Malignant Hyperthermia

An important complication of anesthesia is malignant hyperthermia, an autosomal dominant disorder of the regulation of calcium transport in the skeletal muscles resulting in a hypermetabolic crisis. Malignant hyperthermia is marked by high fever, muscle rigidity, rhabdomyolysis, and respiratory and metabolic acidosis. The mortality rate reaches 90% if not quickly identified and treated. Management involves stopping the offending agent and administering dantrolene.

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Malignant hyperthermia (MH) is a hypermetabolic response in a patient exposed to a volatile anesthetic or succinylcholine resulting in fever, muscle rigidity, rhabdomyolysis, and pulmonary and cerebral edema.


  • Anesthesia-induced condition
  • Rare (< 1:100,000)
  • Very dangerous → 80%–90% mortality without proper treatment
  • 90% cure rate when treated appropriately
  • Seen in patients of all ethnicities and geographic distributions
  • Twice as common in males
  • Up to 50% of cases occur in patients < 19 years of age.


Triggering substances:

  • Inhalation anesthetics (e.g., halothane, enflurane, and isoflurane) 
  • Succinylcholine (muscle relaxant)

“Safe” anesthetics for patients with previously diagnosed malignant hyperthermia:

  • “Laughing gas” (nitrous oxide)
  • Barbiturates
  • Benzodiazepines
  • Etomidate
  • Propofol
  • Ketamine
  • Opioids
  • Non-depolarizing muscle relaxants


  • Autosomal dominant genetic disorder of hypermetabolism of skeletal muscle after exposure to certain anesthetics
  • Due to mutations encoding for:
    • Dihydropyridine (DHP) receptors → sense action potential in T tubules
    • Ryanodine (RYR1) receptors → release calcium from sarcoplasmic reticulum into intracellular space
  • Defects lead to continuous muscle contraction, causing:
    • Cellular metabolism (hypermetabolism) 
    • ↓ ATP
    • O₂ consumption and CO₂ production
    • Tissue hypoxia and lactic acidosis
    • Heat production
    • Cell destruction causing CK release and myoglobinuria


Clinical features

Symptoms may appear at any point during anesthesia (induction, maintenance, rarely after discontinuation). Symptoms follow a regular pattern; the speed of progression through symptoms varies, however.

Early signs:

  • Rapid rise in end-tidal carbon dioxide (ETCO₂): earliest symptom
  • Arrhythmias:
    • Tachycardia 
    • Peaked T waves
    • Due to hyperkalemia
    • Often misinterpreted as too low a depth of anesthesia
  • Muscular rigor (masseter spasms specific for succinylcholine-induced MH): blood pressure is initially (decreased blood pressure is sign of circulatory failure)

Late signs:

  • Fever (not required for diagnosis)
  • Rhabdomyolysis
  • Myoglobinuria
  • Renal failure
  • Cerebral edema
  • Pulmonary edema

Laboratory findings

  • Metabolic/respiratory acidosis:
    • Respiratory acidosis: caused by in CO₂ due to hypoventilation
    • Metabolic acidosis: due to lactic acid production
  • Hyperkalemia: due to potassium released from damaged cells
  • CK: released by muscle breakdown
  • Myoglobinuria:
    • Smooth muscle cell breakdown releases myoglobin.
    • Myoglobin spills into urine.


Care in the ICU is necessary as the condition can reactivate after apparent improvement.

Immediate actions

  • Termination of triggering substances
  • Hyperventilation with 100% oxygen
  • Terminating surgery as soon as possible
  • If necessary, change to safer anesthetics (IV agents).


  • Inhibits ryanodine receptor
  • Prevents release of Ca2+ from sarcoplasmic reticulum of skeletal muscle
  • Leads to muscle relaxation
  • Has no negative effects if patient not in HM

Symptomatic treatment

  • Active cooling: 
    • Ice packs to groin
    • Cooled IV fluids
    • Flushing bladder with cold fluid
  • Balance acidosis with sodium bicarbonate.
  • Treat electrolyte abnormalities.
  • Treat hyperkalemia in patients with arrhythmias.

Potential complications

  • Severe metabolic acidosis
  • Hyperkalemia
  • Renal failure
  • Cerebral edema
  • Pulmonary edema

Clinical Relevance

Related conditions

  • Serotonin syndrome: fever, autonomic dysfunction, rigidity/spasticity related to overdoses of selective serotonin reuptake inhibitors (SSRIs) or other antidepressants. Presents with more GI symptoms (nausea, vomiting) than in MH.
  • Neuroleptic malignant syndrome (NMS): rare, idiosyncratic, and potentially life-threatening reaction to neuroleptic (e.g., antipsychotic) drug. Very similar to serotonin syndrome, but without the GI symptoms and more muscle rigidity. Treated similarly to serotonin syndrome, by discontinuing causative drugs and offering supportive care.

Differential diagnosis

Presentations with altered mental status, autonomic dysfunction, and fever:

  • Meningitis/encephalitis
  • Toxic encephalopathy
  • Excited delirium
  • Heatstroke
  • Status epilepticus
  • Alcohol or sedative withdrawal
  • Hypertensive crisis
  • Thyrotoxicosis


  1. Litman, R. S. (2019). Malignant Hyperthermia: Diagnosis and management of acute crisis. In M. Crowly (Ed), UpToDate. Retrieved February 2, 2021, from
  2. Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. (2015). Malignant hyperthermia: a review. Orphanet J Rare Dis. 
  3. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. (2010). Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 
  4. Malignant Hyperthermia Association of the United States. Retrieved February 15, 2021, from

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