomal dominant, most commonly due to mutations in the RYR1 gene, which encodes for ryanodine receptor type 1 (RyR1). In the acute setting, diagnosis is based on clinical features (e.g., tachycardia, muscle rigidity, rapid rise in body temperature) and increased end-tidal CO₂. Supportive laboratory findings include hyperkalemia, elevated creatine kinase, and mixed respiratory and metabolic acidosis. Management involves cessation of the triggering agent, immediate dantrolene, and hyperventilating the patient with 100% oxygen. After resolution of the acute episode, malignant hyperthermia susceptibility testing (genetic testing or caffeine-halothane contracture test) is required to confirm the diagnosis and inform future management. Without appropriate treatment, the mortality rate is ∼ 80%.

• Sex: : ♂ > ♀ (2:1)
• Incidence: ∼ 700 per year in the US

Epidemiological data refers to the US, unless otherwise specified.

The etiology of malignant hyperthermia involves a combination of genetic susceptibility and exposure to triggering agents. ^[1]

• Genetic malignant hyperthermia susceptibility
  • Primarily autosomal dominant with reduced penetrance
  • < 10% of cases are due to spontaneous mutation. ^[2]
  • Most cases are associated with mutations in the genes encoding ryanodine receptor 1 (RyR1) or dihydropyridine receptors (DHPR). ^[1]
  • May occur in conjunction with neuromuscular disorders caused by the same mutations (e.g., central core disease) ^[3]
• Triggering agents ^[1]
  • Volatile anesthetics (e.g., isoflurane, sevoflurane, desflurane, halothane; except nitrous oxide)
  • Succinylcholine

Administration of triggering substances → ↑ calcium release from the sarcoplasmic reticulum or delay in its reuptake → ↑ calcium in muscle cells → ↑ contractility of the skeletal muscle → ↑ metabolism → ↑ oxygen consumption in addition to ↑ CO₂ production, heat, and lactate (malignant hyperthermia) → mixed respiratory and metabolic acidosis → uncoupled oxidative phosphorylation → breakdown of the cell's energy supply → cell death

Smooth muscle and cardiac muscle remain unaffected.

Clinical features typically occur minutes to hours after exposure to triggering agents. ^[1]

• Early signs ^[1]
  • Tachycardia
  • Tachypnea ^[3]
  • Cyanosis
  • Generalized muscle rigidity, masseter rigidity
  • Elevated body temperature ^[1]
    • Rapid rise in temperature (∼ 1°C every 5–10 minutes)
    • Hyperthermia can reach > 44°C.
• Late signs: features of end-organ damage ^[1]
  • Cardiac arrhythmias
  • Signs of acute kidney injury (e.g., oliguria)
  • Signs of cerebral edema (e.g., seizures)
  • Signs of disseminated intravascular coagulation (e.g., bleeding, thrombosis)
  • Signs of rhabdomyolysis (e.g., dark urine, muscle pain, swelling, weakness of the affected muscles)

A rise in body temperature may be an early or late sign of malignant hyperthermia. ^[4]

General principles

• Diagnosis in the acute setting is clinical, based on: ^[4]
  • Exposure to a trigger (e.g. isoflurane)
  • Increased end-tidal CO₂: typically one of the earliest signs of malignant hyperthermia
  • Clinical features of malignant hyperthermia (e.g., muscle and jaw rigidity)
• Laboratory findings support the acute diagnosis, e.g., mixed respiratory and metabolic acidosis.
• After resolution of the acute episode, refer for malignant hyperthermia susceptibility testing to confirm the diagnosis and inform future management.

Initial evaluation ^[1][3]

• Monitoring
  • Continuous increase in end-tidal CO₂
  • ECG: may show ECG findings of hyperkalemia
• Laboratory studies
  • Arterial blood gas: mixed respiratory and metabolic acidosis (↑ pCO₂, ↓ pO_2, and ↑ lactate)
  • BMP
    • Hyperkalemia
    • ↑ Creatine kinase
  • Myoglobinemia
  • Myoglobinuria

Laboratory findings of muscle breakdown (e.g,. myoglobinemia, ↑ creatine kinase) support the diagnosis in patients with clinical features of malignant hyperthermia. ^[1]

Testing for malignant hyperthermia susceptibility ^[5]

• Indications include: ^[5]
  • Positive family history
  • Personal history of malignant hyperthermia or exertional heat illness ^[5]
  • Persistently increased creatine kinase
• Methods
  • Molecular genetic testing
    • Preferred test
    • Tests for mutations in genes that encode for RyR1 (RYR1) and DHPR channels (e.g., CACNA1S)
  • Caffeine-halothane contracture test
    • Criterion standard
    • A fresh muscle sample is obtained, and muscle strips are exposed to caffeine and halothane.
    • The test is considered positive if any of the strips contract.

• Sepsis ^[1]
• Allergic reaction (e.g., to anesthetic)
• Transfusion reaction
• Other causes of drug-induced hyperthermia
  • Serotonin syndrome
  • Neuroleptic malignant syndrome
  • Anticholinergic syndrome
  • See “Differential diagnosis of drug-induced hyperthermia" for a table comparing these syndromes.
• Thyrotoxic crisis
• Pheochromocytoma
• Acute porphyria crisis
• Levodopa withdrawal syndrome

The differential diagnoses listed here are not exhaustive.

Management is challenging because some conditions manifest similarly to malignant hyperthermia, and treatment must be started before laboratory confirmation. ^[1]

Initial management ^[1]

Management of malignant hyperthermia requires a multidisciplinary team that includes anesthesiology and critical care specialists (e.g., rapid response team). ^[1]

• Discontinuation of triggering agents ^[6]
  • Remove the vaporizer if inhalational anesthetics were used.
  • Switch to a clean ventilator and breathing circuit or attach a charcoal filter.
• Immediate IV injection of dantrolene ; administer as continuous injections until acute symptoms resolve. ^[4]
• Cooling measures (e.g., ice packs, cooling blankets, IV cold saline, forced air cooling, ice-water immersion) ^[6]
• Hyperventilation with 100% O₂ at 10 L/minute ^[1]

Dantrolene (a ryanodine receptor antagonist) directly deals with distressed muscles.

Further management ^[1]

• Treatment of metabolic acidosis (e.g., IV sodium bicarbonate)
• Management of hyperkalemia
• Volume repletion to increase diuresis and myoglobin clearance
• Maintenence dantrolene for 24 hours ^[1]
• Monitoring
  • Intensive care monitoring for at least 24 hours
  • Continuous cardiac monitoring and monitoring of core temperature and end-tidal CO₂ levels
  • Repeat laboratory studies at least every 6 hours.

Dantrolene interacts with calcium antagonists, potentially leading to hyperkalemia. ^[1]

Follow-up ^[1]

• On discharge, refer to a specialist and/or a malignant hyperthermia center for confirmatory testing for malignant hyperthermia susceptibility.
• If malignant hyperthermia susceptibility is confirmed:
  • Advise the patient to wear a medical alert bracelet.
  • Inform all health care providers (e.g., by updating allergy list).
  • Recommend testing for relatives.
• Nontriggering agents should be used in future procedures (e.g., local anesthetics, total intravenous anesthesia). ^[3]

• Without rapid and appropriate treatment, the mortality rate is ∼ 80%. ^[5]
• If adequately treated with dantrolene, the mortality rate is ∼ 10%. ^[5]