Malignant Hyperthermia (MH): A Comprehensive Overview

By SWA

Malignant Hyperthermia (MH) is a rare, life-threatening pharmacogenetic disorder triggered by specific anesthetic agents. First recognized in the mid-20th century, MH remains a significant concern in surgical and emergency medicine due to its rapid onset and potential for fatal outcomes if not promptly diagnosed and treated. At the heart of MH lies a genetic susceptibility, primarily involving mutations in the RYR1 gene, which disrupt calcium regulation in skeletal muscle cells, leading to a cascade of hypermetabolic events.

1. What Is Malignant Hyperthermia?

Malignant hyperthermia is a severe reaction to certain anesthetic drugs, particularly volatile inhalational anesthetics and succinylcholine, a depolarizing neuromuscular blocker. It can occur during or shortly after surgery and is characterized by:

  • Rapid rise in core body temperature

  • Muscle rigidity

  • Increased heart rate (tachycardia)

  • Excessive carbon dioxide production (hypercapnia)

  • Acidosis

  • Rhabdomyolysis (muscle breakdown)

  • Hyperkalemia (elevated potassium levels)

  • Potential progression to multi-organ failure and death

Without immediate intervention, MH is often fatal. However, when promptly recognized and treated—primarily with dantrolene—survival rates improve dramatically.

2. Triggers and Associated Drugs

Primary Triggering Agents

The main drugs known to induce MH in susceptible individuals are:

  • Volatile anesthetic gases:

    • Halothane

    • Isoflurane

    • Sevoflurane

    • Desflurane

  • Succinylcholine (suxamethonium):

    • A fast-acting paralytic agent used during intubation and surgical procedures.

Other Potential Triggers (Anecdotal and Under Investigation)

  • Serotonergic drugs (e.g., SSRIs, MAOIs) – suspected due to interactions with calcium signaling.

  • Phosphodiesterase type III inhibitors – used in cardiac care; may indirectly influence muscle metabolism.

  • Statins – though rare, statin-induced myopathies have raised concerns about potential MH-like reactions.

Local Anesthetics

Local anesthetics such as lidocaine are generally considered safe in MH-susceptible individuals. However, rare reports suggest that hypermetabolic responses resembling MH may occur under certain conditions, especially in high doses or in combination with other agents.

Ryanodine

Ryanodine, a plant alkaloid once used as an insecticide, binds directly to the ryanodine receptor (RyR1) and can induce MH-like symptoms in animal models. Its interaction with the RYR1 receptor underscores the central role of calcium dysregulation in MH.

3. Symptoms of Malignant Hyperthermia

Symptoms often begin intraoperatively or shortly after anesthesia induction and include:

  • Rapid hyperthermia (temperature may rise by more than 1°C every five minutes)

  • Generalized muscle rigidity, especially in the jaw (masseter spasm)

  • Tachycardia and tachypnea

  • Increased end-tidal CO₂ despite controlled ventilation

  • Dark-colored urine (due to myoglobin from muscle breakdown)

  • Hyperkalemia, which can lead to life-threatening arrhythmias

Prompt recognition is vital, as delaying treatment increases the risk of complications such as renal failure, disseminated intravascular coagulation (DIC), and death.

4. Genetics and Inheritance

Autosomal Dominant Inheritance

Malignant hyperthermia is inherited in an autosomal dominant pattern, meaning only one mutated copy of the gene is sufficient to confer susceptibility.

Key Genes Implicated

  1. RYR1 (ryanodine receptor 1):

    • The primary gene associated with MH.

    • Encodes a calcium release channel in skeletal muscle.

    • Mutations result in uncontrolled calcium release, causing sustained muscle contraction and hypermetabolism.

  2. CACNA1S:

    • Encodes a voltage-dependent calcium channel involved in muscle excitation-contraction coupling.

  3. STAC3:

    • A newer gene implicated in Native American Myopathy, which includes MH susceptibility.

5. Role of RS Numbers and Genetic Testing

SNPs (Single Nucleotide Polymorphisms)

SNPs are the most common form of genetic variation and can alter how proteins function.

RS Numbers

  • “RS” refers to a Reference SNP cluster ID used by genetic databases (e.g., NCBI dbSNP).

  • Example: rs1800544 – a variation associated with MH susceptibility in the RYR1 gene.

  • RS numbers allow researchers and clinicians to track and identify specific mutations linked to disease risk.

Genetic Testing in MH

  • Definitive diagnosis can involve genetic sequencing of the RYR1, CACNA1S, and STAC3 genes.

  • Muscle contracture tests (e.g., caffeine-halothane contracture test or CHCT) are used when genetic results are inconclusive.

  • Early identification allows anesthetic planning for at-risk individuals, avoiding triggering agents.

6. Epidemiology and Risk

  • Prevalence: Estimated between 1 in 5,000 to 1 in 50,000 anesthetic administrations.

  • Higher risk in:

    • Children and young adults

    • Males (more commonly affected)

    • Individuals with a family history of MH or unexplained deaths under anesthesia

MH susceptibility may also be present in individuals with central core disease, a congenital myopathy linked to RYR1 mutations.

7. Treatment and Emergency Management

Immediate Intervention

  1. Discontinue triggering agents immediately.

  2. Administer dantrolene sodium:

    • The only known antidote for MH.

    • Works by inhibiting calcium release from the sarcoplasmic reticulum, counteracting the hypermetabolic response.

    • Initial dose: 2.5 mg/kg IV, repeated as necessary.

Supportive Measures

  • Hyperventilation with 100% oxygen.

  • Active cooling (ice packs, cold IV fluids).

  • Management of acidosis, hyperkalemia, and arrhythmias.

  • Diuresis and fluid support to prevent kidney damage from rhabdomyolysis.

Post-Crisis Care

  • ICU monitoring for at least 24–48 hours.

  • Genetic counseling and referral for MH susceptibility testing.

  • Family screening due to autosomal dominant inheritance.

8. Prevention and Screening

  • Preoperative evaluation should include a detailed family and anesthesia history.

  • Alert bracelets, medical alert systems, and inclusion in medical records are essential for known MH-susceptible individuals.

  • MH testing is recommended for:

    • Anyone with personal or family history of MH.

    • Individuals with unexplained intraoperative complications.

    • Patients with associated congenital myopathies.

9. Conclusion

Malignant hyperthermia is a critical medical emergency rooted in a genetic predisposition to calcium dysregulation in skeletal muscle. While rare, the rapid and life-threatening nature of an MH crisis necessitates awareness, preparedness, and rapid intervention by surgical and anesthesia teams.

Modern genetic tools, including identification of specific RYR1 SNPs via RS numbers, offer opportunities for early detection and prevention. With proper precautions and the availability of dantrolene, outcomes for MH patients have significantly improved.

Ultimately, understanding the molecular mechanisms, inheritance patterns, and clinical management of MH is vital for ensuring patient safety during anesthesia and for guiding genetic counseling for affected families.

References:

Disease Overview: https://rarediseases.org/rare-diseases/ryr-1-related-diseases/

Malignant hyperthermia https://medlineplus.gov/genetics/condition/malignant-hyperthermia/

MALIGNANT HYPERTHERMIA, Causes, Signs and Symptoms, Diagnosis and Treatment.
https://www.youtube.com/watch?v=up90wYFtn3Q

Malignant hyperthermia https://www.mayoclinic.org/diseases-conditions/malignant-hyperthermia/symptoms-causes/syc-20353750

See also:
Regarding anticoagulpy and Aspirin
https://swaresearch.blogspot.com/2024/04/regarding-anticoagulant-therapy.html

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742

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