SPECIFIC ORGAN AND TISSUE ABNORMALITIES

Skeletal Muscle

Affected human muscle frequently has no histologic defect or else has protean nonspecific pathology so variable that none can be directly attributed to MH. These include central cores, internal nuclei, target fibers, supercontracted fibrils, and marked variation in fiber diameter.^[45]

Metabolism, Enzymatic Considerations, Heat Production, Contractures, and Fiber Type

Affected muscle is close to loss of control of intracellular Ca²⁺ . With that, aerobic (oxygen consumption [V̇O₂ ]) and glycolytic metabolism increase dramatically. There is an approximately threefold increase in V̇O₂ and a 15- to 20-fold increase in blood lactate level, with related acid-base imbalances. The earliest changes appear as an increase in muscle intracellular Ca²⁺ concentration ^[35] and in the venous effluent from skeletal muscle, as decreases in pH or partial pressure of oxygen (PO₂ ), or as increases in PCO₂ , lactate, potassium, or temperature.^[46] These changes occur before the increases in heart rate, temperature, and circulating catecholamine levels. The most sensitive early sign during anesthesia is an increase in expired carbon dioxide (during constant ventilation), but it can be misleading (see "Diagnosis"). Heat production during acute MH derives from aerobic metabolism, glycolysis, neutralization of hydrogen ions, and hydrolysis of high-energy phosphate compounds involved in ion transport and in the contraction-relaxation process.^[47] Precise calculations of the expended energy are difficult because of unsteady metabolic and circulatory states, variable and uncontrolled heat loss, and production of heat by neutralization of acid.

Muscle rigidity in MH is a contracture, similar to a muscle cramp, that is nonpropagated, prolonged, and sometimes irreversible. Contractures are used in tissue baths in the laboratory to study various aspects of MH. The lack of consistent correlation of fiber type or fiber proteins with abnormal function underscores the difficulties in analyzing this disorder; stress is necessary to detect the abnormality. The altered RYR1 protein is expressed in fast and slow fibers.

Calcium

The SR is the intracellular organelle primarily responsible for control of intracellular Ca²⁺ transients, and mitochondria serve a secondary reserve function in binding Ca²⁺ . When intracellular Ca²⁺ levels increase beyond the capabilities of the SR, mitochondria aid in binding. The mitochondrion provides the greatest supply of ATP through aerobic metabolism; only secondarily does it bind and store Ca²⁺ . There is evidence of muscle mitochondrial binding and accumulation of Ca²⁺ during acute episodes of porcine MH.^[48] Mitochondrial deficiencies do not explain the diminished aerobic responses in MH. V̇O₂ consistently increases about threefold during MH, in contrast to the 10-fold increase possible during severe exercise. In view of the serious acid-base imbalances and depletion of muscle energy stores, this increase seems paradoxically low.

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Ca²⁺ antagonists are associated with hyperkalemia and potentially increased mortality in vivo when used in conjunction with dantrolene. ^[49] They do not prevent or effectively treat MH in susceptible pigs.^{[50] [51]} In addition to the risk of hyperkalemia with Ca²⁺ antagonists and dantrolene, there is the added hazard that the hyperkalemia could trigger MH in susceptible skeletal muscle.^[52]

Electrophysiologic Measurements

The Ca²⁺ -control abnormalities of MH are reflected in altered electrophysiology. Multiple-pulse stimulation of porcine muscle (i.e., six pulses with 5-msec spacing) demonstrated an increase in tension and an increased rate of rise of tension in susceptible pigs; this difference was accentuated after dantrolene was given, and the susceptible pig muscle recovered much more effectively from the effects of dantrolene than did that of the normal animals.^[53] This confirms abnormally increased Ca²⁺ transients through intracellular organelles. Similar differences in humans were inaccurate by MH testing,^[54] although one study suggests better precision.^[55] During slaughter, affected swine are found to have a lower (and rapidly declining) resting membrane potential than that of normal swine.^{[56] [57]} This may contribute to the rapid decline of muscle pH and energy stores because this is prevented or attenuated by curarization and ventilation to maintain oxygenation.^[56] Halothane lowers mechanical threshold in susceptible and normal muscle, predisposing susceptible muscle toward the development of a contracture.^[58]

Channelopathies

One of the considerations regarding MH and disorders of EC coupling is the existence of channelopathies, disorders of the voltage-gated ion channels that control fluxes of ions across membranes.^[18] These channels are ion-conducting proteins with a membrane-spanning pore, gates, and voltage sensors, equipping them for passage of sodium, calcium, and chloride ions. Chloride channels provide 75% to 80% of membrane conductance at rest, contributing to the fast repolarization phase of the action potential. These channels are present in the surface and inner membranes of all excitable and most nonexcitable cells. There are naturally occurring mutations that alter their function with specific pathologic consequences. Abnormalities relating to skeletal muscle pathology include those of the sodium channel (i.e., hyperkalemic periodic paralysis, paramyotonia congenita, and some others, known collectively as potassium-aggravated myotonias), potassium channel (i.e., myokymias such as episodic ataxia), calcium channel (i.e., DHPR mutations causing hypokalemic periodic paralysis or dysgenic muscle in mice), and the chloride channel (i.e., myotonia congenita in humans, mice, and goats). The RYR1 is not a voltage-gated channel.

Implications of Findings in Skeletal Muscle

The single-point mutation of RYR1 in all susceptible swine is the major cause of porcine MH,^[36] and other abnormalities are secondary or occur in parallel. Inositol trisphosphate is a major physiologic second messenger mobilizing Ca²⁺ from endoplasmic reticulum, but it does not seem to be involved in MH because it lacks the surface membrane interactions possessed by the RYR1 for SR.^{[17] [19] [20]} Altered lipase, fatty acids, and triglycerides may play a more important role.^[59] Free radical peroxidation probably occurs during porcine MH as an adaptive response to sustained stress that contributes to abnormal calcium homeostasis and fatty acid metabolism. ^[60] Volatile anesthetics and succinylcholine represent a stress for skeletal muscle because they perturb membranes and disturb Ca²⁺ homeostasis. In general, normal muscle can withstand and compensate for these stresses. In susceptible muscle, the membrane perturbation induced by halothane or the depolarization induced by succinylcholine may cause an earlier Ca²⁺ release that strikingly stimulates greater Ca²⁺ release. Coupled with the lower mechanical threshold, an early MH response may result.^[58] Although MH-susceptible muscle may briefly tolerate these stresses, a cascading cycle of increasing metabolism, temperature, and acidosis eventually results. Skeletal muscle, about 40% of body weight, represents a sleeping giant in regard to metabolism, and once aroused, it dominates whole-body responses. MH-affected muscle may always be closer to loss of control than normal muscle. Normal muscle can respond abnormally with extremely prolonged effort, such as the overstraining disease or capture myopathy of wild animals after prolonged chase.^[61]