Malignant hyperthermia

Malignant hyperthermia (MH) is a subclinical myopathy in which general anesthesia triggers an uncontrollable contraction of skeletal muscle that leads to a life-threatening hypercatabolic state and an increase in body temperature. The disease is primarily autosomal dominant; mutations in receptors (especially ryanodine receptor type 1) predispose to volatile anesthetic agents or succinylcholine causing an accumulation of intracellular calcium in skeletal muscle that leads to its overactivation and hypermetabolism. In the acute setting, diagnosis is based mainly on clinical presentation and end-tidal capnography, which reveals an increase in end-tidal CO₂. Immediate treatment measures involve stopping the triggering agent and administration of dantrolene. In nonacute settings, there are specific diagnostic tools (e.g., caffeine-halothane contracture test) to confirm suspected cases. MH is a lethal disease and has a high mortality rate if left untreated.

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

Epidemiological data refers to the US, unless otherwise specified.

• Inherited susceptibility: primarily autosomal dominant with reduced penetrance
  • ∼ 50% of cases: associated with a mutation in the ryanodine receptor type 1 (RYR-1) .
  • Some cases (< 10%) are due to a spontaneous mutation. ^[1]
• Triggering agents
  • Volatile anesthetics (except nitrous oxide)
  • Succinylcholine

Administration of triggering substances → calcium release from intracellular compartments 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.

• Early signs
  • Tachycardia
  • Tachypnea
  • Cyanosis
  • Rigidity
• Late signs
  • Elevated body temperature (up to 45ºC/113°F)
  • Signs of secondary organ damage
    • Complex arrhythmias
    • Oliguria (acute kidney injury)
    • Seizures
    • Bleeding and/or thrombosis (disseminated intravascular coagulation)
    • Myoglobinuria , muscle pain, swelling, and weakness of the affected muscles (rhabdomyolysis)

Although the rise in body temperature is usually a late sign in malignant hyperthermia, it may occur as an early sign in severe cases.

Diagnosis is generally clinical, based on intraoperative signs and symptoms (e.g., muscle and jaw rigidity, hyperthermia) in connection with increased end-tidal CO₂ and signs of muscle breakdown. Patients with a positive family history, suspicious clinical history, or masseter muscle rigidity should receive confirmatory preoperative testing to rule out the risk of MH.

Preoperative diagnostics ^[2]

• Gold standard: caffeine-halothane contracture test (CHCT)
  • A muscle sample is obtained under regional anesthesia.
  • The muscle sample is divided with the grain of the fibers into six strips.
  • After tissue viability testing via electrical stimulation, the muscle strips are mounted into a bath.
  • Three strips are exposed to 3% halothane, and the remaining three other strips are exposed to caffeine.
  • The test is considered positive if any of the strips contract.
  • Disadvantages: only available at select testing centers, which will likely require the patient to travel.
• Molecular genetic testing: low sensitivity, but highly specific and less expensive and invasive than CHCT

Intraoperative diagnostics

• Clinical features: See “Clinical features” above.
• Respiratory parameters: continuous increase in end-tidal CO₂
• Blood tests
  • Arterial blood gas: ↑ pCO₂, ↓ pO_2, and ↑ lactate (mixed respiratory and metabolic acidosis)
  • Electrolyte abnormalities: hyperkalemia, hypercalcemia ^[1]
  • Myoglobinemia, ↑ creatine kinase
• Urine: myoglobinuria

• See “Differential diagnosis of drug-induced hyperthermia” for details.
• Thyrotoxic crisis
• Pheochromocytoma
• Acute porphyria crisis
• Levodopa withdrawal syndrome
• Sepsis

The differential diagnoses listed here are not exhaustive.

• Discontinuation of potential triggering agents
• Immediate administration of dantrolene (ryanodine receptor antagonist)
  • Mechanism of action
    • Ryanodine receptor antagonist
    • Prevents release of calcium from the sarcoplasmic reticulum of striated muscle → reduced muscle rigidity and hyperthermia
  • Indications
    • Neuroleptic malignant syndrome
    • Malignant hyperthermia
  • Adverse effects
    • CNS: headache, dizziness, mental/mood changes, seizures, hallucinations, insomnia, malaise
    • Gastrointestinal: nausea, diarrhea or constipation, vomiting
    • Other: muscle weakness, allergic reaction, blood count changes
  • Interactions
    • Increase in the activity of nondepolarizing muscle relaxants
    • Dantrolene interacts with calcium antagonists, potentially leading to hyperkalemia, which can be unpredictable → cardiac arrhythmias
• Cooling measures (e.g., ice packs, cool water blankets, ice-water immersion, IV iced saline, forced air cooling) ^[3]
• Ventilation
  • Increase respiratory minute volume by at least 3-fold.
  • Ventilation with 100% O₂
• Expedited completion of surgery

Dantrolene directly deals with distressed muscle.

If adequately treated, the mortality rate is < 10%. In the absence of rapid, appropriate treatment, the mortality rate is ∼ 70%.