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 Overview of Heat Illness Heat illness encompasses a number of disorders ranging in severity from muscle cramps and heat exhaustion to heatstroke (which is a life-threatening emergency). Heat illness, although preventable... read more .)
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.
Hyperkalemia Hyperkalemia Hyperkalemia is a serum potassium concentration > 5.5 mEq/L (> 5.5 mmol/L), usually resulting from decreased renal potassium excretion or abnormal movement of potassium out of cells. There are... read more , respiratory and metabolic acidosis, hypocalcemia Hypocalcemia Hypocalcemia is a total serum calcium concentration 8.8 mg/dL ( 2.20 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration 4.7 mg/dL ( 1.17... read more , and rhabdomyolysis with creatine kinase elevation and myoglobinemia may occur, as may coagulation abnormalities (particularly disseminated intravascular coagulation [DIC] Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more ). In older patients and patients with comorbidities, DIC may increase the risk of death.
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
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) Key Points 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,... read more . 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
Treatment of Malignant Hyperthermia
Rapid cooling and supportive measures
It is critical to cool patients with malignant hyperthermia as quickly and effectively as possible (see Heatstroke: Treatment Treatment Heatstroke is hyperthermia accompanied by a systemic inflammatory response causing multiple organ dysfunction and often death. Symptoms include temperature > 40° C and altered mental status... read more ) 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 Rhabdomyolysis Rhabdomyolysis is a clinical syndrome involving the breakdown of skeletal muscle tissue. Symptoms and signs include muscle weakness, myalgias, and reddish-brown urine, although this triad is... read more , severe hyperthermia, and disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more . 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 Tracheal Intubation Most patients requiring an artificial airway can be managed with tracheal intubation, which can be Orotracheal (tube inserted through the mouth) Nasotracheal (tube inserted through the nose)... read more ) 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. 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.
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