Malignant Hyperthermia (MH)

How malignant hyperthermia happens

Muscle contraction is controlled by calcium released from stores inside muscle cells through a channel called the ryanodine receptor (RYR1). In people with MH susceptibility, a genetic change makes this channel overactive in response to triggering drugs. Calcium floods the muscle cells, which contract continuously and burn energy at a furious rate. This produces:

• large amounts of carbon dioxide and heat
• muscle rigidity
• muscle breakdown (rhabdomyolysis), releasing potassium (hyperkalemia) and myoglobin into the blood
• acidosis

Without treatment, this can lead to heart rhythm problems, kidney failure, bleeding disorders and death.

Genetics

MH susceptibility is usually inherited in an autosomal dominant pattern: a person with one affected gene copy is susceptible, and each child has a 50 percent chance of inheriting it. Most cases involve variants in the RYR1 gene, with a smaller number in CACNA1S and STAC3. Susceptibility is estimated to be present in up to about 1 in 2,000 to 3,000 people, but reactions are much rarer because they require exposure to triggering drugs. Many susceptible people have had previous uneventful anesthetics.

MH is linked to certain muscle diseases, including central core disease and King-Denborough syndrome.

Signs of a reaction

Reactions usually begin during anesthesia but can occur up to about an hour after it ends. Signs include:

• Rising end-tidal carbon dioxide despite increased ventilation, often the earliest sign
• Jaw muscle rigidity (masseter spasm) after succinylcholine
• Generalized muscle rigidity
• Fast heart rate and irregular rhythms
• Rapidly rising body temperature, which can exceed 40 °C (104 °F). This is often a later sign
• Fast breathing in a patient breathing on their own
• Sweating and mottled skin
• Dark urine from myoglobin
• High potassium and acidosis on blood tests

Conditions that can look similar

Other causes of high temperature and rigidity include neuroleptic malignant syndrome from antipsychotic medicines, serotonin syndrome from serotonin-boosting drugs, heat stroke, thyroid storm and sepsis. Timing in relation to anesthesia is the key clue for MH.

Diagnosis

During a reaction

Diagnosis is based on the clinical picture in the operating room, supported by blood gases, potassium, creatine kinase (CK) and myoglobin levels. Treatment is not delayed for tests.

Testing for susceptibility

• Genetic testing for known RYR1, CACNA1S and STAC3 variants. A positive test confirms susceptibility, but a negative test does not rule it out because not all causative variants are known.
• Caffeine-halothane contracture test (or in vitro contracture test): a muscle biopsy from the thigh is exposed to caffeine and halothane in a specialized lab. It is the most sensitive test and is performed at a small number of centers.

Relatives of someone who had an MH reaction are offered genetic counseling and testing.

Treatment of an acute reaction

• Stop all triggering anesthetic agents immediately and switch to trigger-free anesthesia.
• Hyperventilate with 100 percent oxygen.
• Give dantrolene intravenously. Dantrolene blocks calcium release in muscle and is the specific antidote. Operating rooms that use triggering agents keep dantrolene readily available.
• Cool the patient with ice packs, cold IV fluids and other measures.
• Treat high potassium, acidosis and heart rhythm problems.
• Protect the kidneys with IV fluids to flush myoglobin.
• Intensive care monitoring for at least 24 hours, as reactions can recur.

Before dantrolene became available, MH was fatal in most cases. With rapid recognition and treatment, mortality is now low, generally under 5 percent.

Living with MH susceptibility

• Tell every surgeon, dentist and anesthesia provider about your susceptibility or family history.
• Wear a medical alert bracelet.
• Trigger-free general anesthesia (IV anesthetics such as propofol, opioids and non-depolarizing muscle relaxants), local anesthesia and regional anesthesia such as epidurals are safe.
• Avoid extreme exertion in hot environments and stay well hydrated, as some susceptible people have heat or exercise-related muscle breakdown.
• Relatives should be informed so they can be assessed.

Frequently asked questions

What is malignant hyperthermia?

Malignant hyperthermia is a rare inherited reaction to certain general anesthesia drugs, mainly anesthetic gases and succinylcholine. It causes a rapid rise in body temperature, muscle rigidity, fast heart rate and acid buildup. It is life-threatening but treatable with the antidote dantrolene.

What triggers malignant hyperthermia?

The triggers are volatile inhaled anesthetic gases, such as sevoflurane, desflurane and isoflurane, and the muscle relaxant succinylcholine. IV anesthetics like propofol, opioids, nitrous oxide, local anesthetics and non-depolarizing muscle relaxants are considered safe.

Is malignant hyperthermia genetic?

Yes. It is usually inherited in an autosomal dominant pattern, most often through variants in the RYR1 gene. Each child of a susceptible parent has a 50 percent chance of inheriting it. A family history of anesthesia problems should always be shared before surgery.

Can you have anesthesia if you are MH susceptible?

Yes. People with MH susceptibility can safely have surgery using trigger-free general anesthesia, regional anesthesia such as epidurals, or local anesthesia. The anesthesia team prepares the equipment to remove traces of anesthetic gases and keeps dantrolene available.