Which drugs cause malignant hyperthermia?

October 10, 2025 •

3 min read

Malignant hyperthermia (MH) occurs in approximately 1 in 100,000 adults receiving anesthetics, but the underlying genetic susceptibility may be far more common. This rare, but potentially fatal, pharmacogenetic disorder is triggered by a limited number of specific drugs. Knowing which drugs cause malignant hyperthermia is critical for patient safety during surgery.

Quick Summary

Malignant hyperthermia is a hypermetabolic syndrome triggered in genetically susceptible individuals by specific inhaled anesthetics and the muscle relaxant succinylcholine. The reaction can be life-threatening if not treated promptly.

Key Points

Triggering Agents: The primary triggers for malignant hyperthermia are potent volatile inhaled anesthetics (e.g., desflurane, sevoflurane, isoflurane) and the depolarizing muscle relaxant succinylcholine.
Genetic Basis: MH susceptibility is typically inherited in an autosomal dominant pattern and is most often linked to mutations in the RYR1 gene, affecting calcium regulation in muscle cells.
Hypermetabolic Crisis: Exposure to triggering drugs causes an uncontrolled release of calcium, leading to sustained muscle contraction and a rapid increase in metabolism, oxygen consumption, and CO2 production.
Clinical Signs: Early signs include unexplained tachycardia, hypercarbia (high end-tidal CO2), and muscle rigidity. A rapid and severe rise in body temperature is a later, but classic, sign.
Emergency Treatment: The specific and essential treatment for an MH crisis is the intravenous administration of dantrolene sodium, alongside stopping the triggering agents and providing supportive care.
Safe Alternatives: Non-triggering anesthetic agents, including intravenous anesthetics (propofol, ketamine), nitrous oxide, non-depolarizing muscle relaxants, and local/regional anesthesia, are safe for susceptible patients.
Diagnosis: Susceptibility can be diagnosed via a muscle biopsy contracture test or, in some cases, genetic testing.

The Primary Culprits: Identifying Triggering Agents

Malignant hyperthermia (MH) is an inherited disorder of skeletal muscles, leading to a hypermetabolic state in susceptible individuals exposed to specific anesthetic agents. The primary drugs that cause malignant hyperthermia fall into two categories: potent volatile inhalational anesthetics and the depolarizing muscle relaxant succinylcholine.

Volatile Inhalational Anesthetics

These anesthetics, used for general anesthesia, are known triggers for MH. According to the Malignant Hyperthermia Association of the United States (MHAUS), triggering volatile agents include desflurane, sevoflurane, isoflurane, halothane, enflurane, and methoxyflurane. Halothane is used less often now due to its link to MH.

Depolarizing Muscle Relaxant: Succinylcholine

Succinylcholine, used for rapid muscle relaxation, can also trigger MH, even without volatile agents. A warning sign can be severe rigidity of the jaw muscles (masseter muscle rigidity). Its use is approached with caution, especially in children, due to the risk of MH and potential underlying muscular issues.

The Pathophysiology: What Happens During a Malignant Hyperthermia Crisis?

MH is typically caused by a genetic defect, often in the RYR1 gene, which affects calcium release channels in muscle cells. Exposure to a triggering drug causes excessive calcium release into muscle cells from the sarcoplasmic reticulum.

This leads to a hypermetabolic state characterized by:

Sustained muscle contractions, causing rigidity and heat.
Increased metabolism, oxygen use, and carbon dioxide production.
Acidosis from lactic acid buildup.
Rapidly rising body temperature (hyperthermia), often a later sign.
Muscle breakdown (rhabdomyolysis), leading to high potassium (hyperkalemia) and myoglobin release, potentially causing heart and kidney problems.

Safe Anesthetic Alternatives and Management

For patients susceptible to MH, non-triggering anesthetics are essential. A thorough medical history, including family history, is vital for planning safe anesthesia.

Comparison of Triggering vs. Non-Triggering Agents


Anesthetic Agent Type	Triggering Potential	Examples of Drugs	Patient Management
Volatile Anesthetics	High Risk	Desflurane, Sevoflurane, Isoflurane, Halothane	Avoid. Use alternative agents and flush the anesthesia machine to remove residual volatile gases.
Depolarizing Muscle Relaxants	High Risk	Succinylcholine	Avoid. Use non-depolarizing relaxants or alternative techniques for muscle relaxation.
Intravenous Anesthetics	Safe	Propofol, Ketamine, Etomidate, Thiopental	Preferred. These agents can be used for induction and maintenance of general anesthesia.
Non-Depolarizing Muscle Relaxants	Safe	Rocuronium, Vecuronium, Cisatracurium	Preferred. These are safe alternatives to succinylcholine for muscle relaxation.
Inhaled Non-Volatile Anesthetics	Safe	Nitrous Oxide	Safe. Can be used as part of a balanced anesthetic technique.
Regional/Local Anesthesia	Safe	Lidocaine, Bupivacaine, Ropivacaine	Preferred. Excellent choice for many procedures, entirely avoiding general anesthesia triggers.

Emergency Management of an MH Crisis

Prompt action is critical during a suspected MH crisis. Key management steps include:

Immediately stopping all triggering anesthetic agents.
Administering dantrolene sodium intravenously as quickly as possible. Dantrolene is the specific antidote and helps reverse the hypermetabolic state by inhibiting calcium release.
Providing supportive care, such as hyperventilating with 100% oxygen, cooling the patient, and managing complications like electrolyte imbalances and acidosis. Calcium channel blockers should not be used.

Conclusion

Malignant hyperthermia is a life-threatening pharmacogenetic disorder caused by certain inhalational anesthetics and succinylcholine in susceptible individuals, primarily due to mutations in the RYR1 gene. This triggers uncontrolled calcium release in muscle cells, leading to a hypermetabolic crisis with symptoms like muscle rigidity, rapid heart rate, increased carbon dioxide, and hyperthermia. Rapid recognition and treatment with dantrolene are crucial for survival, significantly lowering mortality rates. Safe anesthetic alternatives are available, and with proper protocols, surgery can be safely performed on MH-susceptible patients. Awareness of MH and its triggers is essential for anesthesia providers.

Frequently Asked Questions

The earliest signs of a malignant hyperthermia reaction are typically an unexplained increase in heart rate (tachycardia) and a rise in end-tidal carbon dioxide levels, despite increased ventilation.

Yes. A susceptible individual can undergo uneventful anesthesia with triggering agents on multiple occasions and still react to them on a subsequent exposure. Past uneventful anesthetics do not guarantee future safety.

Yes, malignant hyperthermia susceptibility is inherited. It is an autosomal dominant disorder, meaning only one parent needs to carry the altered gene for their child to have a 50% chance of inheriting the condition.

The primary treatment is the immediate discontinuation of triggering agents and the intravenous administration of dantrolene sodium, the specific antidote. Supportive care, such as cooling measures and managing metabolic abnormalities, is also critical.

Safe anesthetic options include intravenous anesthetics like propofol and ketamine, the gas nitrous oxide, non-depolarizing muscle relaxants (e.g., rocuronium), and local or regional anesthesia.

While rare, some individuals with MH susceptibility can experience a hypermetabolic reaction from non-anesthetic triggers, including vigorous exercise or heat stress.

Early recognition of the signs is the most crucial factor for a good outcome. Rapid activation of the emergency protocol, including discontinuing triggers and administering dantrolene within minutes, is essential.