Malignant hyperthermia is a life-threatening elevation in body temperature usually resulting from a hypermetabolic response to concurrent use of a depolarizing muscle relaxant and a potent, volatile inhalational general anesthetic. Manifestations can include muscle rigidity, hyperthermia, tachycardia, tachypnea, rhabdomyolysis, and respiratory and metabolic acidosis. Diagnosis is clinical; patients at risk can be tested for their susceptibility. The highest priority treatments are rapid cooling and aggressive supportive measures including the use of dantrolene.Malignant hyperthermia is a life-threatening elevation in body temperature usually resulting from a hypermetabolic response to concurrent use of a depolarizing muscle relaxant and a potent, volatile inhalational general anesthetic. Manifestations can include muscle rigidity, hyperthermia, tachycardia, tachypnea, rhabdomyolysis, and respiratory and metabolic acidosis. Diagnosis is clinical; patients at risk can be tested for their susceptibility. The highest priority treatments are rapid cooling and aggressive supportive measures including the use of dantrolene.
The muscle relaxant involved is usually succinylcholine; the inhalational anesthetic is most often halothane, but other anesthetics (eg, isoflurane, sevoflurane, desflurane) may also be involved (The muscle relaxant involved is usually succinylcholine; the inhalational anesthetic is most often halothane, but other anesthetics (eg, isoflurane, sevoflurane, desflurane) may also be involved (1). This combination of medications causes a similar reaction in some patients with muscular dystrophy and myotonia. Although malignant hyperthermia may develop after the first exposure to these medications, patients require 3 exposures on average.
Cases of malignant hyperthermia in the absence of anesthetic agents have been reported; these may be triggered by exercise or heat exposure (1).
The incidence of malignant hyperthermia is estimated at between 1 in 35,000 to 68,000 surgical discharges (0.001% to - 0.003%) (1).
Reference
1. Pinyavat T, Riazi S, Deng J, et al. Malignant Hyperthermia. Crit Care Med. 2024;52(12):1934-1940. doi:10.1097/CCM.0000000000006401
Pathophysiology of Malignant Hyperthermia
Susceptibility to malignant hyperthermia is inherited, with autosomal dominant inheritance and variable penetrance. Most often, the causative mutation affects the ryanodine receptor of skeletal muscle (1). Estimates of the prevalence of potential susceptibility-causing mutations range from 1 in 10,000 to 1 in 2000, but it is not yet clear how these translate into clinical susceptibility.
The mechanism may involve anesthetic-induced potentiation of calcium (Ca) exit from the sarcoplasmic reticulum of skeletal muscle in susceptible patients. As a result, Ca-induced biochemical reactions are accelerated, causing severe muscle contractions and elevation of the metabolic rate, resulting in respiratory and metabolic acidosis. In response to the acidosis, patients breathing spontaneously develop tachypnea that only partially compensates.
Pathophysiology references
1. Gonsalves SG, Ng D, Johnston JJ, et al. Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology. 2013;119(5):1043-1053. doi:10.1097/ALN.0b013e3182a8a8e7
Complications
Hyperkalemia, respiratory and metabolic acidosis, hypocalcemia, and coagulation abnormalities including disseminated intravascular coagulation (DIC) may occur. DIC is the usual cause of death and most frequently occurs at temperatures > 41°C. Rhabdomyolysis, characterized by creatine kinase elevation and myoglobinemia may result in acute renal failure.
Symptoms and Signs of Malignant Hyperthermia
Malignant hyperthermia may develop during anesthesia or the early postoperative period. Clinical presentation varies depending on the medications used and the patient’s susceptibility. Muscular rigidity, especially in the jaw, is often the first sign, followed by tachycardia, other arrhythmias, tachypnea, acidosis, shock, and hyperthermia. Hypercapnia (detected by increased end-tidal carbon dioxide [CO2]) may be an early sign. Temperature is usually ≥ 40° C and may be extremely high (ie, > 43° C). Urine may appear brown or bloody if rhabdomyolysis and myoglobinuria have occurred.
Diagnosis of Malignant Hyperthermia
Typical symptoms after anesthesia is administered
Testing for complications
Susceptibility testing for people at risk
The diagnosis is suspected by the appearance of typical symptoms and signs within 10 minutes to, occasionally, several hours after inhalational anesthesia is begun (1). Early diagnosis can be facilitated by prompt recognition of jaw rigidity, tachypnea, tachycardia, and increased end-tidal CO2.
There are no immediate confirmatory tests, but patients should have testing for complications, including an electrocardiogram, blood tests (complete blood count with platelets, electrolytes, blood urea nitrogen, creatinine, creatine kinase, calcium, prothrombin time, partial thromboplastin time, fibrinogen, D-dimer), and urine testing for myoglobinuria.There are no immediate confirmatory tests, but patients should have testing for complications, including an electrocardiogram, blood tests (complete blood count with platelets, electrolytes, blood urea nitrogen, creatinine, creatine kinase, calcium, prothrombin time, partial thromboplastin time, fibrinogen, D-dimer), and urine testing for myoglobinuria.
Other diagnoses must be excluded. Perioperative sepsis may cause hyperthermia but rarely as soon after anesthetic induction. Inadequate anesthesia can cause increased muscle tone and tachycardia but not elevated temperature. Thyroid storm and pheochromocytoma rarely manifest immediately after anesthetic induction (2).
Susceptibility testing
Testing for susceptibility to malignant hyperthermia is recommended for people at risk based on a family history of the disorder or a personal history of a severe or incompletely characterized previous adverse reaction to general anesthesia. The caffeine-halothane contracture test is considered the gold standard and measures the response of a muscle tissue sample to caffeine and halothane (Testing for susceptibility to malignant hyperthermia is recommended for people at risk based on a family history of the disorder or a personal history of a severe or incompletely characterized previous adverse reaction to general anesthesia. The caffeine-halothane contracture test is considered the gold standard and measures the response of a muscle tissue sample to caffeine and halothane (3). Genetic testing is more easily available than contracture testing but may be limited based on the type of mutation detected.
Diagnosis references
1. Hopkins PM, Girard T, Dalay S, et al. Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists. Anaesthesia. 76:655-664, 2021. doi: 10.1111/anae.15317
2. Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015 Aug 4;10:93. doi: 10.1186/s13023-015-0310-1.
3. Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry. The North American Malignant Hyperthermia Registry of MHAUS. . The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry. The North American Malignant Hyperthermia Registry of MHAUS.Anesthesiology. 1998;88(3):579-588. doi:10.1097/00000542-199803000-00006
Treatment of Malignant Hyperthermia
Stop volatile anesthetic agents
Administer dantroleneAdminister dantrolene
Rapid cooling and other supportive measures
It is critical to cool patients with malignant hyperthermia as quickly and effectively as possible (see Heatstroke: Treatment) to prevent damage to the central nervous system and also to give patients supportive treatment to correct metabolic abnormalities. Outcome is best when treatment begins before muscular rigidity becomes generalized and before development of rhabdomyolysis, severe hyperthermia, and disseminated intravascular coagulation. Dantrolene, initially 2.5 mg/kg IV every 5 minutes as needed should be given in addition to physical cooling measures. A total dose of 10 mg/kg with no clinical improvement should prompt reconsideration of the diagnosis. The dose of dantrolene is titrated based on heart rate and end-tidal CO. Dantrolene, initially 2.5 mg/kg IV every 5 minutes as needed should be given in addition to physical cooling measures. A total dose of 10 mg/kg with no clinical improvement should prompt reconsideration of the diagnosis. The dose of dantrolene is titrated based on heart rate and end-tidal CO2. In some patients, tracheal intubation (see Airway Establishment and Control/Tracheal Intubation), paralysis, hyperventilation, and induced coma are required to control symptoms and provide support. Arrhythmias may be treated with amiodarone or short-acting beta blockers; non-dihydropyridine calcium channel blockers such as verapamil and diltiazem should be avoided (), paralysis, hyperventilation, and induced coma are required to control symptoms and provide support. Arrhythmias may be treated with amiodarone or short-acting beta blockers; non-dihydropyridine calcium channel blockers such as verapamil and diltiazem should be avoided (1). Benzodiazepines given IV, often in high doses, can be used to control agitation. Malignant hyperthermia has a high mortality rate and may not respond to even early and aggressive therapy (2, 3).
If malignant hyperthermia occurs outside of the surgical area, anesthesiology should be consulted immediately and preprepared malignant hyperthermia equipment and protocols used. The Malignant Hyperthermia Association of America (MHAUS) provides a hotline (+1-800-644-9737) staffed by experts who can help guide treatment (2, 3).
Treatment references
1. Malignant Hyperthermia Association of the United States (MHAUS). Calcium Channel Blockers. Accessed May 2, 2025.
2. Hopkins PM, Girard T, Dalay S, et al. Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists. Anaesthesia. 2021;76(5):655-664. doi:10.1111/anae.15317
3. Pinyavat T, Riazi S, Deng J, et al. Malignant Hyperthermia. Crit Care Med. 2024;52(12):1934-1940. doi:10.1097/CCM.0000000000006401
Prevention of Malignant Hyperthermia
Local or regional anesthesia is preferred to general anesthesia when possible. Potent inhalational anesthetics and depolarizing muscular relaxants should be avoided in patients who are susceptible and those with a strong family history. Dantrolene should be available at the bedside.Local or regional anesthesia is preferred to general anesthesia when possible. Potent inhalational anesthetics and depolarizing muscular relaxants should be avoided in patients who are susceptible and those with a strong family history. Dantrolene should be available at the bedside.
Key Points
Malignant hyperthermia develops in genetically susceptible patients who have been exposed (usually more than once) simultaneously to a depolarizing muscle relaxant and a potent, volatile inhalational general anesthetic.
Complications can include hyperkalemia, respiratory and metabolic acidosis, hypocalcemia, rhabdomyolysis, and DIC.
Suspect the diagnosis if patients develop jaw rigidity, tachypnea, tachycardia, or increased end-tidal CO2 within minutes or sometimes hours after inhalational anesthesia is begun.
Treat with aggressive, early cooling and IV dantrolene.Treat with aggressive, early cooling and IV dantrolene.
Test people at risk with genetic testing or muscle biopsy.
