Malignant Hyperthermia

Basics

Definition:

• A hypermetabolic crisis that occurs when susceptible patients are exposed to a triggering anesthetic agent (halogenated anesthetics or succinylcholine)
  • Underlying defect is abnormally increased Ca2+ levels in skeletal muscle resulting in sustained muscle contraction
• Calcium pump attempts clearance → increased ATP usage
• Results of hypermetabolic rate
  • Increased O2 consumption, CO2 production, severe lactic acidosis, hyperthermia, risk of rhabdomyolysis, hyperkalemia, and arrhythmia

Genetics:

• Genetic hypermetabolic muscle disease
• 80% of cases: RYR-1 receptor mutation (affects calcium release channel in sarcoplasmic reticulum)
  • Autosomal dominant inheritance with variable penetrance and expression, but autosomal recessive forms also described (especially that associated with King-Denborough syndrome)
• At least 6 chromosomal loci identified, but >80 genetic defects associated with MH

Incidence:

• Rare, see in 1:15,000 pediatric vs. 1: 40,000 adult patients
• Most common in young males
  • Almost no cases in infants; few in adults >50 years old
• The upper Midwest has highest incidence in US (geographic variation of gene prevalence)
• MH may occur on a patient’s 2nd exposure to triggers
  • nearly 50% of MH episodes had at least one prior uneventful exposure to an anesthetic
• Risk factors include personal/family history of MH, pediatric age, comorbid myopathies (Central Core disease and King Denborough Syndrome), caffeine intolerance, history of unexplained fevers/cramps/weakness, h/o exercise induced rhabdomyolysis, trismus on induction (precedes 15-30% of MH)

Sequence of Events

1. Triggers
   • All halogenated inhalational agents (not N2O)
   • Succinylcholine
2. Increased Cytoplasmic Free Ca2+
   • Masseter muscle rigidity (trismus)*; more common if succinylcholine used
     • If there is rigidity of other muscles in addition to trismus, the association with MH is absolute
   • Total body rigidity
3. Hypermetabolism
   • Increased CO2 production (most sensitive and specific sign of MH!) and metabolic acidosis
     • Note sympathetic surge of increased HR and BP
   • Increased O2 consumption (decreased ScvO2)
     • Body will compensate with tachypnea
   • Increased heat production
     • A late sign of MH; temperature can rise 1-2˚C every 5 minutes
   • Increased utilization of ATP to clear calcium: metabolic acidosis
4. Cell Damage & Rhabdomyolysis
   • Leakage of K+ , myoglobin, CK (may see dark-colored urine)
5. Secondary systemic manifestations
   • Rhabdomyolysis→
     • Acute renal failure
     • Hyperkalemia/Arrhythmias
     • DIC / Hemorrhage / Compartment syndrome
   • Metabolic exhaustion: increased cellular permeability→
     • Whole body edema & Cerebral Edema
   • Death (due to DIC and organ failure); previously 70% mortality, now 5% with dantrolene

Notable Features

• Not all patients with trismus will go on to have MH, and not all MH cases will be heralded by trismus
• Earliest recognized signs of MH= muscle rigidity, tachycardia, and hypercarbia
• The signs & symptoms of MH are seen often in the OR and are non-specific***
• Clinically, you may first see trismus, but often hypercarbia will be your first sign
  • Without another reasonable explanation for this (hypoventilation, pneumoperitoneum), you should start looking for other signs.
  • Any increased oxygen consumption? (decreased SpO2 or ScvO2?)
  • Increased metabolic & sympathetic activity? (increased etCO2 , HR, temperature, lactate)
  • Signs of rhabdo or any electrolyte abnormalities? (Hyperkalemia/arrhythmias, CKMB, urine myoglobin/blood tinged urine)

Differential Diagnosis

Condition	Differences
Neuroleptic Malignant Syndrome (NMS)	More common in patients receiving antidopaminergic agents or in withdrawal from dopamine agents as in Parkinson’s, usually develops over days rather than minutes to hours
Thyroid Storm	Usually associated with hypokalemia
Sepsis	fever, tachypnea, tachycardia, metabolic acidosis
Pheochromocytoma	increased HR, increased BP, but normal EtCO2 and Temp
Drug-induced	e.g. ecstasy, cocaine, amphetamines, PCP, LSD
Serotonin syndrome	associated drugs interactions MAOIs + merperidine or MAOIs+ SSRIs
Iatrogenic hyperthermia
Hypercarbia from CO2 insufflation for laparoscopy	see increased EtCO2 with tachycardia

Treatment

Acute phase

Immediate Actions	Call for Help & obtain MH cart inform team and start preparing dantrolene or ryanodex D/C volatile agents and succinylcholine (no need to change machine or circuit) Switch to 100% O2 with high flows >10L/min; increase minute ventilation Halt surgery vs. finish ASAP with TIVA; arrange for ICU bed Call MH hotline (1-800-MH-HYPER) Labs: ABG, lactate, K+/electrolytes, CK, Coags; place foley to monitor UOP
Dantrolene	(interferes with RYR-1 Ca2+ channel) 2.5 mg/kg IV push q5min; patient may need >10mg/kg; continue giving until stable. Give through large bore IV or central line (risk of phlebitis); assign several people to prepare this 1 vial = 20mg Dantrolene (dissolve in 60 cc sterile water); solution has mannitol **New Ryanodex (250mg vial in 5cc sterile water) Continue until stable (decrease in EtCO2, rigidity, and tachycardia); continue dantrolene infusion 0.25mg/kg/hr for at least 24 hrs
Treat Acidosis	Hyperventilate patient • Sodium Bicarbonate 1-2 mEq/kg
Treat hyperkalemia & ARF	CaCl2 (10mg/kg) or Calcium gluconate (30mg/kg); Bicarbonate, hyperventilate Insulin and glucose (10 units in 50cc D50 Sodium bicarbonate (1-2 mEq/kg) Diuresis; urine output goal > 1-2cc/kg/hr to help prevent pigment induced nephropathy/ARF and reduce hyperkalemia; consider IV fluids, diuretics, and alkalinize urine
Treat dysrhythmias	Avoid CCBs (may promote hyperkalemia and depress cardiac output) Treat hyperkalemia and acidosis; if refractory, may need to add an antiarrhythmic
Treat temp	Cool if temp >39 degrees C (cooling blankets, ice, cold NS, lavage stomach/bladder/rectum)
Labs	ABG, lactate, K+/electrolytes, CK, urine myoglobin, Coagulation studies

Post-Acute phase

Admit to ICU	ICU admission for at least 24 hrs (recrudescence rate 25%)
Continue monitoring	Labs: serial ABG, lactate, Electrolytes (K+ , Ca2+), CK/serum myoglobin, Urine myoglobin, Coags EtCO2, temp, urine output/color *Watch for DIC and renal failure*
Counsel patient and family	Future precautions Refer to MHAUS Refer patient and family to nearest Biopsy Center for follow-up

Susceptibility

Who is Susceptible

• Autosomal dominant inheritance pattern
  • All closely related family members considered susceptible in absence of testing (even if they had prior uneventful anesthetics)
• Several rare musculoskeletal disorders linked to MH
  • Central Core Disease
  • King Denborough Syndrome
  • Multiminicore myopathy
• Other disorders:
  • Muscular dystrophy and other neuromuscular diseases, upon exposure to triggering agents, have weak associations with MH-like events
    • Avoid succinylcholine as can cause rhabdomyolysis; controversial whether to avoid volatile anesthetics
    • Experts believe brief exposure is a small risk (i.e. inhalational induction in pediatric patients)
  • History of exertional heat stroke or exercise-induced rhabdomyolysis - some suggestion that these people may harbor genetic changes found in MH-susceptible individuals

Susceptibility Testing

• Caffeine-Halothane Contracture Test (CHCT)
  • Takes fresh muscle biopsy and exposes to triggers
  • Gold Standard; used to rule-out MH
    • High Sensitivity >97%
    • Specificity 80-93%
    • 10-20% false positive rate but zero false negative rate
  • Available at 9 U.S. testing centers
• Molecular Genetics
  • RYR1 mutation screening
  • Low sensitivity, but high specificity (rule-in criteria)
    • Only screens for 20% of recognized mutations
  • Typically reserved for patients with a positive CHCT, relatives of known MH susceptibility, or patients with highly suspicious MH episode

Prevention in susceptible patients

1. Machine
   • Change circuit and CO2 absorbent
   • Remove or disable vaporizers
   • Refer to anesthetic machine regarding time required to flush machine (FGF of 10 L/min for ≥20 minutes)
     • During case, keep flows > 10L/min to avoid “rebound phenomenon” (release of dissolved residual volatile anesthetic agent)
2. Monitors
   • Standard ASA monitors, especially temperature and ETCO2
3. Anesthetic
   • Avoid succinylcholine and volatiles
   • All other non-triggering agents are okay (including N2O)
4. Emergency
   • Know where to find the MH cart
   • Have dantrolene or rhyanodex available

ITE tips:

Which of the following findings is NOT consistent with a diagnosis of malignant hyperthermia?

• a. PaCO2 150 mm Hg
• b. MVO2 50 mm Hg
• c. pH 6.9
• d. Onset of symptoms an hour after end of operation

Answer: b. MH reflects a hypermetabolic state. Clinical signs include tachycardia, tachypnea, arterial hypoxemia, hypercarbia, metabolic acidosis, hyperkalemia, hypotension, muscle rigidity, trismus after succinylcholine administration, and increased temperature. Mixed venous oxygen tension would be very low (normal MVO2 is 30-35, so an elevated MVO2 of 50 would not be consistent with MH, and answer b is incorrect).