Nonsyndromic Malignant Hyperthermia Susceptibility

Excerpt

Clinical characteristics: Malignant hyperthermia susceptibility (MHS) is a pharmacogenetic disorder of skeletal muscle calcium regulation associated with uncontrolled skeletal muscle hypermetabolism. Manifestations of malignant hyperthermia (MH) are precipitated by volatile anesthetics (i.e., halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with a depolarizing muscle relaxant (specifically, succinylcholine). The triggering substances cause uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate. Affected individuals experience acidosis, hypercapnia, tachycardia, hyperthermia, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase (CK) concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for kidney failure. In nearly all individuals, the first manifestations of MH (hypercapnia, tachycardia, and tachypnea) occur in the operating room; however, MH may also occur in the early postoperative period. There is mounting evidence that some individuals with MHS will also develop MH with exercise and/or on exposure to hot environments. Without proper and prompt treatment with dantrolene sodium, mortality can be over 80%.

Diagnosis/testing: The diagnosis of MHS is established with in vitro muscle contracture testing by measuring the contracture responses of biopsied muscle samples to halothane and graded concentrations of caffeine. The diagnosis of MHS can also be established by identification of a pathogenic variant in RYR1 (in 60%-70% of individuals with MHS), CACNA1S (~1%), or STAC3 (<1%) by molecular genetic testing.

Management: Targeted therapy: Administration of intravenous dantrolene sodium (initial dose of 2.5 mg/kg) as early as possible during an MH episode.

Treatment of manifestations: Early diagnosis of an MH episode is essential. Successful treatment of an acute episode of MH, in addition to administration of intravenous dantrolene sodium, includes: discontinuation of potent inhalation agents and succinylcholine; increase in minute ventilation to lower end-tidal CO₂; communication with Malignant Hyperthermia Association of the US (MHAUS) helpline; cooling measures if body temperature is >38.5 °C; treatment of cardiac arrhythmias if needed (do not use calcium channel blockers); monitoring blood gases, serum concentrations of electrolytes and CK, blood and urine for myoglobin, and coagulation profile; treatment of metabolic abnormalities.

Prevention of primary manifestations: Individuals undergoing general anesthesia that exceeds 30 minutes in duration should have their temperature monitored using an electronic temperature probe. Individuals with MHS should carry proper identification (e.g., MedicAlert^® bracelet) as to their susceptibility.

Agents/circumstances to avoid: Avoid potent inhalation anesthetics and succinylcholine. Calcium channel blockers should not be given together with dantrolene because life-threatening hyperkalemia may result. Serotonin antagonist (5-HT3 antagonist) antiemetics should be used cautiously. Individuals with MHS should avoid extremes of heat but not restrict athletic activity unless there is a history of overt rhabdomyolysis and/or heat stroke. Strenuous activities at high ambient temperatures should be avoided or performed with caution. In individuals with MHS undergoing cardiac bypass surgery, aggressive rewarming should be avoided, as it may be associated with development of clinical signs of MH.

Evaluation of relatives at risk: It is appropriate to clarify the status of at-risk relatives of an individual diagnosed with MHS to identify those who also have an increased susceptibility to MH and thus would benefit from avoiding anesthetic agents that increase the risk for an MH episode. Evaluations include: multigene panel testing (if the MHS-related causative variant in the family is known) and muscle biopsy and contracture testing (if the MHS-causative pathogenic variant in the family is not known or if an at-risk relative is found to be negative for the familial pathogenic variant on targeted testing but has not undergone multigene panel testing).

Pregnancy management: If a pregnant woman with MHS requires a non-emergent surgery, a non-triggering anesthetic (local, nerve block, epidural, spinal anesthesia, or a total intravenous general anesthetic) should be administered. Continuous epidural analgesia is highly recommended for labor and delivery. If a cesarean delivery is indicated in a woman who does not have an epidural catheter in place, neuraxial (spinal, epidural, or combined spinal-epidural) anesthesia is recommended (if not otherwise contraindicated). If a general anesthetic is indicated, a total intravenous anesthetic technique should be administered, with an anesthesia machine that has been prepared for an individual with MHS.

Genetic counseling: MHS is inherited in an autosomal dominant manner. Most individuals diagnosed with MHS have a parent with MHS, although the parent may not have experienced an episode of MH. Each child of an individual with MHS has a 50% chance of being MH susceptible. If an MHS-causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.