Intracellular events

Whatever the mechanism underlying the pathophysiology of malignant hyperthermia, it is generally accepted that an uncontrolled influx of Ca 2+ into the cytoplasm results in a severe metabolic disturbance within the cell and rapid depletion of ATP. In normal circumstances, muscle contraction, glycolysis, and mitochondrial function are regulated by intracellular Ca2+ concentration. Calcium is pumped back into stores by Ca2+-ATPase to initiate muscle relaxation, while glycolysis and aerobic metabolism proceed just rapidly enough to maintain energy balance. In a malignant hyperthermia crisis Ca 2+ is released into the cytoplasm at enhanced rates, overpowering the Ca2+-ATPase pump. Glycolysis, aerobic metabolism, and anaerobic metabolism are activated in an attempt to replenish ATP levels. Phospholipase A2 is also activated by Ca2+, causing liberation of long-chain fatty acids and an increase in sarcoplasmic and mitochondrial membrane permeability, with further loss of Ca2+ regulation.

Damage to the sarcoplasmic membrane leads to loss of Mg2+ and K+. If it is severe, larger molecules, namely creatine kinase and myoglobin, are also lost. As muscle is a major source of body heat, increased activity results in an increased core temperature. Thus a disruption of the normal control of Ca 2+ regulation within the cell results in the severe metabolic disturbances seen in malignant hyperthermia and accounts for the observed clinical signs and symptoms ( Fig. 1) (MacLennan and Phillips 1992).

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Fig. 1 Diagram showing the intracellular kinetics of calcium: SR, sarcoplasmic reticulum.

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