Malignant Hyperthermia

Updated: Jul 24, 2020
Author: James W Chapin, MD; Chief Editor: John Geibel, MD, MSc, DSc, AGAF 



Malignant hyperthermia (MH) is a life-threatening clinical syndrome of hypermetabolism involving the skeletal muscle. It is triggered in susceptible individuals primarily by the volatile inhalational anesthetic agents and the muscle relaxant succinylcholine, though other drugs have also been implicated as potential triggers.[1] MH is not an allergy but an inherited disorder that is found both in humans and in swine.

In persons susceptible to MH, the ryanodine receptor in skeletal muscle is abnormal,[2] and this abnormality interferes with regulation of calcium in the muscle. An abnormal ryanodine receptor that controls calcium release causes a buildup of calcium in skeletal muscle, resulting in a massive metabolic reaction.

This hypermetabolism causes increased carbon dioxide production, metabolic and respiratory acidosis, accelerated oxygen consumption, heat production, activation of the sympathetic nervous system, hyperkalemia, disseminated intravascular coagulation (DIC), and multiple organ dysfunction and failure. Early clinical signs of MH include an increase in end-tidal carbon dioxide (even with increasing minute ventilation), tachycardia, muscle rigidity, tachypnea, and hyperkalemia. Later signs include fever, myoglobinuria, and multiple organ failure.

Anesthetics are inconsistent in triggering MH. A susceptible individual may undergo anesthesia with MH-triggering agents on multiple occasions without incident but may still react to such agents on a subsequent occasion. A history of uneventful anesthesia with MH-triggering agents does not rule out susceptibility to MH. In fact, there are reports of MH episodes occurring even with the use of supposedly safe agents.

More than 30 mutations account for human MH.[3] Genetic testing is available to establish a diagnosis, but the caffeine halothane contracture test (CHCT) remains the criterion standard. Dantrolene, the antidote, decreases the loss of calcium from the sarcoplasmic reticulum in the skeletal muscle and restores normal metabolism.[4, 5] Early detection and treatment improve the outcome.


MH is a subclinical myopathy that allows large quantities of calcium to be released from the sarcoplasmic reticulum (SR) of skeletal muscle and cause a hypermetabolic state after exposure to triggering agents. Altered calcium channel gating kinetics in the SR is the underlying cause. The sustained elevation of calcium allows excessive stimulation of aerobic and anaerobic glycolytic metabolism, which accounts for respiratory and metabolic acidosis, rigidity, altered cell permeability, and hyperkalemia.

Arterial carbon dioxide tension (PaCO2) may exceed 100 mm Hg, and pH may drop below 7. The earliest sign is increased end-tidal carbon dioxide. A threefold increase in oxygen consumption and a 15- to 20-fold increase in blood lactate can be seen. Tachycardia, dysrhythmias, and a sympathetic catecholamine surge occur. The hypermetabolism evokes a massive exothermic response, leading to extreme temperature elevation. Rhabdomyolysis leads to increased levels of potassium, myoglobin, and creatine kinase, as well as edema formation.

The elevated myoglobin may damage the kidneys. Without adequate treatment, the process may progress to multiple organ failure and death. Dantrolene inhibits the release of calcium from the SR and reverses the process. Calcium-channel blockers are associated with hyperkalemia if used in conjunction with dantrolene and are not recommended.

The large ischemic demands imposed by the hypermetabolic state prevailing during acute MH can severely impair myocardial function. The extreme temperature elevation, hyperkalemia, acidosis, and cerebral edema can affect the central nervous system (CNS), causing coma, areflexia, and dilated pupils. Activation of the sympathetic nervous system occurs early.

DIC can occur as a consequence of the release of tissue thromboplastin. Pulmonary changes are secondary to systemic effects. Eventually, metabolic exhaustion ensues, leading to increased cellular permeability, whole-body edema, compartment syndrome in the extremities, cerebral edema, and death.


MH is inherited as an autosomal dominant trait with reduced penetrance. It is associated with mutations in two genes: RYR1, which encodes the skeletal muscle isoform of the calcium-release channel of the sarcoplasmic reticulum (ryanodine receptor type 1 [RYR-1]),[6] and CACNA1S, which encodes the alpha subunit of the L-type calcium channel isoform of the sarcolemma (dihydropyridine receptor). An aberrant termination of RYR-1 activity is found in MH-susceptible persons.

RYR1 is located on chromosome 19. Mutations in this gene occur in at least 50% of persons with MH and all families of central core disease. More than 30 mutations and one deletion are associated with a positive CHCT, a clinical MH episode, or both. CHCT is the criterion standard for establishing the diagnosis of MH.

Muscle biopsy for MH is done at five sites in North America; the patient must travel to the testing center to have the biopsy performed. Genetic DNA testing can be done with a blood sample sent to one of the four testing sites.


The reported frequency of MH in the United States ranges from 1 in 10,000 patients receiving anesthetics to 1 in 50,000; the reported frequency in children is higher. The true incidence of MH has not been established with precision, because of a lack of universal reporting in the United States. In addition, many MH-susceptible persons have not been exposed to the triggering agents. The annual number of suspected MH cases per year in the United States is around 700.

Larach et al reported that in 291 MH episodes recorded in the North American Malignant Hyperthermia Registry database between 1987 and 2006, there were eight cardiac arrests and four deaths, and the median age of patients experiencing cardiac arrest or death was 20 years.[7]


If an MH reaction is treated early in the process, complete recovery can be expected. Multiple organ failure and death can occur, however, and one or two deaths are reported to the MH hotline each year. Before the approval of dantrolene by the US Food and Drug Administration (FDA) in the late 1970s for use in the treatment of MH, the mortality of an acute MH reaction was greater than 70%. Currently, the mortality of acute MH is less than 5%.

Patient Education

In 1981, family members of patients who had died of MH founded the Malignant Hyperthermia Association of the United States (MHAUS) to provide information to the lay public and health care workers about MH and to support research and education. In 1982, MHAUS started an around-the-clock hotline to answer questions about MH and to give guidance concerning treatment of acute cases. A North American registry keeps reports of acute MH cases for research purposes. All hotline reports are reviewed.

The telephone number for the MHAUS hotline is (800) MH-HYPER or (800) 644-9737. The MHAUS Web site at can be used for information and protocols.



History and Physical Examination

Malignant hyperthermia (MH) may occur either in the operating room (OR) or in the early postoperative period. The earliest sign is an increase in end-tidal carbon dioxide.

A fulminant reaction is obvious, with very high end-tidal carbon dioxide (>100 mm Hg), a low pH with a metabolic component, tachycardia and dysrhythmias, rigidity (in some cases), rapidly increasing temperature, a mottled skin color, hyperkalemia, myoglobinuria, muscle edema, sympathetic hyperactivity with eventual metabolic exhaustion, increased cellular permeability, whole body edema, disseminated intravascular coagulopathy (DIC), and cardiac and renal failure.

Early diagnosis and treatment with dantrolene can improve the outcome. Fortunately, fulminant reactions are rare; most reactions are slower and display more subtle changes. Larach et al devised an MH grading scale based on points given to various signs and laboratory tests to help with the diagnosis of MH.[8]

The hotline run by the Malignant Hyperthermia Association of the United States (MHAUS) can be consulted for assistance in treatment. Many calls to the hotline are for high carbon dioxide values that are not reduced by increasing the minute ventilation, tachycardia, rigidity, masseter rigidity after succinylcholine administration, or postoperative fever. Other calls involve questions about safe technique for a patient with known MH.

Often, the hotline consultant will refer the patient to an MH testing center for muscle biopsy and a caffeine halothane contracture test (CHCT). In many cases, the consultant determines that the patient does not actually have MH. Some of the reactions reverse after discontinuance of the triggering agent and do not necessitate the use of dantrolene.

Clinical conditions associated with susceptibility to MH include King-Denborough syndrome, central core disease, and minicore myopathy.[9, 10] Individuals with these disorders have RYR1 mutations and should be considered at risk for MH.

King-Denborough syndrome is characterized by short stature, musculoskeletal abnormalities, and mental retardation. Some individuals with this syndrome also have central core disease. Central core disease is characterized by hypotonia, muscle weakness, and central cores on muscle biopsy. Minicore myopathy is a group of disorders characterized by severe hypotonia and generalized weakness.

It was long thought that muscular dystrophy was associated with susceptibility to MH, but that association is being questioned. There have been numerous reports of pediatric patients with Duchenne muscular dystrophy or Becker muscular dystrophy who experienced hyperkalemic cardiac arrest after induction with inhalation agents and succinylcholine but did not experience hypermetabolism. In addition, anesthesia-induced rhabdomyolysis (AIR) is seen in patients with muscular dystrophy with no signs of MH.

Although muscular dystrophy is not associated with MH, it is nonetheless wise to refrain from administering inhalational agents and succinylcholine to patients with muscular dystrophy so as to avoid AIR and hyperkalemic cardiac arrest.[11]

Masseter muscle rigidity (MMR) after succinylcholine administration may be associated with susceptibility to MH. Brief rigidity (< 20-30 s) is a normal response to succinylcholine. Rigidity lasting longer than 1 minute is seen as abnormal, and 20% of these patients will develop clinical MH within the next hour. Some patients have “jaws of steel,” which make airway management difficult.

Elective cases should be canceled, and the patient should be observed in the hospital for 24 hours for signs of MH. In the case of an emergency operation, safe techniques should be used, and MH should be watched for. Administration of dantrolene should be considered. All patients with MMR experience rhabdomyolysis and may have very high creatine kinase levels and myoglobinuria.



Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, there are a number of other conditions and circumstances that may mimic malignant hyperthermia (MH), including the following:

  • Contrast dye
  • Diabetic coma
  • Drug toxicity
  • Environmental heat gain
  • Equipment malfunction, increased carbon dioxide, rebreathing, soda lime exhaustion
  • Exercise hyperthermia
  • Freeman-Sheldon syndrome
  • Hypokalemic periodic paralysis
  • Intracranial free blood
  • Muscular dystrophies (eg, Duchenne and Becker)
  • Myotonia
  • Ventilation problems

Although its clinical picture is similar to that of MH, neuroleptic malignant syndrome (NMS) is caused by the central effects of drugs with dopamine antagonist properties, including antipsychotics (eg, haloperidol) and antiemetics (eg, metoclopramide and droperidol). The onset of the syndrome occurs hours to days after initiation of treatment with the drug.

Clinically, a patient with NMS displays motor impairment, rigidity, akinesia, or extrapyramidal signs. Mental status deteriorates, and coma or delirium may develop. Hyperpyrexia is noted, with dehydration and hypotension. The duration is 7-10 days. Treatment consists of stopping the drug, controlling the symptoms, and administering dopamine agonists (eg, bromocriptine). Dantrolene will lower the temperature.

Differential Diagnoses



Caffeine Halothane Contracture Test

The caffeine halothane contracture test (CHCT) is the criterion standard for establishing the diagnosis of malignant hyperthermia (MH). The test is performed on freshly biopsied muscle tissue at 30 centers worldwide; one of these centers is located in Canada, and four are located in the United States.

The CHCT testing centers in North America are located at the following sites:

  • Toronto General Hospital, Malignant Hyperthermia Investigation Unit, Eaton 3-323, 200 Elizabeth St,Toronto, Ontario M5G 2C4, (416) 340-3128,
  • Uniformed Services University of the Health Sciences, Bethesda, MD (Military & Civilian); Sheila M Muldoon, MD; (301) 295-3532;
  • University of California, Davis; Timothy Tautz, MD; (530) 752-7805;
  • University of Minnesota, Minneapolis; Paul A Iaizzo, PhD; (612) 624-7912 or (612) 624-3959; (for more information on this center:
  • Wake Forest University, Winston-Salem, NC; Alan G Woodruff, MD; (336) 716-7447;

​The patient must consult the testing center and receive approval for testing, then travel to one of the testing sites. The CHCT involves extraction of 2 g of muscle, usually from the thigh. This tissue must be tested immediately after extraction; its usability for testing lasts only a few hours.

The CHCT should be considered for all those determined to be at risk for MH (eg, those with a family history or a previous possible episode). A negative CHCT result is the only way to prove that a patient is not susceptible to MH. The cost of the test is at least $5000, but it is covered by most insurance providers.

Sevoflurane has received some preliminary study as an alternative to halothane in MH testing.[12]

Molecular Genetic Testing

Molecular genetic testing (DNA testing) is less expensive and less invasive than the muscle contracture test. It is 25-30% sensitive and is highly specific for MH susceptibility. The DNA is extracted from cells in a blood sample.

MH is associated with more than 30 mutations, and 30% of patients with known MH have one of these mutations. RYR1 (the gene coding for the ryanodine receptor in skeletal muscle) is associated with as many as 50-60% of MH cases in families. Mutation of CACNA1S is responsible for 1% of all cases of MH susceptibility.

Many more variations remain to be discovered. When one of the more than 30 known mutations is identified, the patient is considered to be MH-susceptible. However, a negative genetic test result does not mean that a person is MH-negative. A CHCT is needed to determine MH-negative status.

Once a family member tests positive on the CHCT, the patient can undergo genetic tests, which, if yielding positive results, can be used for the rest of the family. If the family member with the positive CHCT result is positive for one of the 30-plus mutations, the remaining family members can be tested for that mutation; if test results are positive, they are determined to be MH-susceptible. Family members who do not have one of the 30-plus mutations must still be treated as MH-susceptible and should therefore undergo a CHCT.

Molecular genetic testing centers in North America are located at the following sites:

  • Center for Medical Genetics, University of Pittsburgh Medical Center, Pittsburgh, PA; (800) 454-8155;
  • Prevention Genetics, LLC, Marshfield, WI; Eric W Johnson, PhD; (715) 387-0484;
  • North American Malignant Hyperthermia Registry (Database) of the Malignant Hyperthermia Association of the United States (MHAUS), Department of Anesthesiology, Children’s Hospital, University of Pittsburgh, Pittsburgh, PA 15213-2583; Dr Barbara Brandon, Director; (888) 274-7899, FAX (412) 692-8658;

The results of MH testing should be reported to the North American Malignant Hyperthermia Registry of MHAUS to advance the understanding of the genetics of MH. Further information is available at



Dantrolene and Supportive Care

Indications for treatment of malignant hyperthermia (MH) with dantrolene include signs of hypermetabolism, a rapid rise in carbon dioxide in the face of an increase in the minute ventilation, tachycardia, muscle and or jaw rigidity (after succinylcholine), and fever (a late sign).

Not all of these indications are present in all patients. If an acute MH reaction appears likely, it is best to start giving dantrolene and other recommended treatment modalities promptly rather than wait too long and have a bad outcome. The longer the wait before initiation of therapy, the lower the likelihood of a complete recovery. If an MH reaction is suspected, referral to a MH muscle biopsy testing center is indicated.

A fulminant, rapidly progressive MH reaction requires early diagnosis and early rapid administration of dantrolene, discontinuance of triggering agents, and assistance from extra personnel. The surgeon should be notified immediately and should stop the procedure as soon as possible (see below). (For more information, see Malignant Hyperthermia in the Operating Room.) 

Cooling and early treatment of hyperkalemia are desirable. Calcium-channel blockers should be avoided if dantrolene is used, because they may cause hyperkalemia. An MH tote or cart containing dantrolene and the necessary supplies should be readily available to help reverse the process more quickly. The recommendation is that 36 dantrolene vials (containing 20 mg/vial) should be immediately available wherever general anesthesia is administered. Availability of a further 24 vials within 1 hour has also been recommended.[13] It is helpful to place an MH treatment poster in the operating room.

Dantrolene is a hydantoin derivative that directly interferes with muscle contraction by inhibiting calcium ion release from the sarcoplasmic reticulum, possibly by binding to ryanodine receptor type 1 (RYR-1). The initial dose is 2.5 mg/kg, repeated every 5 minutes until reversal of the reaction occurs or a total dose of 10 mg/kg (or 20 mg/kg, according to some practitioners) is reached. If there is no clinical response, another diagnosis should be considered.

Dantrolene will also lower an elevated temperature in disorders other than MH, such as thyroid storm, neuroleptic malignant syndrome (NMS), and sepsis. Each 20-mg vial of lyophilized powder contains sodium hydroxide for a pH of 9-10 and mannitol, which makes the solution isotonic. The half-life is 6-10 hours.

Once the initial reaction is controlled, continued monitoring in the intensive care unit (ICU) for 24-48 hours is recommended, along with administration of dantrolene (1 mg/kg every 4-6 hours, or an equivalent amount given as a continuous infusion). Myoglobinuria should be watched for and treated with fluids and diuretics if it occurs. The creatine kinase level will peak about 8-10 hours after the event and should be followed until it returns to near normal.

A newer version of dantrolene dissolves in 15 seconds and thereby improves the rapidity of treatment. Another improvement is the addition of charcoal filters that can be placed in the anesthesia machine circuit. These filters can remove the inhalation agent in 1-2 minutes and help quickly reverse the effects of the MH reaction.

The patient and the family members will need to be educated about MH and should be referred to a testing center for a caffeine halothane contracture test (CHCT). Relevant information is available from the Malignant Hyperthermia Association of the United States (MHAUS) at

Cancellation or Modification of Surgical Procedure

A diagnosis of trismus after giving succinylcholine with induction raises the question of whether the surgical procedure should be canceled; a clinical episode will follow the trismus 20% of the time. When the anesthesia provider first suspects that an MH reaction may be occurring, the surgeon should be notified promptly, and a decision should be made about whether the procedure is to be continued or canceled. If the procedure is canceled, the patient should be observed in the hospital for 24 hours for signs of MH.

If the procedure is to be performed, the following considerations should be kept in mind in planning anesthesia for an MH-susceptible patient:

  • Avoid triggering agents (eg, major inhalational agents and succinylcholine)
  • Use nontriggering general, regional, spinal, epidural, or local anesthesia or monitored anesthesia care (MAC)
  • Watch for signs of MH
  • Use a clean anesthesia machine; remove vaporizers or tape them in the off position, change soda lime and barium hydroxide lime, replace the circuits, replace the fresh gas tubing if possible, and run oxygen through the machine at 10 L/min for 20 minutes (10 minutes if the fresh gas tubing was replaced)
  • The procedure can be done on an outpatient basis; if all goes well, the patient can safely be dismissed after 2-3 hours


Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Skeletal Muscle Relaxants

Class Summary

These agents may be helpful in the treatment of malignant hyperthermia (MH).

Dantrolene sodium (Dantrium, Revonto)

Indications for treatment of malignant hyperthermia with dantrolene include signs of hypermetabolism, a rapid rise in carbon dioxide in the face of an increase in minute ventilation, tachycardia, muscle and/or jaw rigidity (after succinylcholine), and fever (a late sign).

Dantrolene may work by reducing or preventing the increase in myoplasmic calcium ion concentration responsible for activating the catabolic processes associated with malignant hyperthermia.

The initial dose is 2.5 mg/kg, repeated every 5 minutes until reversal of the reaction occurs or a total dose of 10 mg/kg (or 20 mg/kg, according to some practitioners) is reached. If there is no clinical response, another diagnosis should be considered.


Questions & Answers


What is malignant hyperthermia (MH)?

What causes malignant hyperthermia (MH)?

What is the role of anesthetics in the etiology of malignant hyperthermia (MH)?

What is the role of genetic testing in the diagnosis of malignant hyperthermia (MH)?

What is the pathophysiology of malignant hyperthermia (MH)?

What is the role of arterial carbon dioxide tension (PaCO2) in the pathogenesis of malignant hyperthermia (MH)?

What are the effects of large ischemic demands of acute malignant hyperthermia (MH)?

What causes disseminated intravascular coagulation (DIC) in malignant hyperthermia (MH)?

What causes malignant hyperthermia (MH)?

How are muscle biopsies performed for malignant hyperthermia (MH)?

What is the prevalence of malignant hyperthermia (MH)?

What is the prognosis of malignant hyperthermia (MH)?

Where can patient education resources for malignant hyperthermia (MH) be found?


What is the earliest sign of malignant hyperthermia (MH)?

What are the signs and symptoms of malignant hyperthermia (MH)?

What improves the outcome in malignant hyperthermia (MH)?

What is the Malignant Hyperthermia Association of the US (MHAUS) and how do they help with the diagnosis of malignant hyperthermia (MH)?

Which clinical conditions increase the risk for malignant hyperthermia (MH)?

What are the signs and symptoms of King-Denborough syndrome in malignant hyperthermia (MH)?

What is the role of muscular dystrophy in the etiology of malignant hyperthermia (MH)?

What are the signs and symptoms of masseter muscle rigidity (MMR) in malignant hyperthermia (MH)?

What is involved in the monitoring for malignant hyperthermia (MH)?


Which conditions should be included in the differential diagnoses of malignant hyperthermia (MH)?

How is neuroleptic malignant syndrome (NMS) differentiated from malignant hyperthermia (MH)?

What are the differential diagnoses for Malignant Hyperthermia?


How is malignant hyperthermia (MH) diagnosed?

Where are caffeine halothane contracture test (CHCT) testing centers for malignant hyperthermia (MH) located?

How is caffeine halothane contracture test (CHCT) for malignant hyperthermia (MH) performed?

What is the role of molecular genetic testing (DNA testing) in the evaluation of malignant hyperthermia (MH)?

Where are molecular genetic testing (DNA testing) centers located for malignant hyperthermia (MH)?


What are the indications for treatment of malignant hyperthermia (MH)?

How is fulminant, rapidly progressive malignant hyperthermia (MH) treated?

What is included in supportive care for malignant hyperthermia (MH)?

What is the role of dantrolene in the treatment of malignant hyperthermia (MH)?

What monitoring should be performed for malignant hyperthermia (MH) in the ICU?

What improvements have been made to dantrolene for the treatment of malignant hyperthermia (MH)?

When is cancellation or modification of the surgical procedure indicated in malignant hyperthermia (MH)?

How is anesthesia given to a patient with malignant hyperthermia (MH)-susceptibility?


What are the goals of drug treatment for malignant hyperthermia (MH)?

Which medications in the drug class Skeletal Muscle Relaxants are used in the treatment of Malignant Hyperthermia?