Malignant Hyperthermia: Causes, Symptoms, Diagnosis, and Treatment

What is Malignant Hyperthermia?

Malignant hyperthermia (MH) is a rare, inherited genetic disorder that, in the vast majority of cases, manifests following the administration of certain drugs used in general anesthesia, particularly halogenated volatile gases and succinylcholine. More recently, it has been demonstrated that MH can also be triggered by severe physical stressors, such as intense physical exercise or extreme heat exposure.

The initial clinical manifestations include:

• Muscle rigidity, which often starts with jaw stiffness (masseter spasm), is a common symptom
• Tachycardia refers to an elevated heart rate
• Tachypnea refers to an elevated respiratory rate
• Hyperthermia: body temperature exceeding 40°C (104°F) and potentially rising to 46°C (115°F) if untreated

These manifestations arise from an abnormal reaction of anesthetic drugs on skeletal muscle cells, triggering an uncontrolled acceleration of metabolic activity and generating sustained, powerful muscular contractions throughout the body.

If not promptly recognized and treated, MH can rapidly progress to a severe shock state complicated by:

• Acute renal failure
• Acute respiratory failure
• Cardiac arrest

The syndrome may develop as early as a few minutes after drug administration or may be delayed by up to 12 hours. However, most cases appear within the first hour of anesthetic exposure.

There is no cure for the underlying genetic condition. However, early recognition enables rapid discontinuation of the triggering agents and immediate implementation of cooling measures and symptom management, dramatically improving outcomes.

Malignant hyperthermia is a genetically determined, autosomal dominant condition transmitted from parent to child. Diagnosis of susceptibility can be confirmed through genetic testing, which identifies specific mutations in the genes responsible for the disorder.

Thanks to major advances in understanding the clinical presentation and pathophysiology of MH, mortality has fallen from approximately 80% thirty years ago to less than 5% today. This dramatic improvement highlights the importance of anesthesiology awareness, preparedness, and dantrolene availability.

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Causes

Malignant hyperthermia is caused by a mutation in a gene located on chromosome 19p. Specifically, the causative gene is designated RYR-1 and encodes the ryanodine receptor type 1 (RyR1), a calcium release channel found on the sarcoplasmic reticulum of skeletal muscle cells. This receptor plays a central role in regulating intracellular calcium levels and, consequently, in controlling muscle contraction.

The condition follows an autosomal dominant inheritance pattern, meaning:

• It can be transmitted from either parent to a child, regardless of sex
• A 50% probability of inheritance exists for each child of an affected parent
• The presence of the mutation on only one of the two homologous chromosomes is sufficient for the disease to potentially manifest

To date, more than 90 distinct mutations in the RYR-1 gene have been identified. However, only a subset of these are definitively causative of malignant hyperthermia. Additional mutations in the CACNA1S gene (encoding a voltage-sensitive calcium channel subunit) account for a small proportion of cases.

MH is rare but not negligible: its incidence ranges from 1 in 5,000 to 1 in 100,000 general anesthetics, depending on the population studied. However, the frequency of susceptibility-conferring genetic mutations in the general population is substantially higher. These mutations affect approximately 1 in 3,000 individuals, as many carriers never undergo triggering anesthetic exposure. Notably, MH susceptibility also occurs in certain animal species, including pigs, dogs, and horses.

Disease Mechanisms

When the RYR-1 receptor carries a causative mutation, its function is dysregulated: upon exposure to triggering anesthetic agents, the receptor becomes hyperactivated, releasing a massive and uncontrolled flood of calcium from the sarcoplasmic reticulum into the muscle cell cytoplasm.

This abnormal calcium surge drives:

1. Sustained, generalized skeletal muscle contraction, also known as rigidity, occurs because calcium acts as the essential trigger for muscle fiber contraction.
2. Explosive increase in metabolic rate: muscle cells consume enormous amounts of ATP and oxygen in their futile attempt to pump excess calcium out of the cytoplasm.
3. Rapid, severe hyperthermia occurs when body temperature rises at a rate of 1°C every 5 minutes. This can lead to life-threatening levels, often exceeding 41°C and sometimes reaching as high as 46°C.

The consequences of this uncontrolled metabolic storm cascade throughout the body:

• Hypercapnia occurs when there is a markedly increased production of carbon dioxide due to hypermetabolism.
• Hypoxemia: decreased blood oxygen saturation, since oxygen is rapidly consumed by overactive muscles.
• Rhabdomyolysis is the destruction of skeletal muscle fibers, which releases myoglobin and intracellular contents into the bloodstream.
• Hyperkalemia is a dangerous elevation of potassium in the blood. It occurs when potassium is released from damaged muscle cells and can trigger fatal cardiac arrhythmias.
• Metabolic and respiratory acidosis, caused by CO₂ accumulation and lactic acid production.
• Disseminated intravascular coagulation (DIC), particularly in the most severe and prolonged cases.

Triggering Drugs

The anesthetic agents known to trigger malignant hyperthermia in susceptible individuals include:

Volatile Halogenated Anesthetic Gases

• Halothane, the classic triggering agent, has now been largely withdrawn from use in developed countries.
• Sevoflurane, widely used in modern anesthetic practice, is a potent MH trigger.
• Desflurane can also trigger MH in susceptible patients.
• Isoflurane, also a recognized trigger.

All volatile halogenated agents directly activate the mutant RyR1 receptor, initiating the pathological calcium release cascade.

Depolarizing Neuromuscular Blocking Agent

• Succinylcholine (suxamethonium) is a depolarizing neuromuscular blocker. It is widely used to achieve rapid muscle relaxation for endotracheal intubation and surgical procedures involving the abdomen and thorax. When combined with a volatile agent in a susceptible patient, the risk and severity of MH are substantially increased.

Important: All other classes of anesthetic agents, including non-depolarizing neuromuscular blockers, propofol, opioids, benzodiazepines, local anesthetics, and nitrous oxide, are considered safe for use in MH-susceptible patients.

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Symptoms

Malignant hyperthermia is triggered in the vast majority of cases during the administration of general anesthesia, though in some patients, the onset may be delayed by up to several hours after exposure.

The initial signs and symptoms vary depending on which triggering agents are used and the degree of the patient’s genetic susceptibility. However, the first sign is almost always rigidity of the masseter muscle, the main jaw-closing muscle. This may appear as difficulty opening the mouth after succinylcholine administration, a phenomenon called masseter muscle rigidity (MMR).

Subsequent manifestations include:

• Rapidly rising body temperature: fever that escalates at an alarming rate, often exceeding 40°C.
• Generalized muscle spasms and rigidity, which involve all major muscle groups.
• Tachycardia sometimes occurs alongside dangerous cardiac arrhythmias.
• Tachypnea reflects the body’s attempt to eliminate excess CO₂.
• Profuse sweating, as the body attempts to dissipate heat.
• Skin mottling or cyanosis in severe cases

In the operating room context, early warning signs detectable by monitoring include:

• An unexpected rise in end-tidal CO₂ (ETCO₂) on capnography, often the earliest measurable sign.
• Unexpected increase in oxygen consumption.
• Acidosis on arterial blood gas analysis.

If untreated, the syndrome progresses rapidly toward life-threatening organ failure:

• Acute renal failure can result from myoglobinuria, where reddish-brown urine serves as a warning sign of rhabdomyolysis.
• Respiratory failure
• Cardiac arrest can result from severe hyperkalemia or arrhythmia.
• Disseminated intravascular coagulation (DIC)
• Cerebral edema and brain damage

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Diagnosis

The diagnosis of malignant hyperthermia during an acute episode is primarily clinical, relying on the rapid recognition of characteristic signs in the perioperative context. There is no bedside test that can confirm the diagnosis in real time; therefore, clinical suspicion must be acted upon immediately without awaiting laboratory confirmation.

Clinical Diagnosis

Recognition rests on the constellation of early warning signs appearing shortly after anesthetic induction:

• Masseter muscle rigidity
• Unexplained, rapidly rising ETCO₂
• Tachycardia and cardiac arrhythmias
• Increasing body temperature
• Metabolic and respiratory acidosis
• Generalized muscle rigidity

Rhabdomyolysis, the destruction of skeletal muscle fibers, may be identified by:

• Markedly elevated serum creatine kinase (CK) levels
• Red-brown (cola-colored) urine due to myoglobinuria

Genetic Testing

Genetic analysis targets known RYR-1 and CACNA1S mutations on chromosome 19 and chromosome 1, respectively. Genetic testing can identify susceptible individuals before any anesthetic exposure, but the absence of a known mutation does not completely exclude susceptibility, as not all causative variants have been catalogued.

In Vitro Contracture Test (IVCT): The Gold Standard for Susceptibility Testing

The In Vitro Contracture Test (IVCT), also known as the Caffeine-Halothane Contracture Test (CHCT) in North America, is the definitive diagnostic test for MH susceptibility. The procedure involves:

1. Muscle biopsy is typically taken from the vastus lateralis (the thigh muscle) under local anesthesia
2. Laboratory exposure of the fresh biopsy specimen to increasing concentrations of caffeine and halothane
3. Measurement of contractile response: Susceptible muscle tissue contracts at lower concentrations than normal tissue

Because it is invasive and technically demanding, the IVCT is reserved for specific patient groups. It is indicated in individuals with:

• Family history of malignant hyperthermia
• Prior personal episode of MH or suspected MH
• Exertional rhabdomyolysis: episodes of muscle breakdown after moderate physical exertion
• Known or suspected neuromuscular disease (e.g., central core disease, multiminicore disease)
• Prior episode of neuroleptic malignant syndrome
• History of severe, frequent muscle cramps and easy fatigability

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Treatment

Since MH is caused by an underlying genetic mutation, no curative treatment exists. Management is therefore focused on immediate emergency intervention aimed at halting the triggering cascade and controlling its life-threatening consequences.

Emergency Protocol: Step-by-Step

Upon recognition or strong suspicion of MH, the anesthesiologist must act immediately and decisively:

1. Declare a medical emergency: activate the emergency team and call for help.
2. Immediately discontinue all triggering agents. Stop all volatile anesthetic gases and succinylcholine at once. If possible, remove the vaporizer.
3. Hyperventilate with 100% oxygen. Increase oxygen flow to the maximum to flush out volatile agents and compensate for hypercapnia. If available, use fresh breathing circuits.
4. Administer dantrolene sodium at high doses (2.5 mg/kg IV bolus). Repeat every 5 minutes until symptoms resolve; total doses of 10 mg/kg or more may be required. Dantrolene is a skeletal muscle relaxant that directly inhibits RyR1, blocking pathological calcium release. It is the only specific pharmacological antidote for MH and must be available in all facilities where volatile anesthetics are used.
5. Active physical cooling:
   • Apply cold, wet towels to the skin surface
   • Place ice packs in the axillae, groin, and neck (areas of superficial major blood vessels)
   • Administer cold intravenous fluids (saline at 4°C, up to 15 mL/kg over 15 minutes)
   • Continue cooling until core body temperature falls below 38.5°C (101.3°F)
6. Treat metabolic complications:
   • Sodium bicarbonate for severe metabolic acidosis
   • Calcium chloride or gluconate and insulin/glucose for hyperkalemia-induced arrhythmias
   • Antiarrhythmic drugs (avoid calcium channel blockers, as they are dangerous when combined with dantrolene)
7. Monitor closely: continuously track core temperature, ETCO₂, cardiac rhythm, arterial blood gases, electrolytes, renal function, and urine output. Aim for a urine output of more than 1 mL/kg/h to prevent myoglobin-related renal injury
8. Transfer to ICU for continued dantrolene infusion and monitoring for at least 24–48 hours, as MH can recur

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Prevention

Unfortunately, routine preoperative workup does not reliably identify MH susceptibility, as standard blood tests, ECG, and imaging do not screen for the condition.

Creatine Kinase (CK) Screening

Preoperative measurement of creatine kinase (CK) can provide a partial indication of muscle vulnerability, as some (though not all) MH-susceptible individuals have chronically elevated baseline CK levels. However, this is neither sensitive nor specific enough to serve as a reliable screening tool.

Genetic Testing for At-Risk Individuals

Genetic testing for known RYR-1 and CACNA1S mutations is available and can identify susceptible individuals. However, a negative genetic test does not guarantee safety, as many causative mutations have yet to be characterized. A positive result warrants documented MH susceptibility status and specific precautions for all future anesthetic procedures.

Important Consideration: Prior Safe Anesthesia Is Not Reassuring

A history of previous uneventful general anesthesia does not exclude MH susceptibility. An individual may have undergone multiple prior anesthetics without incident. However, they can still develop MH if certain triggering conditions, like a specific drug combination, dose, or physiological context, were not previously encountered.

Precautions for MH-Susceptible Patients Undergoing Surgery

When a known or suspected MH-susceptible patient requires surgery, the following strict precautions must be implemented:

• Use only non-triggering anesthetic agents: total intravenous anesthesia (TIVA) using propofol, opioids, non-depolarizing neuromuscular blockers, and nitrous oxide (all considered safe)
• Use a dedicated, vapor-free anesthetic machine: the breathing circuit, vaporizers, and carbon dioxide absorber must be thoroughly purged and free from residual volatile agents (flushing with high-flow oxygen for at least 20 minutes with the vaporizer removed)
• Pre-stock all emergency medications: dantrolene (minimum 36 vials, 720 mg, must be immediately accessible in the operating room), sodium bicarbonate, cold IV fluids, and other resuscitation drugs
• Continuous core temperature monitoring throughout the procedure
• Avoid additional at-risk drugs: phenothiazines and haloperidol are also contraindicated in MH-susceptible patients, as they may lower the threshold for triggering reactions
• Extended postoperative monitoring in a recovery area equipped for MH management
• Patient and family counseling: all first-degree relatives of an MH-susceptible individual should be considered potentially susceptible and counseled accordingly. The patient should carry a medical alert card or wear a medical alert bracelet.

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Sources and Bibliography

• Hopkins PM, Gupta PK, Bilmen JG. Malignant hyperthermia. Handb Clin Neurol. 2018
• Riazi S, Kraeva N, Hopkins PM. Malignant Hyperthermia in the Post-Genomics Era: New Perspectives on an Old Concept. Anesthesiology. 2018
• Kollmann-Camaiora A, Alsina E, Domínguez A, et al. Clinical protocol for the management of malignant hyperthermia. Rev Esp Anestesiol Reanim. 2017
• SIAARTI Clinical Standards: Management and Treatment of Malignant Hyperthermia. 2016
• European Malignant Hyperthermia Group (EMHG): Guidelines for the Investigation of Malignant Hyperthermia Susceptibility
• Malignant Hyperthermia Association of the United States (MHAUS)
• Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet Journal of Rare Diseases. 2015