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.)
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.
Hyperkalemia, respiratory and metabolic acidosis, hypocalcemia, and rhabdomyolysis with creatine kinase elevation and myoglobinemia may occur, as may coagulation abnormalities (particularly disseminated intravascular coagulation [DIC]). In older patients and patients with comorbidities, DIC may increase the risk of death.
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.
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.
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.
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. This test can be done only at certain referral centers and requires excision of about 2 g of muscle tissue. Because multiple mutations may be involved, genetic testing has limited sensitivity (about 30%) but is quite specific; patients in whom a mutation is identified do not require the CHCT.
1. Hopkins PM, Rüffert H, Snoeck MM, et al: European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth 115(4):531-9, 2015. doi: 10.1093/bja/aev225. Epub 2015 Jul 18. PMID: 26188342
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 Airway 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.
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. Nondepolarizing muscular blockers are the preferred preanesthetic drugs. Preferred anesthetics include barbiturates (eg, thiopental), etomidate, and propofol. Dantrolene should be available at the bedside.
Malignant hyperthermia develops in genetically susceptible patients who have been exposed (usually more than once) simultaneously to a depolarizing muscle relaxant (most often succinylcholine) and a potent, volatile inhalational general anesthetic (most often halothane).
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.
Test people at risk by the caffeine halothane contracture test or genetic testing if those tests are available.