++
Malignant hyperthermia (MH) is a genetically linked skeletal muscle disease that presents when susceptible patients are exposed to triggering agents such as inhaled volatile agents and succinylcholine. On a cellular level, MH involves a disruption in skeletal myocyte calcium regulation that leads to a hypermetabolic state which can present with minimal clinical manifestations to severe systemic instability and even death. MH is rare, with an estimated incidence anywhere from 1:4200 to 1: 250 000 anesthetics. The incidence is higher in younger males, but all age groups and sexes can be susceptible. While once associated with high mortality rates (70%–80%), MH now carries a much lower mortality rate (5%) due to advances in intraoperative monitoring, MH susceptibility testing, and treatment options.
++
In normal excitation-contraction coupling a depolarization at the motor endplate propagates along the sarcolemma and down the t-tubules where it then reaches the transmembrane L-type voltage-gated calcium channel dihydropyridine receptor (DHPR). A conformational change in the DHPR activates the ryanodine receptor type 1 (RYR1), found within the membrane of the intracellular calcium-storing sarcoplasmic reticulum. Once activated, the RYR1 allows the release of calcium ion stores into the sarcoplasm where it will bind to troponin C and shift tropomyosin away from the myosin-binding site of actin. This allows the initiation of adenosine triphosphate (ATP)-dependent sarcomere contraction. Contraction is terminated with the reuptake of calcium into the sarcoplasmic reticulum via ATP-dependent calcium transporters.
++
In MH-susceptible patients this well-regulated calcium handling is disrupted after exposure to a triggering agent. In most cases, the point of failure occurs with the RYR1 receptor allowing continuous outflow of calcium from the sarcoplasmic reticulum. With abundant calcium in the sarcoplasm and no ability to regulate its reuptake, the sarcomere is in a state of constant troponin disinhibition leading to sustained muscle contraction. This sustained contraction comes at a significant energy cost to the body due to its dependence on ATP. Skeletal muscle will quickly ramp up aerobic metabolism, rapidly consuming oxygen and energy substrates leading to excessive carbon dioxide and heat production. The body will eventually transition to anaerobic metabolism with a quickly developing lactic acidosis when aerobic metabolism fails to meet this energy demand. If allowed to progress, this process will eventually lead to rhabdomyolysis with the breakdown of skeletal muscle cells and leakage of intracellular contents into systemic circulation. It is important to note that while 70% of patients with confirmed MH have mutations in RYR1, several other gene mutations do exist that can lead to MH including mutations in DHPR.
+++
Clinical Presentation
++
Genetic studies have shown that MH susceptibility mutations are inherited in an autosomal dominant fashion with incomplete penetrance which accounts for its variation in clinical presentation. The initial signs of MH can occur at any point during the anesthetic or even several hours after, although late presentation is rare.
++