Physiology · Year 1 · from Physiology
Case 2: Malignant Hyperthermia - Ryanodine Receptor Dysfunction
Clinical Image
Source: Wikimedia Commons - Rhabdomyolysis urine - CC BY-SA 3.0
Patient Presentation
A 22-year-old male undergoes general anesthesia for an elective knee arthroscopy. Shortly after administration of sevoflurane and succinylcholine, the anesthesiologist notices masseter muscle rigidity during intubation. Over the next 15 minutes, the patient develops tachycardia (150 bpm), marked hyperthermia (temperature rising to 40.5C), muscle rigidity throughout the body, and mixed respiratory and metabolic acidosis. The end-tidal CO2 rises dramatically despite increased minute ventilation. His urine becomes dark brown.
Demographics
- Age: 22 years
- Sex: Male
- Procedure: Knee arthroscopy under general anesthesia
- Triggering agents: Sevoflurane (volatile anesthetic) and succinylcholine
Chief Complaint
Intraoperative crisis: Hyperthermia, muscle rigidity, tachycardia, and acidosis
Physical Examination (Intraoperative)
- Vital signs: HR 150, BP 180/110, Temp 40.5C (rising rapidly), SpO2 88% despite 100% FiO2
- EtCO2: 85 mmHg (severely elevated, indicating hypermetabolism)
- Muscle tone: Generalized rigidity, masseter spasm
- Skin: Mottled, diaphoretic
- Urine: Dark brown (myoglobinuria)
Workup
- Arterial blood gas: pH 7.12, PaCO2 72, PaO2 68, HCO3 14, lactate 12 (severe mixed acidosis)
- Serum potassium: 7.1 mEq/L (dangerous hyperkalemia from muscle breakdown)
- Creatine kinase: 45,000 U/L (massive muscle breakdown)
- Myoglobin: Markedly elevated in serum and urine
- Genetic testing (after recovery): RYR1 mutation identified
- Caffeine-halothane contracture test: Positive (gold standard if genetic testing unavailable)
Diagnosis
Malignant Hyperthermia (MH)
Treatment
- STOP all triggering agents immediately (discontinue sevoflurane)
- Call for MH cart and additional help
- Hyperventilate with 100% oxygen using clean circuit (no volatile anesthetics)
- DANTROLENE 2.5 mg/kg IV bolus, repeat every 5 minutes until symptoms resolve (may need 10+ mg/kg)
- Active cooling: Ice packs, cold IV fluids, cooling blanket
- Treat hyperkalemia: Calcium, insulin/glucose, bicarbonate, consider dialysis
- Maintain urine output >2 mL/kg/hr with fluids and mannitol to prevent myoglobin-induced renal failure
- Monitor and treat arrhythmias (avoid calcium channel blockers with dantrolene)
- ICU admission for continued monitoring
- Genetic counseling and testing for patient and first-degree relatives
- MedicAlert bracelet and anesthesia warning letter
Physiological Principles Demonstrated
- Excitation-contraction coupling: Normally, action potentials traveling down T-tubules activate dihydropyridine receptors (DHPR), which mechanically couple to ryanodine receptors (RyR1) in the sarcoplasmic reticulum, causing calcium release that initiates contraction.
- RyR1 mutation effects: In MH, mutant RyR1 channels have abnormal sensitivity to triggering agents. Volatile anesthetics and succinylcholine cause uncontrolled, sustained calcium release from the SR.
- Hypermetabolic state: Sustained elevated cytoplasmic calcium causes continuous cross-bridge cycling, depleting ATP and generating heat. SERCA works overtime trying to pump calcium back into the SR, further consuming ATP.
- CO2 production: The hypermetabolic state massively increases CO2 production, causing the characteristic dramatic rise in end-tidal CO2 often the first sign.
- Rhabdomyolysis: Sustained contraction, ATP depletion, and membrane damage cause muscle cell death, releasing myoglobin, CK, and potassium.
- Dantrolene mechanism: Dantrolene directly blocks RyR1 calcium release channels, interrupting the cycle of uncontrolled calcium release and muscle contraction. It is the specific antidote for MH.
- Temperature rise is a late sign: The hyperthermia results from heat generated by sustained muscle contraction and metabolism; rising EtCO2 and muscle rigidity typically precede fever.