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. This drug combination causes a similar reaction in some patients with muscular dystrophy and myotonia. Although malignant hyperthermia may develop after the first exposure to these drugs, on average, patients require 3 exposures.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. This drug combination causes a similar reaction in some patients with muscular dystrophy and myotonia. Although malignant hyperthermia may develop after the first exposure to these drugs, on average, patients require 3 exposures.
(See also Overview of Heat Illness.)
Pathophysiology of Malignant Hyperthermia
Malignant hyperthermia affects about 1/20,000 people. Susceptibility is inherited, with autosomal dominant inheritance and variable penetrance. Most often, the causative mutation affects the ryanodine receptor of skeletal muscle; however, > 22 other causative mutations have been identified.
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.
Complications
Hyperkalemia, respiratory and metabolic acidosis, hypocalcemia, and rhabdomyolysis with creatine kinase elevation and myoglobinemia may occur, as well as coagulation abnormalities, including disseminated intravascular coagulation.
Symptoms and Signs of Malignant Hyperthermia
Malignant hyperthermia may develop during anesthesia or the early postoperative period. Clinical presentation varies depending on the drugs 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
Clinical evaluation
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 immediately confirmatory tests, but patients should have testing for complications, including 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 immediately confirmatory tests, but patients should have testing for complications, including 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.
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 (CHCT) is the most accurate. It measures the response of a muscle tissue sample to caffeine and halothane. Genetic testing is also easily available but may be limited based on the type of mutation detected. 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 (CHCT) is the most accurate. It measures the response of a muscle tissue sample to caffeine and halothane. Genetic testing is also easily available but may be limited based on the type of mutation detected.
Diagnosis reference
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
Treatment of Malignant Hyperthermia
Rapid cooling and supportive measures
DantroleneDantrolene
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 2.5 mg/kg IV every 5 minutes as needed, up to a total dose of 10 mg/kg should be given in addition to the usual physical cooling measures. The dose of dantrolene is titrated based on heart rate and end-tidal CO2. In some patients, tracheal intubation (see . Dantrolene 2.5 mg/kg IV every 5 minutes as needed, up to a total dose of 10 mg/kg should be given in addition to the usual physical cooling measures. The dose of dantrolene is titrated based on heart rate and end-tidal CO2. In some patients, tracheal intubation (seeAirway Establishment and Control/Tracheal Intubation) paralysis, and induced coma are required to control symptoms and provide support. Benzodiazepines given IV, often in high doses, can be used to control agitation. Malignant hyperthermia has a high mortality and may not respond to even early and aggressive therapy.
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.
