Malignant Hyperthermia
Rare but lethal pharmacogenetic disorder triggered by volatile anesthetics or succinylcholine. Rising ETCO2 is the earliest sign. Dantrolene is the ONLY specific treatment. Mortality exceeds 70% without treatment, but drops below 5% with early dantrolene.
🔍 Overview
Overview
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.
Triggers
- 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
Pathophysiology
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.
Presentation
- 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
🚨 Management
Immediate Management
STOP all triggering agents IMMEDIATELY. Discontinue volatile anesthetic. Turn off vaporizer. Disconnect circuit from anesthesia machine. Hyperventilate with 100% O2 at high fresh gas flows (>10 L/min). Do NOT waste time changing the circuit, just flush with high-flow O2.
- 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).
Dantrolene is the ONLY specific treatment. Every OR must have it stocked. Know where it is BEFORE you need it. Each vial is 20 mg, a 70 kg patient needs ~9 vials for the first dose. It takes time to reconstitute (each vial requires 60 mL sterile water), call for help immediately. Newer formulations (Ryanodex) come as 250 mg/vial requiring only 5 mL to reconstitute.
Clinical Example: A 25-year-old male undergoing appendectomy under general anesthesia with sevoflurane. 30 minutes into the case, the anesthesiologist notices ETCO2 climbing from 38 to 72 despite increasing minute ventilation. HR jumps to 130. Jaw is rigid. Temperature probe shows 39.2°C and rising. This is MH until proven otherwise, STOP sevoflurane, call for dantrolene, hyperventilate with 100% O2, and begin active cooling.
🧪 Workup
Diagnostic Workup
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)
Post-Crisis, Confirmatory Testing
- 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.
💊 Medications
Medications
| Drug | Indication | Dose | Notes |
|---|---|---|---|
| Dantrolene (Dantrium) | SPECIFIC treatment for MH | 2.5 mg/kg IV push, repeat q5min PRN | No max dose in crisis. Each 20 mg vial needs 60 mL sterile water to reconstitute. Typical total 10 mg/kg. Continue 1 mg/kg IV q6h x 24-48h after crisis to prevent recrudescence. |
| Dantrolene (Ryanodex) | Newer formulation | 2.5 mg/kg IV push | 250 mg/vial, reconstitutes in only 5 mL. Much faster preparation. Single vial may cover initial dose for most patients. |
| Calcium gluconate 10% | Hyperkalemia cardioprotection | 30 mL (3 amps) IV over 5-10 min | Stabilizes cardiac membrane. Does not lower K+. |
| Regular insulin + D50 | Hyperkalemia treatment | 10 units insulin IV + 50 mL D50 | Drives K+ intracellularly. Check glucose q1h. |
| Sodium bicarbonate | Severe acidosis / hyperK | 1-2 mEq/kg IV | For pH <7.2. Also helps drive K+ intracellularly. |
| Amiodarone | Ventricular arrhythmias | 150 mg IV over 10 min, then 1 mg/min | For VT/VF. Do NOT use calcium channel blockers (lethal interaction with dantrolene). |
NEVER use calcium channel blockers (verapamil, diltiazem) with dantrolene, combination causes fatal hyperkalemia and cardiovascular collapse. Use amiodarone or lidocaine for arrhythmias instead.
🏥 Rounds
Pimp Questions
❓ What is the earliest sign of malignant hyperthermia in the OR?
Rising ETCO2 (end-tidal CO2). This is often the earliest and most sensitive sign, reflecting the massive hypermetabolic state and increased CO2 production. Temperature elevation is often a LATE sign. The ETCO2 may rise to >60-80 mmHg despite adequate ventilation.
❓ What is the underlying mechanism of malignant hyperthermia?
Uncontrolled calcium release from the sarcoplasmic reticulum via defective ryanodine receptors (RYR1 mutation). The massive intracellular calcium causes sustained muscle contraction, ATP depletion, heat generation, and a hypermetabolic state with exponentially increased O2 consumption and CO2 production.
❓ Can you use succinylcholine for intubation in a patient with known MH susceptibility?
NO. Succinylcholine is a known trigger for MH. Use rocuronium (non-depolarizing agent) instead. Rocuronium can be reversed with sugammadex. All non-depolarizing neuromuscular blockers are safe in MH-susceptible patients.
Sample Presentation
Mr. Thompson is a 32-year-old male undergoing laparoscopic cholecystectomy under general anesthesia with sevoflurane. 45 minutes into the case, ETCO2 rose from 36 to 78 mmHg despite increasing minute ventilation. HR 142, BP 90/60. Jaw rigidity noted. Temperature probe: 39.8°C and rising rapidly. Volatile anesthetic was immediately discontinued, hyperventilation with 100% O2 initiated, and dantrolene 2.5 mg/kg IV push was given. After 3 doses (total 7.5 mg/kg), ETCO2 began trending down. Active cooling with ice packs and cold NS achieved temp <38.5°C. Labs: CK 45,000, K+ 6.8, pH 7.12, lactate 14. Treated hyperK with calcium, insulin/glucose, and bicarb. Now in ICU on dantrolene 1 mg/kg q6h.
Key Points: Classic MH presentation triggered by sevoflurane. Rising ETCO2 was the earliest sign. Immediate dantrolene was life-saving. Now monitoring for recrudescence (25% risk within 24-36h), renal injury from rhabdomyolysis (CK 45,000, targeting UOP >2 mL/kg/h), and DIC. Will need genetic counseling and screening of first-degree relatives.
Monitoring
- 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).
📋 Summary
Summary
Know the Triggers
Volatile anesthetics (halothane, sevoflurane, isoflurane, desflurane) and succinylcholine. Nothing else triggers it: nitrous oxide, propofol, ketamine, opioids, benzodiazepines and non-depolarizing paralytics are all safe. It is an autosomal dominant ryanodine receptor disorder, so ask about anesthetic problems in relatives, not only in the patient.
Rising End-Tidal CO2 Is the Earliest Sign
An unexplained, rising ETCO₂ that does not respond to increased minute ventilation is the first and most sensitive indicator. Fever is a late sign, so waiting for hyperthermia to make the diagnosis wastes the window in which dantrolene works. Masseter spasm after succinylcholine, tachycardia, rigidity and mixed acidosis follow.
Stop the Trigger Immediately
Discontinue the volatile agent, turn off the vaporizer, and hyperventilate with 100% oxygen at fresh gas flows above 10 L/min. Do not waste time changing the anesthesia circuit or the machine: high flows wash the agent out faster than a swap, and the delay costs more than the residual vapor. Call for help and get the MH cart.
Dantrolene Is the Only Specific Treatment
2.5 mg/kg IV rapidly, repeated every 5 to 10 min until the ETCO₂, rigidity and tachycardia settle, with no real ceiling in a crisis. Mortality exceeds 70% untreated and falls below 5% with early dantrolene. Know where it is stocked before you need it: the standard formulation is 20 mg per vial, so a 70 kg patient needs about 9 vials for the first dose alone, and each vial has to be reconstituted, which is why several people are needed just to mix it.
Never Give a Calcium Channel Blocker With Dantrolene
Verapamil or diltiazem with dantrolene causes fatal hyperkalemia and cardiovascular collapse. Use amiodarone or lidocaine for arrhythmias instead, and treat the underlying hyperkalemia and acidosis, which are usually what is driving the rhythm.
Cool and Correct in Parallel
Active cooling with cold IV fluids, ice packs to the groin and axillae, and lavage if needed; stop at about 38°C to avoid overshoot. Treat hyperkalemia aggressively with calcium, insulin and dextrose, and bicarbonate. Treat the rhabdomyolysis with aggressive fluids targeting a urine output of 1 to 2 mL/kg/h, and follow CK and myoglobin.
Watch Them for 24 to 48 Hours
Recrudescence occurs in up to a quarter of patients, typically within the first 24 h, which is why these patients go to the ICU on continued dantrolene rather than back to the ward. Monitor CK, potassium, coagulation (DIC is a late complication) and renal function serially.
Confirm and Flag It Afterwards
Refer for caffeine-halothane contracture testing or genetic testing of RYR1 and CACNA1S, since the diagnosis is inherited and the implications extend to the family. Give the patient written documentation and a medical alert bracelet, counsel first-degree relatives to be tested, and report to the MH registry. Future anesthesia uses a clean machine and a non-triggering technique.
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