Malignant hyperthermia (MH) is a pharmacogenetic disorder of the ryanodine receptor (RYR1). It is characterized by triggering of acute skeletal muscle hypermetabolism with increased oxygen consumption, as well as markedly increased production of carbon dioxide.
Triggers include halogenated volatile anesthetics, succinylcholine, and possible heat exposure or sustained strenuous exercise.
Epidemiology
Incidence
In 2009: 1:100,000 anesthetics.
Prevalence
Molecular genetic testing of certain populations suggests a prevalence of 1:3,000.
Morbidity/Mortality
Mortality is ~1%; it is increased when associated with significant medical co-morbidities, advanced age, the development of DIC, and heavier and more muscular builds.
Etiology/Risk Factors
Autosomal dominant pattern: Its heritability demonstrates incomplete penetrance and variable phenotypic expression. Sporadic, de novo mutations, without known positive family histories, are also known to occur.
Children <15 years of age; male:female ratio of 2:1; Caucasian race.
May be associated with congenital musculoskeletal defects such as clubfeet, idiopathic scoliosis, etc.
Physiology/Pathophysiology
During normal skeletal muscle contraction, a propagated action potential reaches the L-type voltage-gated calcium channels (dihydropyridine receptors or DHPRs) along the transverse tubule system. DHPRs allow for intracellular calcium entry and cause a conformational change in coupled intracellular calcium channels (RYR1s).
RYR1s control the release of sequestered calcium from within the sarcoplasmic reticulum (SR) into the cytoplasm of skeletal muscle cells to continue the process of excitation–contraction coupling. This calcium binds to troponin complexes, allowing actin–myosin cross-linking and sarcomeric contraction to occur.
In MH, mutations in genes encoding for RYR1, DHPR, or other unidentified proteins lead to disruption of the regulatory process that governs intracellular calcium movement from the SR and, likely, entry from the extracellular space. This leads to the excessive and unregulated release of calcium during excitation–contraction coupling.
When triggered, MH leads to sustained contractions/inability to relax the skeletal musculature, as the intracellular calcium remains outside of the SR. There is an increase in aerobic and anaerobic metabolism, creating a combined respiratory and metabolic acidosis as CO2 and lactate accumulate. Eventually, muscle tissue becomes hypoxic and rhabdomyolysis develops, leading to myoglobinuria and hyperkalemia as metabolites are released into the circulation.
Prevantative Measures
Patients with proven or suspected susceptibility to MH: Attain previous anesthetic records, thoroughly review family history, and the presence of neuromuscular conditions. Additional laboratory work, cardiodiagnostic evaluation, or radiographic imaging beyond what is required for the work-up of the patient's other underlying medical conditions is not warranted.
Avoidance of triggering agents: Strict avoidance of known triggers (succinylcholine, potent halogenated volatile anesthetics); consider alternative techniques to general anesthesia (conscious sedation, local infiltration, and regional anesthesia) if amenable to the surgical procedure in question.
Anesthesia machine: Remove (or temporarily disable) the vaporizers and all removable parts that may have been previously exposed to halogenated volatile anesthetics (CO2 absorber, etc.). Consider an initial 5 minute flush of the circuit at high flows with the circuit attached during set-up. for the first 5 minutes of patient use, consider a fresh gas flow of 10 L/minute, with the filter attached, followed by an additional 5 minutes of flush at high flows with the circuit attached; for the first 5 minutes of patient use, consider a fresh gas flow of 10 L/min for the first 5 minutes of patient use, with the filter still attached, followed by maintenance of flows at >2 L/min for the duration of the case.
Prophylactic dantrolene: Controversial and probably unnecessary; may lead to clinically significant muscle weakness and, in patients with clinical myopathy, respiratory insufficiency. Scrupulous avoidance of halogenated volatile anesthetics and succinylcholine make an MH episode very unlikely.
Ambulatory setting: Ensure the availability of monitors and equipment necessary for the rapid escalation of care, should an MH crisis occur. The on-site presence of sufficient quantities of dantrolene (at least 10 mg/kg at a minimum adult dose or at least 36 vials of 20 mg doses) should also be confirmed.
Discharge from PACU: Following an uneventful surgery and anesthetic, the patient can be discharged home or to an appropriate hospital unit, after 2–4 hours of close postoperative observation.
Diagnosis⬆⬇
Variable onset and presentation: Can range from a dramatic appearance shortly after induction of anesthesia, to a delayed and smoldering presentation hours into a case, or within the first hour after emergence from general anesthesia.
Early clinical signs and symptoms represent increased metabolic demands. Unanticipated hypercarbia is the most reliable early sign; tachycardia and blood pressure lability (typically hypertension but hypotension can also occur); development of dysrhythmias; and masseter muscle or generalized muscular rigidity.
Later findings: Hyperthermia, sweating, skin mottling, hyperkalemia, myoglobinuria (appearing as cola-colored urine), mixed acidosis, elevated creatine kinase (CK) levels, and DIC. In fulminant cases, progression to malignant ventricular dysrhythmias and cardiac arrest may occur in <30 minutes after onset of an episode.
Masseter spasm: A potentially premonitory sign of an impending episode, and usually occurs after the use of succinylcholine; referred to by the term "jaws of steel." The clinician can either cancel the case and consider referring the patient for workup of MH susceptibility or, alternatively, continue with the procedure using a non-triggering anesthetic technique while preparing to treat an episode of MH if it occurs.
Differential Diagnosis
Acute processes that mimic the non-specific signs and symptoms of an MH crisis. Hypercarbia may be seen with insufficient minute ventilation; CO2 insufflation with laparoscopic surgical techniques; subcutaneous emphysema; anesthesia circuit rebreathing from unacceptably low fresh gas flows, faulty inspiratory valves, or other equipment malfunction; embolic phenomena (increased PaCO2 to ETCO2 gradient); and infusions of Dextrose 25% as part of total parenteral nutrition. Hyperthermia can be seen with scoliosis surgery, iatrogenic heating (warm fluids, heating blankets, etc.), and thyroid storm.
Hyperdynamic hemodynamic perturbations: Insufficient depth of anesthesia, thyroid storm, pheochromocytoma, tyramine crisis in a patient on an MAO inhibitor, neuroleptic malignant syndrome (NMS), serotonin syndrome, cerebral ischemia and/or intracranial hemorrhage, anticholinergic crisis, heat stroke, and recreational drug or other sympathomimetic toxin ingestion (i.e., cocaine, methamphetamines, or Ecstasy). Cardiovascular collapse can also be seen in an MH crisis, so septic shock and anaphylaxis should also be considered.
Muscular dystrophies, such as Duchenne or Becker muscular dystrophy, or some individuals with heat- or exercise-induced rhabdomyolysis, may develop fatal hyperkalemia and rhabdomyolysis after exposure to halogenated volatile anesthetics and succinylcholine.
Treatment⬆⬇
MH is a life-threatening medical emergency, and an immediate call for additional trained help should also be included in the first steps of treating a crisis. The surgeon should be notified of the patient's condition, and the procedure should be terminated or concluded as expeditiously as possible while the patient is being resuscitated.
Discontinue the administration of all known triggering agents, switch to non-triggering anesthetic techniques, fluid resuscitation with cooled intravenous fluids, hyperventilate with 100% oxygen to 2 or 3 times normal minute ventilation, and administer dantrolene.
Dantrolene binds to RYR1 and restores the balance between SR calcium release and uptake as well as calcium entry from the extracellular fluid. Thus, it decreases myofibrillar contraction (skeletal muscle relaxation) and "cools down" the hypermetabolic process. The initial recommended dose is 2.5 mg/kg; improvement in the patient's clinical condition can begin in minutes. If not, additional boluses of 2.5 mg/kg can be administered until signs and symptoms have receded. Defervescence typically trails resolution of hypercarbia. Doses in excess of the manufacturer's recommended total dose of 10 mg/kg may occasionally be required in the treatment of fulminant MH.
Monitors: Intravenous access with wide-bore cannulae should be obtained to aid in fluid resuscitation, drug administration, and frequent laboratory blood draws. Consider an arterial (blood gases) and central venous line, especially if the patient's clinical condition deteriorates. If not already in place, an indwelling urinary catheter is mandatory to evaluate the brisk diuresis that occurs with fluid resuscitation and dantrolene therapy (as each vial contains 3 g of mannitol) as well as the presence of myoglobinuria.
Serial laboratory measurements: Serum electrolytes (especially potassium), renal and hepatic function panels, coagulation tests, arterial and/or venous blood gases, and serum myoglobin and CK levels.
Temperature: Follow closely and if >38.5°C, implement cooling measures: Resuscitate with chilled IV fluids and cool with ice packs, cool and dampened linens, and/or misted water with warm air fanning to promote evaporative heat loss.
Hyperkalemia: IV calcium and insulin with dextrose. Beta2-agonists may be considered after dantrolene is started, though they may aggravate any pre-existing tachyarrhythmia and should be used cautiously. Unstable cardiac rhythms may need to be cardioverted or treated with appropriate antiarrhythmic agents (e.g., amiodarone). Exercise caution in the treatment of wide QRS complex rhythms with lidocaine or procainamide, as this may be a sign of hyperkalemia and treatment with class 1 antiarrhythmics may result in asystole.
pH derangements (combined respiratory and metabolic acidosis): Hyperventilation along with bicarbonate administration (concurrent therapy for hyperkalemia) when pH <7.2. Emergent hemodialysis may be necessary for life-threatening hyperkalemia and/or acidosis.
Postoperative care: Intensive care unit, where supportive measures may need to be continued until the signs and symptoms have abated. Recrudescence can occur up to 24 hours after and requires dantrolene at doses of 1 mg/kg every 4–6 hours or via continuous infusion at 0.25 mg/kg/hr. Recrudescence reflects recurrent hypermetabolism and skeletal muscle injury. Signs can include increased ETCO2, paCO2, rapid spontaneous ventilation, myoglobinuria, rigidity, tachycardia, or hyperthermia.
Hospital discharge. There are no definitive laboratory values or criteria following an attack of MH. Typically, the patients should be asymptomatic and clinically stable, and can proceed towards an uneventful recovery at home within 2–3 days.
Follow-Up⬆⬇
After a suspected case of MH presentation, the patient and family members need to be counseled regarding the potential future implications and ramifications of such a diagnosis. As the physician most familiar with MH and the patient's clinical course, the anesthesiologist of record is the person most capable of beginning this process, and he/she should write a letter for the patient's personal medical records attesting to the events as they have unfolded and how the diagnosis of MH was made.
The Malignant Hyperthermia Association of the United States (MHAUS) is a nonprofit organization that provides information on MH for patients, family members, and health care personnel. It also offers medical assistance for elective and emergent questions and advice.
In vitro contracture testing (IVCT) exposes biopsied muscle to caffeine and halothane and tests for contracture. False-positive results can be as high as 15–20% under the North American Malignant Hyperthermia Registry protocol; 6–7% with the European protocol. False-negative results are believed to be very low. IVCT testing is limited by the cost of maintaining the relatively few centers that can perform this form of complex testing, as well as the invasive nature of the test.
An alternative to IVCT is molecular screening for genetic mutations known to produce susceptibility to MH. Although genes encoding for RYR1 proteins (located on chromosome 19) and DHPR proteins (located on chromosomes 1, 7, and 17) are most commonly implicated, there exists considerable heterogeneity in the genetic loci and linkage sites across known susceptible family lines. It must be emphasized that a negative mutation screen does NOT exclude MH susceptibility. Incomplete penetrance and variable phenotypic expression of MH raise the potential for a multi-genic predisposition towards MH susceptibility, with possible epigenetic influences leading to a relatively common final pathway.
References⬆⬇
AllenGC, LarachMG, KunselmanAR.The sensitivity and specificity of the caffeine-halothane contracture test: A report from the North American Malignant Hyperthermia Registry. Anesthesiology. 1998;88(3):579–588.
BrandomBW.Ambulatory surgery and malignant hyperthermia. Curr Opin Anaesthesiol. 2009: 22(6):744–747.
GlahnKPE, EllisFR, HalsallPJ, et al. Recognizing and managing a malignant hyperthermia crisis: Guidelines from the European Malignant Hyperthermia Group. Br J Anaesth. 2010; 105(4):417–420.
PratherStrazis K, FoxAW.Malignant hyperthermia: A review of published cases. Anesth Analg. 1993;77(2):297–304.
WapplerF.Anesthesia for patients with a history of malignant hyperthermia. Curr Opin Anaesthesiol. 2010;23(3):417–422.
T88.3XXA Malignant hyperthermia due to anesthesia, initial encounter
Clinical Pearls⬆⬇
Diagnosis: Initially normal CK levels do NOT exclude MH. CK levels typically peak 8–12 hours following muscle injury and will slowly decline with successful treatment. If an MH episode has been promptly diagnosed and treated, the rise in CK level may be unimpressive.
Adverse drug reaction: Verapamil and/or diltiazem should NOT be used during treatment with dantrolene; hyperkalemia, myocardial depression, and cardiac arrest may result.
Monitoring: Hyperkalemia may also appear after hypermetabolism has been controlled. The authors recommend checking serum potassium levels 1 and 2 hours after initiating dantrolene therapy, and then every 8 hours for 24 hours, or as clinically indicated by ECG signs or evidence of recrudescence.