Malignant hyperthermia (MH) is autosomal dominant disease, which involves the skeletal muscles when exposed to volatile anesthetic drugs with or without muscle relaxants, excessive exercises and heat stress.1 Autosomal dominant disease occur when one copy of the gene is abnormal. This mutated gene can be inherited from parents or it can be a new mutation. From an affected parent there is a 50% chance of an offspring getting the disease and this risk affect both males and females equally.

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The exact incidence of malignant hyperthermia is not known, however “the incidence of malignant hyperthermia during general anesthesia ranges from 1: 5,000 to 1: 50,000 – 100,000.”

What Is The Cause Of Malignant Hyperthermia?

Malignant hyperthermia occurs in genetically susceptible individual when exposed to certain triggering agents such as:

  • Potent volatile inhaled anesthetics
  • Halothane – malignant hyperthermia occurs more with halothane
  • Isoflurane
  • Desflurane
  • Enflurane
  • Sevoflurane
  • Methoxyflurane
  • Ether
  • Depolarizing skeletal muscle relaxant - Succinylcholine

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It also can be triggered by excessive exercises and heat very rarely.

The exact mechanism how these agents trigger malignant hyperthermia is not known clearly, however, it’s shown that excessive uncontrolled release of calcium from the sarcoplasmic reticulum (SR) of the skeletal muscle causes hypermetabolism and gives rise to malignant hyperthermia.

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During the muscle excitation and contraction process, membrane depolarization causes a conformational change in one of the calcium channel called dihydropyridine-sensitive L-type voltage-dependent calcium channel (DHPR), which leads to activation of ryanodine receptor type 1 (RYR1) and this causes rapid release of calcium ions from the SR stores. The calcium ions released, combine with troponin C and moves away the tropomyosin from the myosin-binding site and stimulate a muscle contraction. When the calcium ions are actively pumped back to the SR through the ATP-dependent calcium pump the contraction stops. This normal skeletal muscle function occurs through this process.

So, what happens in people with malignant hyperthermia are there is an uncontrolled released of calcium ions form the SR due to functional changes in the RYR1 and/or DHPR along with other proteins which alter the calcium regulation in the muscle cell. When malignant hyperthermia people are exposed to above mention triggering factors there is a rapid release of calcium ions from the SR into the muscles. 70% of people with malignant hyperthermia carry the mutations in the RYR1 and the other probable mutation (1%) can be in the calcium voltage-gated channel subunit alpha1 S (CACNA1S), which codes for alpha1 subunit of DHPR.

At the early stages the muscle cells try to restore balance by trying to push the calcium ions back to the SR or the extracellular space by using the energy form the ATP. But, with the continuous release of calcium ions and depletion of ATP to push them out of the muscle, the myoplasmic calcium levels increase gradually and reaches the threshold level of muscle fiber contraction and this results in sustained muscle contraction (rigid muscles). The continued muscle contraction reduces the ATP levels further and increase the glucose metabolism, oxygen utilization, carbon dioxide production, heat production, respiratory and metabolic acidosis, disseminated intravascular coagulation and finally multi organ failure, if the triggering factor is not removed. Low ATP levels reduce the integrity of the muscle membrane, this causes leakage of muscle contents like electrolytes, proteins and myoglobin to the blood circulation.

Conclusion

Malignant hyperthermia (MH) is autosomal dominant disease which involves the skeletal muscles when exposed to volatile anesthetic drugs such as halothane, isoflurane, muscle relaxant succinylcholine, excessive exercises and heat stress.2 The exact mechanism how these agents trigger malignant hyperthermia is unknown but it is shown that excessive uncontrolled release of calcium from the sarcoplasmic reticulum (SR) of the skeletal muscle causes hypermetabolism and give rise to malignant hyperthermia. Most of the malignant hyperthermia cases due to functional changes in the RYR1 and DHPR along with other proteins which alter the calcium regulation in the muscle cell. 70% of people with malignant hyperthermia carry the mutations in the RYR1 and the other probable mutation (1%) can be in the calcium voltage-gated channel subunit alpha1 S (CACNA1S) which codes for alpha1 subunit of DHPR.

References:  

Also Read:

Pramod Kerkar

Written, Edited or Reviewed By:

, MD,FFARCSI

Pain Assist Inc.

Last Modified On: August 14, 2019

This article does not provide medical advice. See disclaimer

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