Malignant Hyperthermia

Key Mechanism 1: Genetic Defects in Calcium Regulation

• Approximately 70% of MH cases result from mutations in the ryanodine receptor gene (RYR1) located on chromosome 19q13.1, which encodes the calcium release channel in the sarcoplasmic reticulum
• Approximately 15% of cases involve mutations in the CACNA1S gene (chromosome 1q32), encoding the L-type voltage sensor in the dihydropyridine receptor
• These mutations predispose to abnormal calcium ion (Ca²⁺) efflux from the sarcoplasmic reticulum in response to triggering agents
• Triggering agents bind to the ryanodine receptor-calcium channel complex, causing pathological opening and sustained Ca²⁺ release into the cytoplasm

Key Mechanism 2: Uncontrolled Muscle Contraction and Hypermetabolism

• Elevated cytoplasmic Ca²⁺ activates myosin-actin interactions, leading to sustained, uncontrolled muscle contraction (tetanic state) independent of normal neuromuscular transmission
• Continuous ATP hydrolysis during muscle contraction depletes cellular ATP stores and dramatically increases metabolic rate (up to 10-fold)
• Anaerobic metabolism increases due to accelerated ATP consumption and inadequate oxygen delivery, producing excess lactate and hydrogen ions
• This hypermetabolic state generates tremendous heat production, overwhelming normal thermoregulatory mechanisms
• Muscle membrane integrity is compromised by sustained contraction and cellular hypoxia, leading to rhabdomyolysis

Key Mechanism 3: Secondary Cascades and Organ Injury

• Massive potassium (K⁺) release from damaged muscle cells into plasma causes life-threatening hyperkalemia, which triggers cardiac arrhythmias
• Myoglobin leakage from necrotic muscle cells causes myoglobinuria, leading to acute tubular necrosis and acute kidney injury
• Intracellular calcium dysregulation triggers apoptotic and necrotic muscle cell death
• Tissue hypoxia, acidosis, and cellular breakdown activate coagulation cascades, resulting in consumptive DIC
• Sympathetic hyperactivity occurs secondary to hyperthermia and cellular stress, further elevating catecholamine levels

Major Cause 1: Genetic Susceptibility

• Autosomal dominant inheritance from RYR1 or CACNA1S mutations with incomplete penetrance (not all mutation carriers will develop MH)
• Family history is the most significant risk factor; approximately 50% of first-degree relatives of affected individuals carry the mutation
• No clear phenotypic markers exist to predict which mutation carriers will manifest the condition
• Genetic anticipation does not occur; expressivity varies even within families

Major Cause 2: Triggering Agents

• Volatile anesthetics: Sevoflurane, isoflurane, halothane, enflurane, and desflurane all reliably trigger MH in susceptible individuals
• Depolarizing neuromuscular blocker: Succinylcholine is the most notorious trigger; acts within seconds to minutes
• Non-triggering alternatives include propofol, thiopental, etomidate (induction agents); nitrous oxide (non-volatile gas); non-depolarizing neuromuscular blockers (rocuronium, vecuronium); and local anesthetics (amide and ester types are safe)

Associated Risk Factors

• Central core disease and other congenital myopathies (share RYR1 mutations)
• Elevated baseline creatine kinase (CK) levels
• Family history of unexpected perioperative deaths or muscle disorders
• History of exertional heat stroke or unexplained perioperative complications

Cardinal Symptoms (Intraoperative)

• Masseter muscle rigidity (jaw clenching) immediately after succinylcholine administration; considered an early warning sign (though not universally present)
• Uncontrolled muscle rigidity affecting all skeletal muscles, making ventilation difficult and limiting surgical field visualization
• Tachycardia (often the earliest objective sign), progressing to arrhythmias; may occur before temperature elevation
• Rapid rise in end-tidal CO₂ (ETCO₂) in mechanically ventilated patients; can increase 2-fold within minutes (highly sensitive and specific sign)
• Profuse muscle fasciculations followed by sustained tetanic contraction

Progressive Systemic Manifestations

• Hyperthermia (late sign): Core body temperature rises uncontrollably, often reaching 40-43°C or higher, but may lag 30+ minutes behind biochemical changes
• Myoglobinuria: Tea or cola-colored urine reflecting massive myoglobin excretion; appears post-operatively
• Cyanosis and mottled skin from hypoxemia and peripheral vasoconstriction
• Profuse diaphoresis and skin flushing from sympathetic activation

Physical Examination Findings

• Board-hard muscle consistency on palpation due to sustained contraction
• Trismus (masseter rigidity); may prevent intubation
• Ventricular fibrillation or malignant arrhythmias on cardiac monitor (triggered by hyperkalemia)
• Rhabdomyolysis signs: Swollen, discolored muscles; compartment syndrome (elevated compartment pressures)

In-the-OR Recognition (Clinical Diagnosis)

• High suspicion triggers: Masseter rigidity after succinylcholine + elevated ETCO₂ + tachycardia = presumptive MH
• No single diagnostic test confirms MH intraoperatively; contracture tests require muscle biopsy (see below)
• Immediate cessation of volatile anesthetic and succinylcholine, switch to non-triggering agents
• Laboratory findings support the diagnosis but do not replace clinical judgment

Intraoperative Laboratory Abnormalities

• Serum potassium: Elevation from normal (3.5-5.0 mEq/L) to >6 mEq/L, often reaching 8-12 mEq/L in severe cases; can cause sudden cardiac arrest
• Serum CK: Peak levels of 10,000-100,000+ IU/L (normal <200 IU/L) detected post-operatively due to massive muscle necrosis
• Myoglobin (serum and urine): Marked elevation reflecting rhabdomyolysis
• Arterial blood gas: Metabolic acidosis with elevated lactate (pH <7.2), respiratory acidosis if ventilation becomes inadequate due to muscle rigidity
• Coagulation profile: PT/PTT prolongation, decreased platelets, decreased fibrinogen, and elevated D-dimer (consumptive DIC)
• Renal function: Elevated creatinine and BUN developing over 24-72 hours post-crisis

Post-Operative Confirmatory Testing

• Caffeine Halothane Contracture Test (CHCT): Gold standard for MH diagnosis; fresh muscle biopsy exposed to caffeine and halothane ex vivo measures contracture responses. Positive if caffeine-induced contracture >0.3g or halothane-induced contracture >0.3g in absence of caffeine. Sensitivity ~95%, specificity 78%; performed in specialized centers (requires alive tissue and expertise). Takes days to weeks.

• Calcium Induced Contracture Test (CICT): Alternative muscle biopsy contracture test using calcium instead of halothane; similar sensitivity/specificity

• Genetic Testing: DNA sequencing identifies RYR1 or CACNA1S mutations (increasingly available); establishes definitive diagnosis; does NOT distinguish between MH-susceptible (MHS) and MH-equivocal (MHEh) phenotypes; useful for family counseling but should NOT delay treatment intraoperatively

• Diagnostic Criteria for MH-Susceptible (MHS) Status:
• Positive muscle biopsy contracture test (CHCT or CICT), OR
• Identified pathogenic RYR1/CACNA1S mutation in known MH kindred, OR
• Two or more first- or second-degree relatives with MH or unexplained perioperative deaths

Emergency Management (In-the-OR)

First-Line Agent: Dantrolene Sodium

• Mechanism: Directly blocks calcium release from the sarcoplasmic reticulum by inhibiting the ryanodine receptor; the only agent that directly addresses the pathophysiology
• Dosing: Initial dose 2.5 mg/kg IV bolus; repeat every 5 minutes (up to maximum 10 mg/kg cumulative dose) until:
• Muscle rigidity decreases
• ETCO₂ normalizes
• Vital signs stabilize
• Contractures resolve
• Administration: Dantrolene is supplied as powder requiring reconstitution in sterile water without bacteriostatic agents (3 mg powder per vial; each vial requires ~60 mL sterile water for adequate dissolution); requires assistance from multiple personnel to prepare multiple vials rapidly
• Onset: 5-10 minutes; effects peak at 15-30 minutes
• Duration: 4-6 hours; must continue dosing every 4-6 hours for 24-48 hours post-crisis to prevent recrudescence
• Monitoring post-administration: Reassess muscle rigidity, ETCO₂, temperature, and hemodynamics every 2-5 minutes; repeat dosing if signs persist

Concurrent Management Measures (Do Not Delay Dantrolene)

• Immediate anesthetic cessation: Discontinue ALL volatile anesthetics and succinylcholine; switch to propofol, etomidate, or thiopental for induction if re-induction needed
• Hyperventilate aggressively: Increase minute ventilation to 2-3 times normal to eliminate CO₂ (blown off by hypermetabolism) and improve oxygenation; use 100% oxygen
• Active cooling measures:
• Apply ice packs to groin, axillae, neck (major vascular areas)
• Irrigate body cavities (peritoneal, bladder, stomach) with ice-cold saline if temperature >39°C
• Use cooling blankets or intravascular cooling catheters
• Goal: Core temperature <38.5°C (prevent overshoot hypothermia)
• Treat hyperkalemia urgently (life-threatening):
• Calcium gluconate 10%: 10-20 mL IV over 2-5 minutes (cardiac membrane stabilizer; prevents arrhythmias)
• Regular insulin 1 unit/kg + dextrose 0.5 g/kg IV to shift K⁺ intracellularly
• Sodium bicarbonate 1-2 mEq/kg IV to alkalinize and shift K⁺ intracellularly
• Beta-2 agonists (albuterol nebulized or IV salbutamol) to promote K⁺ uptake
• Avoid succinylcholine (will worsen hyperkalemia)
• Kayexalate and dialysis reserved for persistent or severe hyperkalemia
• Fluid resuscitation and urine output: Establish large-bore IV access (two lines minimum); aggressive isotonic crystalloid administration (targets urine output 200-300 mL/hour) to prevent acute tubular necrosis from myoglobinuria
• Urine alkalinization: Sodium bicarbonate in IV fluids to maintain urine pH >6.5 (myoglobin precipitates in acidic urine, promoting kidney damage)
• Laboratory monitoring: Obtain baseline electrolytes (especially K⁺), CK, myoglobin, arterial blood gas, coagulation panel, and urinalysis immediately
• Cardiac monitoring: Continuous ECG; treat arrhythmias per ACLS; hyperkalemia can cause peaked T-waves, prolonged PR interval, widened QRS, and peaked T-waves

Post-Operative Management (ICU Admission)

• Continue dantrolene: 1 mg/kg IV every 4-6 hours for minimum 24 hours; some experts extend to 48 hours to prevent recrudescence (relapse of crisis)
• Continue aggressive fluid resuscitation: Monitor urine output, electrolytes, BUN/creatinine; expect acute kidney injury in severe cases despite aggressive management
• Maintain urine alkalinization: Sodium bicarbonate to keep urine pH >6.5 until myoglobinuria clears and urine is cola-colored
• Serial potassium monitoring: Check every 30-60 minutes for 4-6 hours, then every 2-4 hours; treat persistent hyperkalemia aggressively
• CK monitoring: Peak at 24-48 hours post-crisis; may reach 100,000+ IU/L in severe cases; normalizes over 5-7 days
• DIC management: Transfuse fresh frozen plasma, cryoprecipitate, and platelets as needed based on PT/PTT/fibrinogen/platelet counts
• Rhabdomyolysis complications: Monitor for compartment syndrome (surgical fasciotomy if compartment pressures elevated despite conservative measures)
• Avoid future triggers: Document in medical record, alert patient and family; MedAlert bracelet recommended

Non-Pharmacological Measures

• Discontinue triggering agents immediately
• Continue mechanical ventilation if muscle rigidity prevents adequate ventilation
• Prepare for difficult airway management if masseter rigidity present

Immediate (During Crisis)

• Cardiac arrhythmias and cardiac arrest: Triggered by severe hyperkalemia; may progress to ventricular fibrillation; hyperkalemia causes peaked T-waves, prolonged PR, widened QRS; responsive to calcium, insulin/dextrose, and sodium bicarbonate
• Pulmonary edema and ARDS: Secondary to sympathetic surge, massive fluid resuscitation, and capillary leak from rhabdomyolysis; may require mechanical ventilation and PEEP

Delayed (24-72 Hours Post-Crisis)

• Acute kidney injury (AKI): Occurs in 25-50% of MH cases despite treatment; caused by myoglobinuria, hyperkalemia-induced tubular necrosis, and volume depletion; may require dialysis; usually resolves within 5-7 days with aggressive fluid management and urine alkalinization
• Disseminated intravascular coagulation (DIC): Results from tissue damage, hypoxia, and acidosis; manifests as thrombocytopenia, PT/PTT prolongation, fibrinogen consumption, and spontaneous bleeding; requires transfusion support and treatment of underlying condition
• Compartment syndrome: Sustained muscle contraction and rhabdomyolysis lead to increased compartment pressures; may require emergency fasciotomy to prevent limb loss; watch for pain out of proportion, paresthesias, pallor, and pulselessness
• Chronic kidney disease: Some patients develop permanent renal impairment after severe AKI
• Malignant hyperthermia recrudescence: Rare (0.25% of cases); recurrence of signs (muscle rigidity, hyperthermia, ETCO₂ elevation) within 24-48 hours post-operatively despite initial successful dantrol

• Earliest sign is not fever: an unexplained rise in end-tidal CO₂ refractory to increased minute ventilation, plus unexplained tachycardia, precedes hyperthermia — which is a late finding. A stem describing "temperature 40°C" is describing a late crisis, not the first clue.
• Single best next step: stop the volatile agent and succinylcholine, switch to a non-triggering technique (propofol/opioid, non-depolarizing blocker), hyperventilate with 100% oxygen, and give dantrolene IV immediately. The Malignant Hyperthermia Association of the United States (MHAUS) protocol also directs calling the MH hotline and activating an MH cart. Dantrolene is not withheld pending labs or confirmatory testing.
• The association examiners test: autosomal dominant RYR1 mutations, and the link to central core disease (and other RYR1 congenital myopathies). A child with a congenital myopathy and elevated baseline CK who needs anesthesia is the classic setup.
• Trismus/masseter rigidity after succinylcholine in a child is the buzzword prompting evaluation for MH susceptibility; board-hard rigidity that persists after a non-depolarizing blocker is given argues strongly for MH rather than inadequate relaxation.
• Hyperkalemia kills first: rhabdomyolysis-driven K⁺ release causes peaked T waves, wide QRS, and arrest. Calcium (membrane stabilization), insulin with dextrose, and bicarbonate come alongside — never instead of — dantrolene.
• Common distractor — the other hyperthermias: neuroleptic malignant syndrome follows dopamine antagonists over days with "lead-pipe" rigidity and elevated CK; serotonin syndrome features clonus and hyperreflexia; both differ from MH's anesthetic trigger and minutes-long onset. Antipyretics are useless in MH because heat is metabolic, not hypothalamic.
• Avoid calcium channel blockers with dantrolene (verapamil in particular) — the combination can precipitate hyperkalemia and cardiovascular collapse; treat arrhythmias per ACLS with other agents.
• Prior uneventful general anesthesia does not exclude MH, a frequent trap: penetrance is incomplete and susceptible patients may tolerate several exposures before a crisis.