Miriam Anixter, MD
DESCRIPTION 
- Malignant hyperthermia (MH) is a condition characterized by elevated calcium concentration in the sarcoplasm after exposure to triggering agents, causing an uncontrolled increase in muscle metabolism.
EPIDEMIOLOGY
- Incidence
- 10.2–13.3 episodes per million hospital discharges (1)
- Prevalence
- The prevalence of the MH-susceptible phenotype has been estimated to be as high as 1:3,000 individuals (2).
RISK FACTORS
- MH is almost exclusively caused by exposure to triggering agents including all potent inhalational anesthetics, such as sevoflurane and desflurane, and the depolarizing neuromuscular blocker succinylcholine. MH-susceptible patients may not have an episode with their first exposure to a triggering anesthetic; 50% of patients may have had 2 or more uneventful general anesthetics. Triggering and severity of an episode may be ameliorated by mild hypothermia (consistent with the comparatively greater incidence in children as mild hypothermia is less common during pediatric anesthesia).
- Stress has clearly been shown to be a trigger in the porcine model of MH, but evidence for this factor is weak in humans. Nonetheless, it has been standard practice to reduce stress in MH-susceptible patients with careful premedication before surgery. There are several case reports of individuals with exercise or heat intolerance who had MH susceptibility demonstrated by halothane–caffeine contracture testing.
- MH episodes are more commonly diagnosed in males (1,2).
Pregnancy Considerations
- MH-susceptible women may carry infants to term. There are anecdotal reports of MH episodes occurring during the stress of delivery in hot weather.
- Epidural analgesia can be given to MH-susceptible patients. Therefore, modern anesthetic techniques can theoretically reduce the risk of MH during delivery.
Genetics
- The genetics of MH are characterized as autosomal dominant with variable penetrance. Between 20% and 70% of MH-susceptible patients have a genetic mutation in the ryanodine receptor. The MH phenotype may be dependent on other proteins that modulate the ryanodine receptor or calcium reuptake (2).
GENERAL PREVENTION
- Patients who have a family history of MH susceptibility, or are themselves MH susceptible, should not be exposed to triggering agents.
- Anesthesia ventilators used on these patients should be flushed according to manufacturer specifications to avoid inadvertent administration of residual potent inhaled anesthetics.
PATHOPHYSIOLOGY
- Increased muscle metabolism during an MH episode increases CO2 production as aerobic metabolism increases in muscle, and lactic acid produced by muscular anaerobic metabolism is neutralized. Metabolic and respiratory acidosis results. In spontaneously breathing patients, tachypnea will be noted; in ventilated patients, increases in end-tidal CO2 occur despite increasing minute ventilation.
- Skeletal muscle rigidity may be caused by uncontrolled stimulation of actin–myosin cross-bridge cycling by increased intracellular Ca2+ and by muscle temperature >43.5°C, which causes irreversible contraction. The rigidity of MH is not affected by neuromuscular blockade.
- Hyperthermia associated with MH is secondary to muscle hypermetabolism and depends on both the ability to dissipate heat produced and the rapidity of definitive treatment.
- Tachycardia and hypertension may be caused directly by hypercarbia, and indirectly by hypercarbic stimulation of catecholamine release. High concentrations of catecholamines, hypercarbia, and cutaneous vasodilatation lead to flushed, diaphoretic skin.
- Local hyperthermia, acidosis, and depletion of adenosine triphosphate (ATP) cause increased membrane permeability and release of potassium by the hypermetabolic muscle. Hyperkalemia leads to arrhythmias, decreased cardiac output, and potential cardiac arrest.
- Muscle hypermetabolism, decreased energy stores, local temperature rise, and decreased perfusion lead to rhabdomyolysis.
- Pulmonary and cerebral edema and disseminated intravascular coagulation (DIC) are associated with severe or untreated MH (2).
ETIOLOGY
- The ryanodine receptor is the calcium-release channel from the sarcoplasmic reticulum (SR). Release of calcium from the SR normally occurs after depolarization via an action potential. Subsequent calcium release into the myoplasm allows actin–myosin cross-bridge cycling (contraction), which is terminated by calcium reuptake into the SR (relaxation). Abnormal stimulation of calcium release by triggering agents causes continuous cross-bridge cycling and consumption of energy stores, both by the contraction apparatus and by sarcoplasmic ATPase (2).
COMMONLY ASSOCIATED CONDITIONS
- Many physicians suspect an increased incidence of MH susceptibility in patients with myopathies. The King–Denborough syndrome is a dysmorphic complex associated with an increased risk of MH. The majority of patients with central core disease are susceptible to MH.
- Duchenne's and Becker muscular dystrophy have been inconsistently associated with MH episodes. These individuals may have acute hyperkalemic arrests and rhabdomyolysis after the administration of succinylcholine secondary to extrajunctional acetylcholine receptors and dystrophin-poor muscle fragility. In addition, dystrophin-poor muscle may have abnormal resting calcium levels, increased calcium release, and impaired calcium-reuptake mechanisms at baseline; the increase of calcium release by inhaled agents may lead to exacerbation of chronic rhabdomyolysis and increased metabolism. The routine use of inhalational anesthetics in these individuals is controversial. If potent inhaled anesthetics are given, careful monitoring of metabolism with end-tidal CO2 and minute ventilation and of muscle injury with serum potassium and urinary myoglobin is prudent.
- The evidence for association of MH susceptibility with other myopathies is limited, but is suspected due to the abnormal calcium regulation in these conditions (2).
[Outline]
HISTORY
- An immediate history of exposure to triggering agents is usually present. Some individuals may have past history remarkable for muscle cramps/weakness, or heat intolerance. Unusual metabolic events not meeting the definition of MH may have occurred during previous anesthetics. A history of an MH episode in a family member may only be elicited after the event (3)[B].
PHYSICAL EXAM
- The first sign may be masseter muscle spasm during succinylcholine administration; this may be severe enough to prevent intubation.
- Approximately 50% of patients with masseter spasm after succinylcholine administration are found to be MH susceptible. When presented with a patient with masseter spasm after succinylcholine administration, consideration should be given to aborting the anesthetic. If the anesthetic is continued with nontriggering drugs, then consideration should be given to what must be done to facilitate early diagnosis and treatment in the event MH develops.
- Other common signs are hypercarbia, rapid increase in temperature, tachycardia, and cola-colored urine (if rhabdomyolysis has occurred) (2,3)[B].
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- Arterial and venous blood gases, serum potassium/other electrolytes, urinalysis, baseline creatine kinase (CK), clotting studies, and creatinine.
- The characteristic metabolic and respiratory acidosis secondary to muscle hypermetabolism, along with signs of muscle breakdown and resolution with dantrolene, favor diagnosis of MH.
- If urine dipstick test is positive for blood, then obtain microscopic analysis for RBCs and quantitative analysis for myoglobin.
- Increased paCO2 will be seen, reflected by increased end-tidal CO2 if this is accurately monitored. A reverse gradient between arterial CO2 and end-tidal CO2 will be present, reflecting muscle hypermetabolism.
- An increased gap between venous pO2 and arterial pO2 will also be present, due to increased oxygen extraction by muscle.
Follow-Up & Special Considerations
- Repeat CK 12–24 hours later and until value returns to baseline. Repeat other abnormal labs at intervals to guide treatment (2)[B].
Diagnostic Procedures/Other
- The halothane–caffeine contracture test is the only approved diagnostic test for susceptibility to MH. It is available in 4 centers in the USA in 2011, and requires 1 g of fresh muscle. Although the test is very sensitive, it lacks specificity. Therefore, the index patient should undergo contracture testing to maximize the predictive value for other family members.
- Testing should be delayed at least 3–6 months after an MH episode.
- Genetic testing may be performed in families with a known mutation associated with MH; ideally, the MH status of the proband is confirmed with contracture testing to improve yield. If a family has a known mutation, screening of other family members can be performed (4)[B].
DIFFERENTIAL DIAGNOSIS
- Sepsis, thyrotoxic crisis, pheochromocytoma, metastatic carcinoid, serotonin syndrome, neuroleptic malignant syndrome, inadequate ventilation, light anesthesia, cocaine intoxication, iatrogenic overheating, central fever, and anaphylactoid reactions
[Outline]
MEDICATION
First Line
- Dantrolene sodium inhibits Ca2+ release from the SR. The dose in the acute period is 2.5 mg/kg IV push, repeated until the signs of MH are reversed (may require up to 10 mg/kg), then 1 mg/kg every 6 hours for 24–36 hours.
- Side effects include muscle weakness, drowsiness, nausea, and phlebitis. Respiratory compromise is uncommon without preexisting or concurrent causes of muscle weakness.
- Precautions
- Dantrolene is an antiarrhythmic, increasing atrial and ventricular refractory periods and increasing action potential duration. Administration of dantrolene in the presence of calcium channel blockers may cause hyperkalemia and profound depression of cardiac contractility, but administration for a suspected MH episode should not be held for this reason.
ADDITIONAL TREATMENT
General Measures
- The definitive treatment of a known or suspected MH episode is administration of dantrolene as soon as possible and immediate discontinuation of triggering agents. Ventilation with high-flow O2 through the anesthesia ventilator should be sufficient, as the concentration of inhalational agent in this ventilator will be less than that in the patient.
- Symptomatic Treatment
- Standard treatment of hyperkalemic dysrhythmias should be initiated. Hyperventilation to approach normocarbia, and bicarbonate or tris(hydroxymethyl)-aminomethane (THAM) administration for initial treatment of the metabolic and respiratory acidosis should be titrated. Hyperthermia should be treated with surface cooling, gastric and intraperitoneal lavage, ice packs in the axillae and groin, and intravascular administration of cold solution. Treatment should be continued until the core temperature is <38.5.
- Aggressive hydration to prevent myoglobin-induced renal failure should be started and monitored by urine output and central venous pressure (CVP).
- If urine pH is low, consider alkalinization (2,5)[B].
SURGERY/OTHER PROCEDURES
When an episode occurs during surgery, the procedure should be terminated as soon as possible.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
- Patients transferred should be treated based on the above guidelines.
Admission Criteria
- Patients should be closely monitored until all vital signs and laboratory parameters have been normal for 24 hours. Speed of recovery is dependent on severity of the episode, rapidity of treatment, and development of other sequelae.
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FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- CK measurements are recommended 6, 12, and 24 hours after the initial episode; CK often peaks 24–36 hours after treatment of MH. CK values >20,000 are almost always associated with an MH episode or other severe myopathy (2)[B].
PATIENT EDUCATION
- Patients who have an MH episode should be counseled regarding the seriousness and heritability of their condition and should wear a “Med-alert” bracelet to inform other health-care professionals. First-degree relatives should be considered susceptible (2)[B].
PROGNOSIS
- Administration of dantrolene and cessation of triggering agents halts the syndrome. Hyperkalemia, associated arrhythmias, and respiratory/metabolic acidosis typically resolve. If rhabdomyolysis was extensive, there may be muscle pain and weakness for weeks to months after resolution of acute MH (2)[B].
[Outline]
ICD9
995.86 Malignant hyperthermia