Malignant Hyperthermia

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Continuing Education Activity

Malignant hyperthermia (MH) is a hereditary disorder of skeletal muscle that classically presents as a hypermetabolic response to halogenated anesthetic gasses and/or the depolarizing muscle relaxant succinylcholine. Genetically susceptible patients can have a malignant hyperthermia reaction in response to triggering agents such as halogenated anesthetic gasses and/or succinylcholine and more rarely to stressors such as vigorous exercise and heat exposure. Nitrous oxide and xenon, although they are inhaled anesthetics, are not halogenated and have not been implicated in malignant hyperthermia. This activity reviews the evaluation and treatment of malignant hyperthermia and the interprofessional team's role in evaluating and treating this condition.


  • Review the most common causes of malignant hyperthermia.
  • Identify the genetic basis of malignant hyperthermia.
  • Outline the treatment of malignant hyperthermia.
  • Summarize the role of the interprofessional team in the evaluation and treatment of malignant hyperthermia.


Malignant hyperthermia (MH) is a hereditary disorder of skeletal muscle that classically presents as a hypermetabolic response to halogenated anesthetic gasses and/or the depolarizing muscle relaxant succinylcholine.


Genetically susceptible patients can have a malignant hyperthermia reaction in response to triggering agents such as halogenated anesthetic gasses and/or succinylcholine and more rarely to stressors such as vigorous exercise and heat exposure.  Nitrous Oxide and Xenon, although they are inhaled anesthetics, are not halogenated and have not been implicated in malignant hyperthermia.


The exact incidence of malignant hyperthermia is unknown. Studies demonstrate that malignant hyperthermia occurs in about 1 in 100,000 adults and 1 in 30,000 in children. The incidence of malignant hyperthermia varies based upon geographic region. There are concentrations of malignant hyperthermia susceptible families present in Wisconsin and the upper Midwest. The mortality rate is 3% to 5%, even when properly treated.

Other disorders are also associated with malignant hyperthermia susceptibility. These include central core disease (a rare, non-progressive myopathy characterized by hypotonia and weakness of proximal muscles) and King-Denborough syndrome (rare myotonia associated with multiple distinct physical features).[1]

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.[2]

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.


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

The uncontrolled release of calcium from the skeletal muscle sarcoplasmic reticulum leads to sustained muscle contraction. The sustained muscle contraction produces a depletion of adenosine triphosphate (ATP) and dramatically increases oxygen consumption, carbon dioxide production, and heat. The depletion of ATP stores leads to membrane integrity failure and cell content leakages such as potassium, creatinine kinase, and myoglobin into the circulation.[3][4]

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 due to elevated carbon dioxide production. Fulminant malignant hyperthermia reactions may have only a few of the usual signs. It requires a high index of suspicion of malignant hyperthermia to effect a timely and correct diagnosis and treatment. Malignant hyperthermia can occur at any time during the intraoperative and postoperative periods.

Susceptible patients can exhibit masseter muscle spasm. If signs of hypermetabolism such as metabolic and respiratory acidosis or an elevation in body temperature accompany the muscle spasm, a diagnosis of malignant hyperthermia must be considered.


The gold standard in the laboratory diagnosis of malignant hyperthermia is the caffeine halothane contracture test (CHCT), although genetic testing is rapidly advancing and may one day replace the 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 of the RYR1 or other associated genetic variants associated with malignant hyperthermia is becoming increasingly more valuable as the 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 "non-triggering anesthetic," which is typically a variety of combinations of intravenous anesthetic agents. The differential diagnosis for malignant hyperthermia can include many other, unrelated disorders such as neuroleptic malignant syndrome, pheochromocytoma, sepsis, thyroid storm, serotonin syndrome, or iatrogenic overheating.[5][6][7]

Treatment / Management

The critical element in the treatment of malignant hyperthermia is immediate dantrolene administration. Once a malignant hyperthermia episode is suspected, all triggering agents must be discontinued and the patient hyperventilated with 100% oxygen with non-triggering anesthetic agents utilized for patient care, and surgery should be ended as soon as possible. Dantrolene in a dose of 2.5 mg/kg must be administered intravenously as soon as possible, up to a maximum dose of 10mg/kg until the reaction subsides. In addition to administering dantrolene, attention also must be paid to correct hyperthermia, acidosis, hypoxemia, arrhythmias, and preserving renal function. Arrhythmias can be treated with antiarrhythmic, and renal function can be protected from possible acute tubular necrosis (due to precipitation of released myoglobin from the skeletal muscles) by maintaining a urine flow of at least 2 ml/kg/hr with furosemide.[8]

The management algorithm includes:

  • Stop the triggering agent.
  • Call for help.
  • Administer dantrolene 2.5 mg/kg until the reaction subsides up to a maximum of 10 mg/kg.
  • Increase ventilation to lower end-tidal CO2.
  • Cooling measures (cold IV fluids and ice packs to exposed surfaces).
  • Treat arrhythmias (e.g., amiodarone;  avoid calcium channel blockers).
  • Laboratory studies include arterial blood gas, electrolytes (especially potassium), serum and urine myoglobin, and coagulation profile.
  • Continue dantrolene at 1 mg/kg every 4 hours for 24 to 48 hours.
  • Ensure urine output of 2 ml/kg/hr (mannitol 3 grams is included in each vial of dantrolene) 

Better patient outcomes are associated with the rapidity of diagnosis, rapid treatment with dantrolene, and prevention of the rapid rise in core temperature by using cooling measures.[9]

After the patient has been stabilized, they must be taken to the intensive care unit for at least 24 hours for monitoring and to watch for signs of recrudescence. Patients at the highest risk for recrudescence are those with a large muscle mass or who have undergone at least 150 minutes of anesthetic exposure before triggering.  

Despite having been performed frequently in the past, pretreating malignant hyperthermia-susceptible patients with dantrolene does not play a role in their care and should not be done. Instead, these patients should receive a non-triggering anesthetic.

Differential Diagnosis

The differential diagnosis for malignant hyperthermia includes the following:

  • Contrast dye
  • Cystinosis
  • Diabetic coma
  • Drug toxicity
  • Environmental heat
  • Equipment malfunction
  • Exercise hyperthermia
  • Freeman-Sheldon syndrome
  • Heatstroke
  • Hyperthyroidism
  • Hypokalemic periodic paralysis
  • Intracranial free blood
  • Multiple organ dysfunction syndrome
  • Muscular dystrophy
  • Myotonia
  • Osteogenesis imperfecta
  • Pheochromocytoma
  • Prader-Willi syndrome
  • Rhabdomyolysis
  • Thyrotoxicosis
  • Ventilation problems
  • Wolf-Hirschhorn syndrome


Complete recovery can occur if the signs and symptoms of malignant hyperthermia are recognized early and proper treatment is started. Multiple organ failure and death can still occur, however, even with prompt treatment. The mortality rate is less than 5%.


The complications of malignant hyperthermia include:

  • Brain damage
  • Cardiac arrest
  • Death
  • Heart failure
  • Internal bleeding
  • Kidney failure
  • Pulmonary edema
  • Skeletal muscle degeneration

Deterrence and Patient Education

Family members of patients who suffer from malignant hyperthermia should be educated on the genetic aspect of the disease. The Malignant Hyperthermia Association of the United States (MHAUS) was founded in 1981 and should be used by affected family members to gain more information. MHAUS 24-hour hotline is (800) MH-HYPER or (800) 644-9737.

Pearls and Other Issues


Dantrolene works by inhibiting calcium ion release from the sarcoplasmic reticulum. Its mechanism of action is through antagonizing the ryanodine receptors, which lessens the excitation-contraction coupling of muscle cells.  

Dantrolene is currently the only specific medication used for treating a malignant hyperthermia crisis. Dantrolene is available in two different formulations. These two formulations differ in the amount of sterile water required to reconstitute each vial and the dantrolene concentration within each vial. One formulation is available in 20 mg vials that must be reconstituted with 60 mL of sterile water per vial, while the other is available in 250 mg vials that must be reconstituted with 5 mL of sterile water per vial. Regardless of which formulation of dantrolene is administered, a dose of 2.5 mg/kg is recommended to treat a malignant hyperthermia episode. Dantrolene is a highly lipophilic drug with low solubility in water, making the reconstitution of the drug in sterile water challenging. The newer formulation that combines nanosuspension technology with a lyophilized formulation resulting in a much faster reconstitution of the drug, which can greatly improve the time to treatment and may be especially useful in locations where only one provider is available to treat the patient.

Keep in mind that additional doses of dantrolene might be necessary to treat malignant hyperthermia triggering events adequately; a dose of 1 mg/kg every 4 to 6 hours is recommended for the first 24 to 48 hours after an episode of malignant hyperthermia.

Dantrolene should not be combined with verapamil, as it may lead to hyperkalemia and hypotension.[1]

All facilities where malignant hyperthermia triggering anesthetics are administered are recommended to stock an adequate amount of dantrolene and other medications and rescue equipment needed to treat a malignant hyperthermia crisis.   

Malignant Hyperthermia Links to Strenuous Exercise, Heat Exposure, or Elevated Body Temperature

Malignant hyperthermia susceptible patients are found to experience a metabolic crisis without exposure to triggering agents. Exposure of these patients to strenuous exercise, heat exposure, or high internal body temperatures (e.g., infections) may precipitate this crisis. Research is currently underway to evaluate this possible link.

Other Issues

Life-threatening laryngospasm is a much more common event than malignant hyperthermia that can be quickly treated with low dose succinylcholine. Many office-based procedural facilities do not stock succinylcholine due to the risk of malignant hyperthermia and the need to stock expensive dantrolene in cases of malignant hyperthermia triggering events. The Society for Ambulatory Anesthesia offered an opinion on the dilemma by stating that succinylcholine could be stocked at these locations for emergency use only with the caveat that procedures should never be done on known malignant hyperthermia susceptible persons in those facilities.  

Patients and their families should be referred to the Malignant Hyperthermia Association of the United States (MHAUS) for information about this disorder and receive follow-up from specialists in this area.  

North American Malignant Hyperthermia Registry

The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States (MHAUS) is a database of information about patients and their families that have experienced malignant hyperthermia episodes. Healthcare providers are encouraged to report malignant hyperthermia and malignant hyperthermia-like episodes to the registry.  

Enhancing Healthcare Team Outcomes

Malignant hyperthermia is a rare, life-threatening disorder. Because of the high morbidity, the disorder is best managed by an interprofessional healthcare team that includes a neurologist, intensivist, anesthesiologist, an internist, nursing staff, and a pharmacist. This interprofessional/collaborative approach will improve patient outcomes. [Level 5]

Even though dantrolene is recommended for treatment, good data supporting its efficacy are still lacking. The patient should be managed in an ICU setting with close monitoring.



Stacey Watt


8/17/2023 4:56:33 PM



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