**2.2 Risk factors**

Apparently, MH can exist regardless of race or gender although predominance in males and adolescents has been suggested25. Family history of fatal general anesthesia complications associated with the use of volatile agents or depolarizing muscle relaxants should make the anesthesiologist aware about the increased risk for MH.

Patients with Duchenne muscular dystrophy, myotonia congenita, myotonic dystrophy, nonspecific myopathies, central core disease, King-Denborough, osteogenesis *imperfecta* and Schwartz-Jampel syndrome have an increased risk for MH syndrome19. Patients who develop masseter muscle rigidity (MMR) after administration of succinylcholine have an increased risk to develop MH in the next minutes, and 25% of these will show positive contracture tests to MH32-33.

#### **2.3 Pathophysiology**

Malignant hyperthermia is an inherited pharmacogenetic disorder of skeletal muscle, characterized by an increased calcium release from the skeletal muscle sarcoplasmic reticulum. A mutation in the ryanodine receptor (RyR) may be the main causative factor in many patients and families with MH34-35. The ryanodine receptor type 1 (RYR1) gene encodes the human skeletal muscle calcium release channel. RYR1 gene is responsible for the release of sarcoplasmic reticulum stores of calcium. In about 50% of MH susceptible families, there is a mutation in RYR136. The large variability among individuals may be explained by different genes causing MH in different families or by other predisposing factors being expressed differently in susceptible patients36.

In the late 1980s, Caffeine Halothane Contracture Test became the gold standard diagnostic test for MH and a variety of neuromuscular disorders associated with MH susceptibility. These disorders include central core disease, Duchenne muscular dystrophy, myotonia congenita, myotonic dystrophy, nonspecific myopathies, and King-Denborough syndrome19. During liver transplantation, some commonly employed anesthetic agents may trigger MH in susceptible patients. This occurrence, in such a complex scenario and with such delicate patients, can make anesthesia management even more challenging. Besides this, dantrolene

In North America and Europe, the incidence of MH is currently estimated to be 1:15,000 anesthetics for children and adolescents and 1:50,000–1:150,000 anesthetics for adults21-23. The prevalence for this syndrome in the general population is unknown because of lack of universal reporting, but although it may be as common as one in 200024. Malignant hyperthermia is more common in male patients25. The incidence and prevalence varies from

Although the incidence of reported episodes of MH has increased, the mortality rate from MH has declined. This may reflect a greater awareness of the syndrome, earlier diagnosis,

Apparently, MH can exist regardless of race or gender although predominance in males and adolescents has been suggested25. Family history of fatal general anesthesia complications associated with the use of volatile agents or depolarizing muscle relaxants should make the

Patients with Duchenne muscular dystrophy, myotonia congenita, myotonic dystrophy, nonspecific myopathies, central core disease, King-Denborough, osteogenesis *imperfecta* and Schwartz-Jampel syndrome have an increased risk for MH syndrome19. Patients who develop masseter muscle rigidity (MMR) after administration of succinylcholine have an increased risk to develop MH in the next minutes, and 25% of these will show positive

Malignant hyperthermia is an inherited pharmacogenetic disorder of skeletal muscle, characterized by an increased calcium release from the skeletal muscle sarcoplasmic reticulum. A mutation in the ryanodine receptor (RyR) may be the main causative factor in many patients and families with MH34-35. The ryanodine receptor type 1 (RYR1) gene encodes the human skeletal muscle calcium release channel. RYR1 gene is responsible for the release of sarcoplasmic reticulum stores of calcium. In about 50% of MH susceptible families, there is a mutation in RYR136. The large variability among individuals may be explained by different genes causing MH in different families or by other predisposing

is hepatotoxic, which can pose another injury risk to the graft20.

country to country, based on differences in gene pools26-30.

anesthesiologist aware about the increased risk for MH.

factors being expressed differently in susceptible patients36.

**2. General Information** 

and better therapy31.

contracture tests to MH32-33.

**2.3 Pathophysiology** 

**2.2 Risk factors** 

**2.1 Incidence and prevalence** 

The vast majority of patients susceptible to MH are asymptomatic in the absence of anesthesia. In humans, the defect only appears to be expressed significantly in skeletal muscle, although receptors are present in cardiac muscle37 and even in the liver38. Recently some authors suggested that RyR's play an active role in the Ca2+ signaling of hepatocytes, creating local Ca2+ microdomains that enhance the responsiveness of neighboring Inositol Trisphosphate Receptors through Ca2+-positive feedback38.

The exact mechanism by which different substances initiate a MH crisis has not been determined. It can be assumed, though, that a defect of intracellular Ca2+ homeostasis plays an important role. Susceptibility to MH is clearly based on an abnormal Ca2+ metabolism within the skeletal muscle, most probably caused by a defective Ca2+ release channel in the sarcoplasmic reticulum (SR), e.g. the ryanodine receptor which is the footplate protein seated between the dihydropyridine receptor and the sarcoplasmic reticulum39-41. The abnormal function of the ryanodine receptor of skeletal muscle in MH causes barely controlled concentration of calcium within the cell when it is not exposed to triggering agents42,43. The added loss of control of intracellular calcium on exposure to triggering agents or heat stress leads to marked metabolic stimulation within the cell to provide extra adenosine triphosphate to drive the calcium pumps that restore calcium to its reservoirs (e.g., sarcoplasmic reticulum, mitochondria, extracellular fluid)44.

On a cellular level, magnesium acts as a physiological calcium inhibitor resulting in lessintense calcium liberation from the sarcoplasmic reticulum. In normal resting muscle, cytosolic Mg2+ exerts a potent inhibitory influence on the SR Ca2+ release channel (ryanodine receptor, RyR1). Impaired Mg2+-regulation of RyR1 has been proposed as a causal factor in MH. The marked potentiation of SR Ca2+ release after a moderate reduction in cytosolic Mg2+ suggests that conditions which cause hypomagnesemia will increase the probability and possibly severity of an MH event. Conversely, maintenance of a normal or slightly increased cytosolic Mg2+ may reduce the probability of MH45. There is increasing evidence to suggest that defective Mg2+ regulation of RyR1 confers susceptibility to malignant hyperthermia. At the molecular level, interactions between critical RyR1 subdomains may explain the clustering of RyR1 mutations and associated effects on Mg2+ regulation46.

MH is a syndrome caused by dysregulation of excitation-contraction (EC) coupling in skeletal muscle. The increased activity of pumps and exchangers trying to correct the increase in Ca2+ causes a need for ATP, which in turn produces heat. Thus, the end result is hyperthermia. The rigidity that is frequently seen during a fulminant MH episode is the result of the inability of the Ca2+ pumps and transporters to reduce the unbound myoplasmic Ca2+ below the contractile threshold44,47. Human malignant hyperthermia is a heterogeneous disorder, and the down-regulation of sodium channel subunit may be involved in the final common pathway through which mutations in any one of several proteins, including the ryanodine receptor, could render a person susceptible48. These changes would prolong the sodium current making the cell membrane depolarized for a longer time, increasing calcium release time period from the terminal cisternae. Patients expressing sodium channel abnormalities are at increased risk for muscle rigidity.

#### **2.4 Triggering agents**

All volatile anesthetics are triggers of malignant hyperthermia and must therefore be strictly avoided in malignant hyperthermia-susceptible patients. Furthermore, the depolarizing muscle relaxant succinylcholine triggers the syndrome49. Isoflurane, desflurane and sevoflurane appear to be less potent triggers than halothane, but these agents can produce a more gradual or fast onset of MH50-56. The onset may be explosive if succinylcholine is used57. Local anesthetics, nondepolarizing muscle relaxants, barbiturates, benzodiazepines, droperidol, ketamine, nitrous oxide, opioids, and propofol are all safe drugs to administer in MH susceptible patients49.
