Malignant Hyperthermia

Malignant hyperthermia (MH) is a rare, life-threatening pharmacogenetic disorder caused by mutations in the RYR1 gene (ryanodine receptor on sarcoplasmic reticulum). Triggered by volatile anesthetics (sevoflurane, desflurane, isoflurane) or succinylcholine. The mutation causes uncontrolled calcium release from the sarcoplasmic reticulum into the myoplasm, leading to sustained muscle contraction, hypermetabolism, and multi-organ failure.

• Volatile anesthetics: sevoflurane, desflurane, isoflurane, halothane (most potent trigger)
• Succinylcholine (depolarizing neuromuscular blocker)
• NOT triggered by: non-depolarizing agents (rocuronium, vecuronium), propofol, benzodiazepines, nitrous oxide, opioids, stress alone, exercise alone

RYR1 mutation causes defective ryanodine receptor on skeletal muscle sarcoplasmic reticulum. Triggering agent causes uncontrolled calcium release into myoplasm, leading to sustained muscle contraction, exponentially increased oxygen consumption and CO2 production, massive ATP hydrolysis, and heat generation. This cascade produces hypercarbia, metabolic acidosis, rhabdomyolysis, hyperkalemia, and eventually cardiac arrest if untreated.

• Earliest sign: Rising ETCO2 (unexpectedly, often >60 mmHg despite adequate ventilation)
• Masseter spasm (trismus after succinylcholine), may be the first clinical sign
• Rapidly rising temperature, can reach >40°C in minutes (1-2°C every 5 min). Temperature rise is often a LATE sign.
• Muscle rigidity, generalized ("board-like")
• Tachycardia, tachypnea, if spontaneously breathing
• Metabolic acidosis, severe mixed respiratory and metabolic
• Hyperkalemia, from rhabdomyolysis and cellular lysis
• Rhabdomyolysis, CK >20,000 IU/L, dark urine (myoglobinuria)
• DIC, late complication
• Cardiac arrhythmias, from hyperkalemia, acidosis, and hyperthermia

• Dantrolene (Dantrium) 2.5 mg/kg IV push, repeat every 5 minutes until symptoms resolve. No maximum dose in an emergency (typically up to 10 mg/kg total, but more may be needed).
• Call for HELP, you need multiple people to mix dantrolene.
• Active cooling: ice packs to groin/axillae/neck, cold IV normal saline, cooling blankets, iced gastric/bladder lavage if refractory. Target temp <38.5°C, then STOP active cooling (risk of overshoot hypothermia).
• Treat hyperkalemia: calcium gluconate 30 mL of 10% IV (or calcium chloride 10 mL), insulin 10 units + D50 50 mL IV, sodium bicarbonate 1-2 mEq/kg. Do NOT use succinylcholine for intubation.
• Treat acidosis: sodium bicarbonate 1-2 mEq/kg IV for pH <7.2.
• Treat arrhythmias: amiodarone for VT. Do NOT use calcium channel blockers (fatal interaction with dantrolene causing hyperkalemia and cardiovascular collapse).

MH is a clinical diagnosis in the acute setting. Do not delay treatment for labs.

• ETCO2, earliest sign in the OR. Rising unexpectedly despite adequate ventilation.
• ABG, severe mixed metabolic and respiratory acidosis (pH <7.2, pCO2 >60, base deficit >-8, lactate elevated)
• CK (creatine kinase), massively elevated (>20,000 IU/L). Peaks at 12-24h. Serial CK q6h.
• BMP, hyperkalemia (from rhabdomyolysis), initially hypercalcemia then hypocalcemia, renal function (AKI from myoglobinuria)
• Myoglobin, serum and urine. Dark/cola-colored urine = myoglobinuria.
• Coagulation panel, PT, PTT, fibrinogen, D-dimer (DIC screen)
• Lactate, markedly elevated (hypermetabolic state)
• Core temperature, continuous monitoring (esophageal or rectal preferred)

• Caffeine-halothane contracture test (CHCT), gold standard for MH susceptibility. Requires a muscle biopsy (usually vastus lateralis). Performed at specialized MH centers. Sensitivity ~97%, specificity ~78%.
• Genetic testing, RYR1 mutation analysis. If positive, confirms susceptibility. But a negative result does NOT rule it out (only ~50-70% of MH families have identifiable mutations).
• Screen first-degree relatives, autosomal dominant inheritance with variable penetrance.

• Continuous ETCO2, most sensitive early indicator. Target normalization (<40 mmHg).
• Core temperature, continuous (esophageal or rectal). Target <38.5°C. Stop active cooling at 38°C to prevent overshoot.
• ABG q30-60 min during acute crisis, trend pH, pCO2, lactate, K+.
• CK q6h x 24h, peak at 12-24h. If >10,000, aggressive IV hydration for renal protection.
• Urine output, target >2 mL/kg/h to prevent myoglobin-induced AKI. Consider mannitol or bicarb drip if myoglobinuria.
• BMP q4-6h, potassium, calcium, creatinine trending.
• Coags q6-12h, DIC surveillance (falling fibrinogen, rising D-dimer, dropping platelets).
• Monitor for recrudescence, MH can recur in 25% of cases within 24-36h. Continue dantrolene 1 mg/kg q6h x 24-48h. Keep in monitored bed (ICU).