Malignant hyperthermia (MH) susceptibility is a complex genetic disorder characterized by hypermetabolic activity leading to crisis following skeletal muscle exposure to a triggering agent. The triggering agent leads to a sharp increase in unbound intracellular calcium from the sarcoplasmic reticulum, stimulating sustained muscle contracture. When the oxygen supply to the muscle is depleted, anaerobic metabolism shift develops, resulting in lactic metabolic acidosis. Finally, after all energy stores are depleted, rhabdomyolysis occurs, resulting in hyperkalemia and myoglobinuria, the latter of which causes acute renal failure. Hyperthermia results from the increased metabolic state.
The earliest signs of MH include tachycardia and elevated end-tidal carbon dioxide level. Labile blood pressure, tachypnea, sweating, muscle rigidity, blotchy discoloration of skin, cyanosis, and dark urine all signal progression of the disorder. Elevation of temperature, which can reach extremely high levels, is a relatively late sign. Ultimately, respiratory and metabolic acidosis, hyperkalemia, hypercalcemia, elevated creatine kinase myoglobinuria, and renal failure can occur, as can disseminated intravascular coagulation and death.
Genetics, risk factors, and triggering agents
Approximately 50% of cases of MH susceptibility are autosomal dominant, and the others arise as de novo mutations. According to the Malignant Hyperthermia Association of the United States (MHAUS; www.mhaus.org), the prevalence is 1 in 2000 individuals, but because of variable expressivity and penetrance, the actual number of cases is far fewer than gene prevalence would indicate. The affected genes are those that code for proteins involving the calcium channel in the sarcoplasmic reticulum.
In addition to known familial susceptibility, diagnosis of certain muscle disorders raises suspicion for MH susceptibility, especially those disorders associated with ryanodine receptor mutations. Conditions previously associated with MH that are no longer felt to represent a greater risk include Noonan syndrome, osteogenesis imperfecta, myotonias, and neuroleptic malignant syndrome. The preoperative history can also help determine whether a patient is at risk for malignant hyperthermia. However, a negative history does not rule out MH susceptibility, because nearly 50% of patients who develop MH have had 1 or 2 prior uneventful exposures to a triggering agent. Patients with a history of unexpected exertional- or heat-induced rhabdomyolysis, as well as those with a history of severe statin-induced myopathy, are at increased risk for MH.
Triggering agents for MH include volatile halogenated inhalational anesthetics such as halothane, sevoflurane, isoflurane, desflurane, and enflurane as well as succinylcholine.
Patients determined to be at high risk for MH may require a muscle biopsy for muscle contracture evaluation (caffeine halothane contracture test) or genetic testing. A negative contracture test essentially rules out MH susceptibility. However, the false-positive rate is 20%, and a positive contracture test should be followed by genetic analysis. However, even if no DNA variation or a DNA variation of undetermined significance is found, this does not mean that MH susceptibility is definitely ruled out. Treatment is indicated based on the preoperative clinical impression.
Prevention and treatment
Patients who are deemed susceptible for MH can be safely anesthetized using nontriggering agents. The anesthesia machine should be cleaned of any traces of volatile anesthetics. Safe, nontriggering agents include all intravenous anesthetics and sedative agents (eg, propofol, ketamine, and barbiturates), all local anesthetics (eg, lidocaine, bupivacaine, and ropivacaine), nondepolarizing muscular blockers, analgesics, and anxiolytics. Prophylactic dantrolene is not recommended.
When MH occurs, it is treated as a medical emergency (see Table 15-1 for the treatment protocol). Before dantrolene, mortality was as high as 70%–80%; now, the rate is less than 5%. MHAUS staffs a 24-hour hotline to advise medical personnel on the diagnosis and treatment of MH: 800-644-9737 (within the United States) or 00 + 1 209-417-3722.
Table 15-1 Malignant Hyperthermia Protocol
Hopkins PM, Rüffert H, Snoeck MM, et al; European Malignant Hyperthermia Group. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115(4):531–539.
Litman RS, Griggs SM, Dowling JJ, Riazi S. Malignant hyperthermia susceptibility and related diseases. Anesthesiology. 2018;128(1):159–167.
Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.