Malignant Hyperthermia

Etiology

Genetically susceptible individuals can have a malignant hyperthermia reaction in response to triggering agents such as halogenated anesthetic agents or succinylcholine and, more rarely, to stressors such as vigorous exercise and heat exposure, sometimes referred to as "awake malignant hyperthermia," as no anesthetic agents are involved.[3] Nitrous oxide and xenon, although they are inhaled anesthetics, are not halogenated and have not been implicated in malignant hyperthermia.[4]

Epidemiology

The exact incidence of malignant hyperthermia is unknown. Study results demonstrate that malignant hyperthermia occurs in about 1 in 100,000 adults and 1 in 30,000 children. Registry analyses from North America document ongoing cases with cardiac arrest and death despite modern practice.[5] 

The incidence of malignant hyperthermia varies based on geographic region. In the United States, clusters of families susceptible to malignant hyperthermia are found in Wisconsin and the upper Midwest. The mortality rate is 3% to 5%, even with proper treatment. Malignant hyperthermia susceptibility is also associated with other disorders, including central core disease (a rare, nonprogressive myopathy characterized by hypotonia and weakness of proximal muscles) and King-Denborough syndrome (a rare myotonia associated with multiple distinct physical features).[6]

Early researchers described rare episodes of stress-induced "awake malignant hyperthermia." Later, Tobin described one of the most convincing cases of fatal, exercise-induced malignant hyperthermia in a 13-year-old boy in whom the causative RYR1 mutation was present and was later found to be present in his family members.[7] Malignant hyperthermia susceptibility has also been described in other species, particularly in swine, where much of the early research into the disease and its treatment originated.[8]

Pathophysiology

Malignant hyperthermia is an autosomal dominant genetic disorder characterized by skeletal muscle hypermetabolism following exposure to halogenated anesthetics, depolarizing muscle relaxants such as succinylcholine, or, occasionally, physiologic stressors. The gene encoding the ryanodine receptor RYR1 is the primary site of mutations linked to malignant hyperthermia. Other genetic loci, such as CACNA1S and STAC3, have been identified as causative of malignant hyperthermia.[3][9][10]

The uncontrolled release of calcium from the skeletal muscle sarcoplasmic reticulum leads to sustained muscle contraction. This sustained contraction depletes adenosine triphosphate (ATP) and dramatically increases oxygen consumption, carbon dioxide production, and heat production. The depletion of ATP leads to loss of membrane integrity and leakage of intracellular contents, including potassium, creatine kinase, and myoglobin, into the circulation.[11][12] Study results have shown the potential of a RyR1-selective inhibitor with superior solubility and rapid clearance to prevent and reverse malignant hyperthermia and heatstroke crises in multiple mouse models. Such research highlights the genetic mechanism of malignant hyperthermia and suggests the potential for additional clinical management options beyond dantrolene.[13]

History and Physical

Signs and symptoms of malignant hyperthermia include tachycardia, tachypnea, hypoxemia, hypercarbia, metabolic and respiratory acidosis, hyperkalemia, cardiac dysrhythmias, hypotension, skeletal muscle rigidity, and hyperthermia. The earliest signs of malignant hyperthermia are usually hypercarbia and tachycardia, resulting from increased carbon dioxide production. Malignant hyperthermia can occur at any time during the intraoperative and postoperative periods. Fulminant malignant hyperthermia reactions may present with only a few of the typical clinical signs, and a high index of suspicion for malignant hyperthermia is required to ensure a timely and accurate diagnosis and treatment.[14]

Susceptible patients can also exhibit masseter muscle spasm. If signs of hypermetabolism, such as metabolic and respiratory acidosis or an elevation in body temperature, accompany the muscle spasms, a diagnosis of malignant hyperthermia must be considered.[15] Use of a malignant hyperthermia clinical grading scale to support diagnosis during a crisis can also be useful. Priority is given to treatment over diagnosis to avoid the risk of a missed diagnosis.[16]

Evaluation

The gold standard for the laboratory diagnosis of malignant hyperthermia is the caffeine-halothane contracture test (CHCT), although genetic testing is rapidly advancing and may one day replace muscle biopsy. The CHCT involves exposing a sample of live muscle fibers to halothane and caffeine to determine the muscle response to halogenated anesthetics. Genetic testing for mutations in the RYR1 gene and other associated variants is becoming increasingly valuable as testing improves. Testing can be expensive and is only available in certain centers. Therefore, when presented with a patient for urgent or emergent surgery who has a history suggestive of a close relative who has had a malignant hyperthermia episode, anesthesiologists will usually provide a "nontriggering anesthetic," which is typically a variety of combinations of intravenous anesthetic agents.[3][17][18][19]

Treatment / Management

The critical element in the treatment of malignant hyperthermia is early administration of dantrolene. Once a malignant hyperthermia episode is suspected, all triggering agents must be discontinued, the patient should be hyperventilated with 100% oxygen, and non-triggering anesthetic agents should be utilized to end the surgery as soon as possible. Dantrolene at 2.5 mg/kg must be administered intravenously immediately, up to a maximum of 10 mg/kg, until the reaction subsides. In addition to administering dantrolene, attention must be paid to preserving renal function and correcting hyperthermia, acidosis, hypoxemia, and arrhythmias. Arrhythmias can be treated with antiarrhythmics, and renal function can be protected by maintaining a urine flow of at least 2 mL/kg/hr with furosemide to prevent acute tubular necrosis, a complication that can develop from precipitation of myoglobin released from skeletal muscle.[20]

Management includes the following key interventions:

• Discontinue the triggering agent.
• Call for additional assistance.
• Administer dantrolene 2.5 mg/kg until the reaction subsides, up to a maximum of 10 mg/kg.
• Increase ventilation to reduce end-tidal carbon dioxide.
• Initiate active cooling measures (cold intravenous fluids and ice packs to exposed surfaces).
• Treat arrhythmias (eg, amiodarone; avoid calcium channel blockers).
• Obtain laboratory studies including arterial blood gas analysis, electrolytes (with attention to potassium), serum and urine myoglobin, and a coagulation profile.
• Continue dantrolene at 1 mg/kg every 4 hours for 24 to 48 hours.
• Maintain urine output of 2 mL/kg/hr; note that each 20 mg vial of dantrolene sodium contains approximately 3 grams of mannitol, which may contribute to osmotic diuresis. 

After initial stabilization, patients should be admitted to the intensive care unit for at least 24 hours to monitor for recrudescence (the return of symptoms following an initial abatement). Patients at the highest risk for recrudescence are those with greater muscle mass or prolonged anesthetic exposure (at least 150 minutes) before symptom onset.[21] Continued dantrolene therapy is recommended during this period. Improved outcomes depend on early recognition, prompt administration of dantrolene, and rapid initiation of active cooling to limit the rise in core temperature.[3][5](B2)

Prophylactic dantrolene is not recommended for malignant hyperthermia–susceptible patients.[22] Instead, prevention relies on the use of non-triggering anesthetics (avoiding halogenated volatile anesthetics and succinylcholine). The team should also prepare a halogenated volatile anesthetic-free anesthesia machine, use total intravenous anesthesia and nondepolarizing neuromuscular blockers, and ensure the immediate availability of dantrolene.[1][23]

Differential Diagnosis

Malignant hyperthermia shares clinical features with several hypermetabolic and neuromuscular disorders, particularly in the perioperative setting. Hyperthermia, tachycardia, acidosis, and muscle rigidity may overlap with other conditions, making early distinction essential to guide appropriate management. Careful attention to triggering exposures, time course, and associated laboratory findings helps differentiate malignant hyperthermia from its mimics.

Neuroleptic malignant syndrome presents with hyperthermia and rigidity but differs in pharmacologic trigger and underlying mechanism; susceptibility to one condition does not confer risk for the other.[24] Exertional heat stroke also demonstrates clinical overlap, and noninvasive phosphorus-31 magnetic resonance spectroscopy and in vitro testing suggest that a subset of patients may have malignant hyperthermia–like myopathy with sarcoplasmic reticulum calcium channel dysregulation.[25] Myotonias and periodic paralysis disorders may yield small contractures at low agonist doses on in vitro contracture testing, limiting specificity and not necessarily indicating a malignant hyperthermia genotype.[26] Additional considerations include sepsis, thyroid storm, pheochromocytoma, equipment or ventilation failure, serotonin syndrome, and iatrogenic overheating, each distinguished by clinical context, medication exposures, and laboratory evaluation.[3][27][28][29]

Prognosis

Prognosis in malignant hyperthermia depends on the timeliness of recognition and intervention, as early diagnosis and prompt treatment markedly reduce morbidity and mortality. Outcomes have improved substantially with increased clinician awareness and the availability of dantrolene, allowing many patients to achieve full recovery when therapy is initiated without delay. Despite appropriate management, severe complications may still occur, particularly in cases with delayed diagnosis or advanced physiologic derangement. Rhabdomyolysis, acute kidney injury, coagulopathy, and multiorgan failure remain important contributors to adverse outcomes. The overall mortality rate is now less than 5% in settings with timely access to treatment.[30]

Complications

Complications of malignant hyperthermia arise from the sustained hypermetabolic state and rapid skeletal muscle breakdown, leading to widespread physiologic derangement. Severity correlates with the duration of untreated symptoms and the extent of the hyperthermia, acidosis, and electrolyte imbalance, particularly hyperkalemia. Major complications include rhabdomyolysis with subsequent myoglobinuria and acute kidney injury, which can progress to renal failure.

Cardiac complications include arrhythmias, cardiac arrest, and heart failure. Coagulopathy, including disseminated intravascular coagulation, may develop in severe cases. Additional complications include pulmonary edema, neurologic injury due to hyperthermia and hypoxia, multiorgan failure, and death.[31]