Malignant Hyperthermia: Recognition and Management

Quick Answer

Malignant hyperthermia (MH) is a pharmacogenetic disorder triggered by volatile anaesthetics (sevoflurane, isoflurane, desflurane, halothane) and suxamethonium. Pathophysiology: Ryanodine receptor (RYR1) or DHPR mutation → excessive calcium release from sarcoplasmic reticulum → hypermetabolism, hyperthermia, rhabdomyolysis. Clinical features: Tachycardia, hypercarbia (increased CO₂ production), muscle rigidity (especially masseter), hyperthermia (often late sign), acidosis, hyperkalemia, myoglobinuria. Treatment: Dantrolene 2.5 mg/kg IV bolus, repeat to 10 mg/kg total until symptoms resolve; stop triggers (change circuit, flush with high fresh gas flow); aggressive cooling (ice packs, cold IV fluids, body cavity lavage); correct acidosis (sodium bicarbonate 1-2 mEq/kg); treat hyperkalemia (calcium, glucose/insulin, bicarbonate); maintain urine output (mannitol, fluids). Postoperative: ICU monitoring 24-48 hours (risk of late recrudescence), dantrolene 1 mg/kg q6h × 24-48 hours, creatine kinase monitoring. Non-triggering anaesthesia: Total intravenous anaesthesia (TIVA) with propofol/remifentanil, regional, local. [1-10]

Pathophysiology

Genetics and Molecular Mechanism

Inheritance:

• Autosomal dominant with variable penetrance
• RYR1 gene: Ryanodine receptor 1 (skeletal muscle calcium channel) - 50-70% of cases
  • Located on chromosome 19q13.1
  • Codes for calcium release channel on sarcoplasmic reticulum
• CACNA1S gene: L-type calcium channel (dihydropyridine receptors, DHPR) - ~1% of cases
  • Located on chromosome 1q32
  • Voltage sensor, activates RYR1

Pathophysiological Cascade:

1. Trigger binding: Volatile anaesthetic or suxamethonium binds to allosteric site on RYR1 (or activates via DHPR)
2. Channel opening: Excessive opening of RYR1 calcium release channels
3. Calcium release: Massive release of Ca²⁺ from sarcoplasmic reticulum into cytosol
4. Muscle hypermetabolism:
   • Hyperactivation of actin-myosin (rigidity)
   • Accelerated glycolysis → lactate production
   • Hyperthermia (heat production)
5. Cellular energy depletion: ATP consumption exceeds production
6. Rhabdomyolysis: Muscle cell breakdown → myoglobin, potassium, creatine kinase (CK) release
7. Disseminated intravascular coagulation (DIC): Tissue factor release, hyperthermia

Why Suxamethonium Triggers MH:

• Depolarization of muscle membrane → action potential
• DHPR senses voltage change → signals RYR1
• In MH, this signal is exaggerated → excessive calcium release
• Non-depolarizing relaxants do not trigger (no depolarization)

Clinical Features

Early Signs (First Signs):

• Unexpected tachycardia: HR >100-120 bpm, out of proportion to stimulus
• Hypercarbia: Increased EtCO₂ despite adequate ventilation (not explained by light anaesthesia or hypoventilation)
  • First and most sensitive sign
  • May increase 2-3× normal
• Masseter spasm: After suxamethonium (trismus)
  • Jaw tightness, difficult intubation
  • May be isolated or herald full MH

Progressive Signs:

• Muscle rigidity: Generalized, not just masseter
• Hyperthermia: Often late sign, but dramatic when present
  • Rise >38.8°C or >2°C/hour
  • Can reach 43-44°C if untreated
  • Rate of rise: 1-2°C every 5 minutes
• Tachypnea: If spontaneously breathing (trying to compensate for metabolic acidosis)
• Arrhythmias: Ventricular ectopy, VT, VF (from hyperkalemia, acidosis, hyperthermia)

Laboratory Abnormalities:

• Metabolic acidosis: pH <7.20, base deficit >-8
• Hyperkalemia: K⁺ >5.5 mmol/L (from cell lysis), can be >6-7 mmol/L
• Hyperlactatemia: Lactate >5-10 mmol/L (anaerobic metabolism)
• Elevated CK: >10,000-20,000 U/L (rhabdomyolysis)
• Myoglobinuria: Dark urine (tea-colored), myoglobin >1,000 ng/mL
• Coagulopathy: DIC (elevated INR, low fibrinogen, thrombocytopenia)
• Hyperglycemia: Stress response
• Hypernatremia: Dehydration

Masseter Spasm (Isolated):

• Definition: Jaw rigidity after suxamethonium, preventing mouth opening >2 cm
• Incidence: 1% of children given suxamethonium
• Significance:
  • 10-30% will develop MH if triggering agents continued
  • May be normal variant or early MH
• Management:
  • If isolated and no other signs: Monitor closely, proceed with non-triggering technique
  • If any other signs (tachycardia, hypercarbia): Treat as MH
  • Cancel elective surgery, test for MH susceptibility

Differential Diagnosis

Other Causes of Hyperthermia:

• Infection/sepsis: Pre-existing fever, septic patient
• Neuroleptic malignant syndrome (NMS): Dopamine antagonists (haloperidol), rigidity, hyperthermia, but:
  • No muscle breakdown (normal CK)
  • Slow onset (days)
  • No anaesthetic triggers
• Serotonin syndrome: Serotonergic drugs (SSRIs, MAOIs), agitation, hyperthermia, but:
  • Mental status changes prominent
  • Less muscle rigidity
  • Different mechanism
• Thyroid storm: Hyperthyroid history, but:
  • Gradual onset
  • Tachycardia, but not usually hypercarbia
• Pheochromocytoma: Catecholamine surge, hypertension, but:
  • No muscle rigidity
  • No hyperkalemia
• Environmental heat stroke: Outside OR, no anaesthetic exposure
• Iatrogenic overheating: Warm blankets, fluid warmers, but:
  • Gradual onset
  • No metabolic acidosis or muscle breakdown

Other Causes of Hypercarbia:

• Inadequate ventilation: Check circuit, reconnect, adjust settings
• Rebreathing: Exhausted soda lime, stuck valve
• Malignant hyperthermia: Hypermetabolism despite adequate ventilation

Other Causes of Hyperkalemia:

• Renal failure: Pre-existing, chronic
• Suxamethonium in burns/neuropathy: Denervation, upregulated receptors (not MH)
• Acidosis: K⁺ shifts out of cells
• Rhabdomyolysis from other causes: Trauma, exertion, seizures, ischemia

Clinical Presentation

Preoperative Assessment

Screening:

• Family history: MH, unexpected death during anaesthesia, muscle disease
• Personal history: Previous anaesthetic complications, muscle cramps, heat intolerance, dark urine after exertion
• Muscle disorders: Central core disease (associated with MH), multiminicore disease
• Rhabdomyolysis history: After exercise, viral illness, statins

Physical Examination:

• Muscle mass: Muscle hypertrophy (some MH patients)
• Pectus excavatum: Associated with central core disease
• Kyphoscoliosis: Associated with muscle disease
• General: No specific physical signs of MH susceptibility

When to Suspect MH Susceptibility:

• Family history of MH or anesthesia-related death
• Personal history of masseter spasm with suxamethonium
• History of exercise-induced rhabdomyolysis
• Central core disease or multiminicore disease
• King-Denborough syndrome (ptosis, short stature, cryptorchidism, scoliosis)

Testing:

• Muscle biopsy with caffeine-halothane contracture test (CHCT): Gold standard (North America)
• In vitro contracture test (IVCT): European protocol
• Genetic testing: RYR1 sequencing (sensitivity 25-50% - misses many mutations)
• Registry: MHAUS (Malignant Hyperthermia Association of the United States), ANZMH (Australia NZ)

Anaesthesia for MH-Susceptible Patients

Non-Triggering Anaesthesia:

• Induction: Propofol, thiopental, etomidate, ketamine
• Maintenance: TIVA (propofol + remifentanil/opioid)
• Muscle relaxants: All non-depolarizing relaxants safe (rocuronium, vecuronium, atracurium)
  • Avoid: Suxamethonium
• Reversal: Neostigmine + glycopyrrolate, sugammadex (all safe)
• Local/regional: Spinal, epidural, peripheral blocks (all safe)
• Adjuncts: Nitrous oxide (controversial but likely safe), midazolam, dexmedetomidine

Machine Preparation (If Using MH-Trigger-Free Machine):

• Dedicated MH-safe machine: Clean machine, never exposed to volatiles
• Standard machine preparation:
  • Remove vaporizers (or disable)
  • Flush with 100% O₂ at 10 L/min for 20 minutes (or use activated charcoal filters - Vapor-Clean)
  • New circuit, bag, soda lime
  • Monitors: Standard (capnography essential)

Monitoring:

• Standard: ECG, SpO₂, BP, temperature (core + skin), EtCO₂
• EtCO₂ trend: Early indicator if MH occurs (should not rise unexpectedly)
• Temperature: Continuous (esophageal or nasopharyngeal)

Management

Acute MH Crisis Management

Immediate Actions:

1. Stop Triggers (0-2 minutes):

• Discontinue all volatile anaesthetics immediately
• Turn off vaporizers, disconnect from circuit
• Hyperventilate with 100% O₂ at high flows (flush system)
• Change breathing circuit entirely (new tubing, bag)
• If suxamethonium used: Do not give additional doses
• Total intravenous anaesthesia: Switch to propofol if continuing surgery

2. Call for Help:

• Alert surgeon (may need to abort or finish rapidly)
• Additional anaesthetic staff
• Pharmacy (dantrolene)
• ICU (for postoperative care)
• MH hotline if available (1-800-MH-HYPER in US, local resources)

3. Administer Dantrolene (2-5 minutes):

• Initial dose: 2.5 mg/kg IV bolus
• Preparation:
  • 20 mg vial mixed with 60 mL sterile water (3.3 mg/mL)
  • Dissolve by shaking (can take 3-5 minutes)
  • Use dedicated large-bore IV line (crystallizes if mixed with other drugs)
• Repeat: 2.5 mg/kg boluses until:
  • Tachycardia resolves
  • EtCO₂ decreases
  • Rigidity eases
  • Temperature stabilizes
• Maximum: 10 mg/kg total (may need up to 30 mg/kg in rare cases)

4. Aggressive Cooling (5-10 minutes):

• Surface cooling:
  • Ice packs to axillae, groin, neck
  • Cold wet towels
  • Forced air cooling (if available)
• Internal cooling:
  • Cold IV fluids (iced saline, 15 mL/kg)
  • Gastric/bladder lavage with iced saline
  • Peritoneal lavage (if available)
  • Cardiopulmonary bypass (last resort for extreme cases)
• Stop active warming: Turn off all warmers
• Target: Temperature <38.5°C (avoid overshoot hypothermia)

5. Correct Acid-Base and Electrolytes:

• Arterial blood gas: Assess pH, lactate, K⁺, Ca²⁺, glucose
• Sodium bicarbonate: 1-2 mEq/kg IV (if pH <7.20)
  • Dose: 50-100 mEq slowly
  • Monitor: Na⁺ (hypernatremia risk)
• Hyperkalemia treatment:
  • Calcium chloride 10-20 mg/kg (stabilize myocardium)
  • Glucose 0.5 g/kg + insulin 0.1 units/kg (shift K⁺ into cells)
  • Sodium bicarbonate (as above)
  • Dialysis if refractory
• Hypocalcemia: Calcium chloride if ionized Ca²⁺ low (dantrolene can cause)
• Glucose: Maintain 6-10 mmol/L

6. Treat Arrhythmias:

• Hyperkalemia: Treat as above (primary cause)
• Standard ACLS: Avoid calcium channel blockers (verapamil, diltiazem) if dantrolene given (hyperkalemia/cardiac arrest risk)
• Amiodarone: Preferred antiarrhythmic
• Defibrillation: As indicated

7. Maintain Urine Output:

• Goal: >1-2 mL/kg/hour (prevent myoglobinuric renal failure)
• Mannitol: 0.25-0.5 g/kg IV (osmotic diuretic)
• Fluids: Aggressive crystalloid resuscitation (avoid hypotonic)
• Furosemide: 0.5-1 mg/kg if needed
• Monitor: Urine color (clear myoglobin), creatinine, CK

8. Supportive Care:

• Monitor: Arterial line (continuous BP, frequent ABGs), central line, urinary catheter
• Coagulation: DIC common (monitor INR, fibrinogen, platelets)
• Positioning: If rhabdomyolysis → compartment syndrome risk (fasciotomy if needed)

Postoperative Management

ICU Admission:

• Duration: 24-48 hours minimum (risk of late recrudescence)
• Monitoring: Continuous temperature, EtCO₂, neuro exam, urine output

Continued Dantrolene:

• Dose: 1 mg/kg IV q6h (or 2.5 mg/kg q12h)
• Duration: 24-48 hours (prevents recrudescence)
• Oral transition: 3-4 mg/kg/day in divided doses (when tolerating)

Late Complications to Monitor:

1. Late recrudescence: MH signs return 4-12 hours later (if dantrolene stopped too early)
2. Myoglobinuric renal failure: Monitor creatinine, maintain urine output
3. Compartment syndrome: Check extremities, measure compartment pressures if concern
4. DIC: Coagulopathy may develop 12-24 hours later
5. Cerebral edema: If temperature >41°C, consider mannitol
6. Pulmonary edema: Fluid resuscitation + capillary leak

Laboratory Monitoring:

• CK: Peak at 12-24 hours (may be >100,000 U/L)
• Electrolytes: q4-6h initially (K⁺, Ca²⁺, phosphate)
• ABG: Acidosis resolution
• Coagulation: DIC screen q12h
• Creatinine: Renal function
• LFTs: Hepatic involvement (transaminases may rise)

Follow-Up

Post-Crisis:

• Counseling: Patient and family about MH diagnosis
• Medical alert: Bracelet/card ("Malignant Hyperthermia Susceptible")
• Family screening: First-degree relatives at 50% risk (should be tested)
• Registry: Enroll in national/international registry
• Genetic counseling: Autosomal dominant inheritance

For Unaffected Family Members:

• IVCT/CHCT: Gold standard for diagnosis
• Genetic testing: If proband mutation known (only 25-50% sensitive)
• Anaesthesia: Treat as MH-susceptible until proven otherwise

Anaesthesia for Subsequent Surgeries

Planning:

• Non-triggering technique: TIVA or regional
• Machine preparation: As above (clean machine or flush 20 minutes)
• Dantrolene availability: Must be immediately available (drawer, not pharmacy)
• Monitoring: Standard + temperature + EtCO₂ trend
• Location: Main OR (not remote location) with full resuscitation capability

Dantrolene Prophylaxis:

• Not routine: If proper non-triggering technique used
• Consider: History of severe MH, muscle biopsy positive but no mutation identified
• Dose: 2.5 mg/kg IV 30 minutes pre-induction

Indigenous Health Considerations

Aboriginal and Torres Strait Islander Patients

Genetic Prevalence:

• No data suggesting different prevalence in Indigenous populations
• RYR1 mutations likely distributed equally

Access Issues:

• Remote anaesthesia: MH management challenging in remote settings (limited dantrolene)
• Dantrolene availability: Remote hospitals may not stock dantrolene (expensive, short expiry)
• Transfer: May need transfer to larger center if MH-susceptible patient requires surgery

Cultural Considerations:

• Family history: Extended family important (autosomal dominant - many relatives affected)
• Medical alert: May not be worn consistently (cultural issues with jewelry)
• Education: Ensure understanding of MH and trigger avoidance
• Registry enrollment: Encourage for research and safety

Māori Health Considerations

Genetic Considerations:

• No specific data on MH prevalence in Māori populations
• Genetic testing available if family history

Cultural Safety:

• Whānau involvement: Important for genetic counseling (many relatives may be affected)
• Communication: Clear explanation of inherited nature
• Medical alerts: Ensure patient carries/wears identification
• Follow-up: Coordination with primary care for family screening

ANZCA Final Exam Focus

SAQ Patterns

Common Questions:

• "Describe the clinical features and management of malignant hyperthermia."
• "What is the mechanism of action of dantrolene?"
• "How would you prepare an anaesthetic machine for an MH-susceptible patient?"
• "What are the differential diagnoses of intraoperative hyperthermia?"

Marking Scheme Priorities:

• Early recognition (EtCO₂, tachycardia, masseter spasm)
• Immediate management (stop triggers, dantrolene 2.5 mg/kg, cooling)
• Dantrolene preparation and dosing (20 mg vial + 60 mL water, up to 10 mg/kg)
• Acid-base and electrolyte correction (bicarbonate, calcium, glucose/insulin)
• Postoperative care (ICU, continued dantrolene, monitoring for recrudescence)
• Non-triggering anaesthesia (TIVA, safe drugs)

Viva Scenarios

Scenario 1: Intraoperative MH Crisis

• Child having tonsillectomy
• Sudden tachycardia 180 bpm, EtCO₂ 60 mmHg (from 35)
• Temperature 39.2°C, masseter rigidity
• Immediate management (stop sevoflurane, dantrolene 2.5 mg/kg, cooling)

Scenario 2: Preparation for MH-Susceptible Patient

• Patient with family history of MH
• Non-triggering technique (TIVA)
• Machine preparation (remove vaporizers, flush 20 minutes, new circuit)
• Dantrolene availability

Scenario 3: Postoperative Management

• MH crisis successfully treated
• 6 hours post-op, temperature rising again
• Late recrudescence (continue dantrolene 1 mg/kg q6h)

Key Points for Examination Success

1. Triggers: Volatile anaesthetics (all) + suxamethonium only
2. First sign: Unexpected EtCO₂ rise (hypercarbia) - most sensitive
3. Dantrolene: 2.5 mg/kg IV bolus, repeat to 10 mg/kg total, 20 mg vial mixed with 60 mL water
4. Immediate actions: Stop triggers, hyperventilate with 100% O₂, change circuit
5. Cooling: Ice packs, cold IV fluids, body cavity lavage, target <38.5°C
6. Hyperkalemia: Calcium stabilizes myocardium, glucose/insulin shifts K⁺ into cells
7. Avoid: Calcium channel blockers with dantrolene (cardiac arrest risk)
8. Postoperative: ICU 24-48 hours, dantrolene 1 mg/kg q6h × 24-48 hours, monitor for recrudescence
9. Non-triggering: TIVA (propofol), all non-depolarizing relaxants safe, regional safe
10. Genetics: Autosomal dominant RYR1 mutation, CHCT/IVCT gold standard for diagnosis

References

1. ANZCA. PS48. Statement on Anaesthesia Care of Patients with Malignant Hyperthermia. 2020.
2. Malignant Hyperthermia Association of the United States (MHAUS). Emergency Therapy for MH. Available at: mhaus.org
3. Hopkins PM et al. European Malignant Hyperthermia Group guidelines. Orphanet J Rare Dis. 2015;10:93.
4. Larach MG et al. Epidemiology of MH. Anesthesiology. 2014;121(2):297-304.
5. Girard T et al. Molecular genetic testing for malignant hyperthermia susceptibility. Anesthesiology. 2021;134(5):783-791.
6. Nelson P et al. Dantrolene in malignant hyperthermia. BJA Educ. 2019;19(12):382-388.
7. Riazi S et al. Malignant hyperthermia in Canada. Can J Anaesth. 2014;61(9):819-826.
8. ANZMH. Australian and New Zealand Malignant Hyperthermia Registry. Available at: anzmh.org.au