Notes · Anaesthesia · 2 November 2026

Malignant hyperthermia

Definition

• Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle calcium regulation that precipitates a hypermetabolic crisis when susceptible individuals are exposed to triggering anesthetic agents (volatile inhalational anesthetics and depolarizing muscle relaxants such as succinylcholine).
• The condition is characterized by rapid rise in body temperature, generalized muscle rigidity, tachycardia, hypercapnia, acidosis, and potentially fatal cardiac arrhythmias if not treated promptly.

Epidemiology

• Incidence in the United States is estimated at 1 : 5,000 to 1 : 50,000 anesthetics, varying with the population screened and the definition used.
• The overall mortality has fallen from > 80 % in the 1960s to < 5 % in centers that follow modern guidelines and have immediate access to dantrolene.
• MH susceptibility (MHS) is inherited in an autosomal dominant pattern; about 1 % of the general population carries a pathogenic RYR1 or CACNA1S mutation, but only a fraction will develop a crisis.

Aetiology

• Genetic mutations:
  • RYR1 (ryanodine receptor type 1) mutations account for ~ 70 % of cases; the receptor controls calcium release from the sarcoplasmic reticulum in skeletal muscle.
  • CACNA1S (α1‑subunit of the dihydropyridine receptor) mutations account for ~ 10 % of cases.
• Triggering agents:
  • Volatile anesthetics (e.g., sevoflurane, desflurane, isoflurane, halothane).
  • Depolarizing muscle relaxant succinylcholine.
  • Non‑triggering agents (e.g., propofol, nitrous oxide, opioids, non‑depolarizing muscle relaxants) are safe in MHS patients.
• Non‑triggering factors:
  • Extreme hyperthermia, vigorous exercise, or heat stroke can rarely provoke a similar hypermetabolic state in susceptible individuals, termed “MH‑like crisis”.

Pathophysiology

• In normal muscle, the ryanodine receptor (RyR1) opens briefly during depolarization, allowing a controlled release of Ca²⁺ from the sarcoplasmic reticulum, which initiates contraction.
• Mutated RyR1 channels become hypersensitive to activation by volatile anesthetics or succinylcholine, leading to uncontrolled calcium leak into the cytoplasm.
• Excess intracellular Ca²⁺ triggers:
  • Sustained muscle contraction → rigidity and increased ATP consumption.
  • Hypermetabolism → rapid rise in CO₂ production (hypercapnia) and O₂ consumption.
  • Heat generation → core temperature may increase > 1 °C every 5 minutes.
  • Activation of the Na⁺/K⁺‑ATPase and Ca²⁺‑ATPase pumps → massive ATP hydrolysis, leading to acidosis (both metabolic and respiratory).
  • Release of potassium from muscle cells → hyperkalaemia, which predisposes to arrhythmias.
  • Rhabdomyolysis → release of myoglobin, creatine kinase (CK), and intracellular enzymes, potentially causing acute kidney injury.

Clinical Features

• Early signs (within minutes of trigger exposure):
  • Unexpected rise in end‑tidal CO₂ (EtCO₂) despite adequate ventilation.
  • Tachycardia (HR > 120 bpm) and arterial hypertension.
  • Muscle rigidity, especially masseter spasm (“jaw lock”) after succinylcholine.
• Progressive signs (5‑30 minutes):
  • Rapid increase in core temperature (often > 38.5 °C, may exceed 41 °C).
  • Generalized hyperthermia and profuse sweating.
  • Metabolic acidosis (pH < 7.25, base deficit > 5 mmol/L).
  • Hyperkalaemia (K⁺ > 5.5 mmol/L) on arterial blood gas.
  • Dark urine from myoglobinuria.
• Late complications:
  • Cardiac arrhythmias (ventricular tachycardia/fibrillation).
  • Disseminated intravascular coagulation (DIC).
  • Acute renal failure due to myoglobin tubular obstruction.

Investigations

• Intra‑operative monitoring:
  • Continuous EtCO₂ – the most sensitive early indicator.
  • Core temperature (esophageal or nasopharyngeal probe).
  • ECG for arrhythmias.
• Laboratory tests (once crisis suspected):
  • Arterial blood gas (ABG) – assess PaCO₂, pH, base excess, lactate.
  • Serum electrolytes – especially potassium and calcium.
  • Creatine kinase (CK) – markedly elevated (> 10 000 U/L) 6‑12 hours after crisis.
  • Myoglobin in urine – positive dipstick for blood without red cells.
  • Serum lactate – often > 4 mmol/L.
• Definitive diagnosis:
  • In‑vitro contracture test (IVCT) on fresh skeletal muscle biopsy (gold standard).
  • Genetic testing for RYR1 or CACNA1S mutations (supportive, not definitive).

Management (2024 MHAUS Guidelines)

1. Immediate actions – stop triggering agents, hyperventilate with 100 % O₂, and discontinue nitrous oxide.
2. Call for help – activate the malignant hyperthermia cart and notify the senior anesthesiologist and surgical team.
3. Dantrolene administration – the only specific antidote:
   • Initial dose 2.5 mg/kg IV bolus (maximum 10 mg per vial).
   • Repeat 2.5 mg/kg every 5 minutes until signs improve (usually total 5‑10 mg/kg).
   • If crisis persists, give a continuous infusion of 0.25 mg/kg/h until the patient is stable.
4. Supportive measures –
   • Cooling: ice packs, cold intravenous fluids (4 °C saline), gastric lavage with cold saline, and surface cooling blankets. Aim to reduce core temperature ≤ 38 °C.
   • Hyperventilation: minute ventilation to keep PaCO₂ 30‑35 mmHg, which helps wash out CO₂ and correct respiratory acidosis.
   • Correct metabolic acidosis: administer sodium bicarbonate 1 mmol/kg IV if pH < 7.1.
   • Treat hyperkalaemia: insulin‑glucose infusion, calcium chloride (to stabilize cardiac membranes), and consider β‑agonists.
   • Maintain urine output: give diuretics (e.g., furosemide) and ensure ≥ 2 mL/kg/h urine output; consider sodium bicarbonate to alkalinize urine and prevent myoglobin precipitation.
   • Monitor: continuous ECG, invasive arterial pressure, core temperature, ABG every 15‑30 minutes, and CK every 6‑12 hours.
5. Post‑crisis care – transfer to ICU for at least 24 hours of observation; repeat CK and renal function tests; arrange genetic counseling and family screening.

Complications

• Cardiac arrest due to arrhythmias or severe hyperkalaemia.
• Acute renal failure from myoglobin-induced tubular obstruction; may require dialysis.
• Disseminated intravascular coagulation secondary to massive tissue injury.
• Persistent hyperthermia leading to cerebral edema or seizures.
• Neurological sequelae (e.g., peripheral neuropathy) after prolonged crisis.

High‑Yield Exam Points

• Triggering agents: volatile anesthetics and succinylcholine; all others are safe.
• Early sign: unexplained rise in EtCO₂ before temperature elevation.
• Definitive treatment: dantrolene 2.5 mg/kg IV repeated until clinical response.
• Genetic basis: autosomal dominant RYR1 mutation in > 70 % of cases.
• IVCT is the gold‑standard diagnostic test; genetic testing is adjunctive.
• Core temperature rise can be > 1 °C per 5 minutes; aim to keep ≤ 38 °C with active cooling.
• Masseter spasm after succinylcholine is a classic early clue but not mandatory for diagnosis.
• Dantrolene storage: must be kept in the operating suite, shelf‑life 2 years, and a full MH cart should contain at least 36 vials (enough for 10 mg/kg in a 70‑kg adult).
• Post‑crisis monitoring: CK peaks at 24‑48 hours; renal function and electrolytes must be followed for at least 48 hours.

Practice questions

1. A 28‑year‑old woman undergoing laparoscopic cholecystectomy develops a sudden rise in end‑tidal CO₂ from 35 mmHg to 65 mmHg, tachycardia, and generalized rigidity after induction with sevoflurane and succinylcholine. Which of the following is the most appropriate immediate step?
A. Administer intravenous propranolol
B. Increase the depth of anesthesia with more sevoflurane
C. Stop the triggering agents and give dantrolene 2.5 mg/kg IV
D. Begin rapid infusion of cold saline without dantrolene

Answer: C — stopping triggers and giving dantrolene is the definitive emergency treatment for malignant hyperthermia.

2. Which genetic mutation is most commonly associated with malignant hyperthermia susceptibility?
A. CFTR
B. RYR1
C. BRCA1
D. HBB

Answer: B — RYR1 mutations account for the majority of MH‑susceptible cases.

3. In the management of an MH crisis, which of the following laboratory findings is least likely to be present early in the event?
A. Hyperkalaemia
B. Metabolic acidosis
C. Elevated creatine kinase > 10 000 U/L
D. Increased PaCO₂

Answer: C — CK rises later (6‑12 hours); early findings are hypercapnia, acidosis, and hyperkalaemia.

AI-assisted study material for exam revision. Always confirm with standard textbooks and current guidelines; not medical advice.