Malignant Hyperthermia: Symptoms, Types, Causes and Treatment

Malignant hyperthermia (MH) is a rare but life-threatening pharmacogenetic disorder that can strike without warning, most often in the context of anesthesia for routine surgery. Prompt recognition and management are critical for survival, as the syndrome can rapidly spiral into a medical emergency. In this article, we'll explore the hallmark symptoms of MH, the types and variants recognized in clinical practice, the underlying causes—including genetic mutations and triggering agents—and the best practices for treatment and acute management. Our aim is to provide a thorough, up-to-date, and accessible overview for both medical professionals and curious readers alike.

Symptoms of Malignant Hyperthermia

Malignant hyperthermia doesn’t always announce itself in dramatic fashion, but when it does, classic symptoms can appear suddenly and progress rapidly. Early recognition is vital, as mortality remains high if treatment is delayed. Let’s look at the characteristic symptoms, how they can vary (especially in children), and key indicators that can help clinicians act swiftly.

Symptom	Description	Onset/Context	Source(s)
Muscle Rigidity	Stiffness, especially jaw/trunk	Early/acute	1,2,3
Rapid Temperature Rise	Sudden, high fever	Within minutes to hours	1,2,3,4
Tachycardia	Fast heart rate	Early/acute	2,3,4
Hypercarbia	Elevated CO₂ despite ventilation	Early/acute	2,3,5
Acidosis	Metabolic and respiratory	Early	1,2,4,5
Hyperkalemia	High blood potassium	Later/complication	2,3,4
Rhabdomyolysis	Muscle breakdown, high CK	Complication	2,5
Skin Mottling	Discoloration (esp. in infants)	Early/variant	3

Table 1: Key Symptoms

Classic Presentation

The most dramatic form of MH typically unfolds in the operating room soon after exposure to triggering anesthetics or muscle relaxants. The initial signs often include:

• Muscle rigidity: Especially in the jaw (masseter spasm) and trunk.
• Rapidly rising body temperature: Sometimes exceeding 40°C (104°F) within minutes.
• Tachycardia and tachypnea: Fast heart and breathing rates as the body struggles to compensate.
• Hypercarbia: A major early clue is an inexplicably high end-tidal CO₂ despite increased ventilation.
• Acidosis: Both metabolic and respiratory, due to excessive CO₂ and lactic acid production.
• Hyperkalemia and rhabdomyolysis: Muscle breakdown leads to a spike in potassium and creatine kinase, which can cause cardiac arrhythmias and kidney injury if not managed promptly 1,2,4,5.

Variations Across Age Groups

MH doesn’t look the same in every patient. In children, for example, the presentation and severity can differ:

• Infants (0–24 months) may have more pronounced skin mottling and metabolic acidosis, but muscle rigidity is less common.
• Older children and teenagers tend to show higher fevers, more severe potassium increases, and classic tachycardia and hypercarbia 3.

Early Detection and Diagnostic Clues

A rise in end-tidal CO₂ that persists despite increasing ventilation is one of the most sensitive and early indicators of MH. This change often precedes the temperature spike or overt muscle rigidity, making it a crucial sign for anesthesiologists to monitor closely 2,5.

Types of Malignant Hyperthermia

Malignant hyperthermia is not a singular entity; rather, it represents a spectrum of clinical presentations and underlying susceptibilities. Understanding these types helps tailor both diagnosis and prevention strategies.

Type	Characteristics/Presentation	Genetic Pattern	Source(s)
Classic MH	Acute, full-blown syndrome	Autosomal dominant	2,8,13
Subclinical/Mild	Mild or delayed symptoms	Often undiagnosed	8
Pediatric Variant	Age-dependent symptom variation	Varies	3
Associated Myopathy	Linked to muscle diseases	RYR1/CACNA1S mutations	10,13

Table 2: Types and Variants of MH

Classic Malignant Hyperthermia

The "classic" type is what most clinicians are trained to recognize: sudden onset muscle rigidity, hyperthermia, and metabolic crisis after anesthesia. This form is typically inherited in an autosomal dominant pattern in humans, meaning a single copy of the mutated gene can confer susceptibility 2,13.

Subclinical and Atypical Presentations

Not all cases are dramatic. Some individuals may have:

• Mild or delayed symptoms: Slight increases in CO₂ or temperature, minimal rigidity, or symptoms only after significant exposure to triggering agents.
• Recrudescence: Symptoms that reappear after initial treatment, seen in about 14% of pediatric cases 3,8.

Pediatric Variants

Children—especially infants—can present differently, with less muscle rigidity and more pronounced metabolic acidosis or skin changes. This emphasizes the need for age-appropriate diagnostic vigilance 3.

MH Associated with Myopathies

Some forms of MH are associated with congenital muscle diseases (e.g., central core disease), and are linked to specific genetic mutations in the RYR1 or CACNA1S genes. These variants may also show susceptibility to non-anesthetic triggers, such as vigorous exercise or heat stress 10,13.

Causes of Malignant Hyperthermia

At its core, malignant hyperthermia is caused by a disturbance in calcium regulation within skeletal muscle cells. This defect is usually latent until triggered by specific agents or stressors.

Cause	Mechanism/Trigger	Genetic Basis	Source(s)
Volatile Anesthetics	Trigger uncontrolled Ca²⁺ release	Autosomal dominant (mainly)	2,4,14
Succinylcholine	Depolarizing muscle relaxant	Enhances anesthetic effect	2,14
Genetic Mutation	Defective RYR1 or CACNA1S genes	Inherited susceptibility	2,10,11,12,13
Non-Anesthetic Triggers	Exercise, heat, stress	Rare in humans	2,10

Table 3: Causes and Triggers

Triggers: Anesthetic Agents and Beyond

Potent volatile anesthetics (halothane, sevoflurane, desflurane, isoflurane) and the muscle relaxant succinylcholine are the classic triggers of MH. These agents cause a massive, uncontrolled release of calcium from the sarcoplasmic reticulum of skeletal muscle, leading to the hypermetabolic crisis 2,4,14.

• Succinylcholine, while acting as a trigger, is especially dangerous when combined with volatile anesthetics 14.
• Non-depolarizing muscle relaxants may actually be protective in some cases 14.

Genetic Susceptibility

Most cases of MH are inherited as an autosomal dominant trait, primarily due to mutations in:

• RYR1 gene: Encodes the ryanodine receptor, the principal calcium release channel in skeletal muscle. Over 400 variants have been identified, with at least 34 proven causal for MH 2,10,12,13.
• CACNA1S gene: Encodes the alpha-1 subunit of the dihydropyridine-sensitive L-type calcium channel. While rarer, mutations here are also implicated 11,13.

Other loci and genes may play a role, indicating considerable genetic heterogeneity 13.

Non-Anesthetic Triggers

While rare in humans, severe physical exertion or environmental heat can occasionally trigger MH in susceptible individuals, a phenomenon more commonly seen in animals or in the context of certain myopathies 2,10.

Pathophysiology: The Calcium Cascade

• The genetic mutations result in leaky or hypersensitive calcium channels in muscle cells.
• Exposure to triggers leads to an uncontrolled flood of calcium, which fuels sustained muscle contraction and hypermetabolism.
• This cascade results in the rapid development of acidosis, hyperthermia, and cellular injury 2,12,13.

Treatment of Malignant Hyperthermia

Rapid, targeted intervention is crucial in managing MH. The mainstay of treatment is pharmacological, but comprehensive supportive care is equally vital for survival.

Treatment	Action/Goal	Notes	Source(s)
Dantrolene Sodium	Blocks abnormal Ca²⁺ release	Specific antidote; must be available in OR	2,4
Immediate Discontinuation	Stop triggering agents	First step	1,2,4
Supportive Measures	Cooling, hydration, electrolyte correction	Prevent complications	1,2,4,5
Monitoring	Vital signs, labs, CK, K⁺, renal function	Ongoing assessment	3,5

Table 4: Main Treatments

Emergency Management Steps

1. Discontinue Triggering Agents

• Immediately stop all volatile anesthetics and succinylcholine.
• Switch to non-triggering agents if anesthesia must continue 1,2,4.

2. Administer Dantrolene Sodium

• Dantrolene is the only specific antidote for MH.
• It acts by inhibiting calcium release from the sarcoplasmic reticulum, halting the hypermetabolic process.
• Prompt administration dramatically improves outcomes; mortality has fallen from 80% to less than 5% in centers with rapid dantrolene access 2,4.

3. Supportive Care

• Active cooling: Use ice packs, cooling blankets, or cold IV fluids to reduce body temperature.
• Correct acidosis and electrolyte imbalances: IV fluids, bicarbonate, and insulin-glucose may be needed for hyperkalemia.
• Treat arrhythmias: Avoid calcium channel blockers, as they may worsen the condition in the presence of dantrolene.
• Monitor for renal failure: Aggressive hydration and diuresis can help prevent kidney damage from myoglobinuria secondary to rhabdomyolysis 1,2,4,5.

Ongoing Monitoring and Prevention

• Close monitoring: Vital signs, urine output, blood gases, potassium, and creatine kinase levels must be tracked.
• Be alert for recrudescence: Symptoms can recur after apparent stabilization, requiring repeated doses of dantrolene and continued observation 3.

Preventive Strategies

• Preoperative screening: Family history and, where indicated, genetic testing or in vitro contracture testing (IVCT) can identify at-risk individuals 2,13.
• Anesthesia planning: Use only non-triggering anesthetics and ensure dantrolene is readily available in all operative settings 2,4.

Conclusion

Malignant hyperthermia, while rare, is a medical emergency that demands vigilance, rapid recognition, and decisive action. Understanding its symptoms, types, genetic causes, and best-practice treatments is crucial for healthcare providers—and can be lifesaving for patients.

Key takeaways from this article:

• Symptoms: Rapid onset muscle rigidity, hyperthermia, tachycardia, hypercarbia, acidosis, and rhabdomyolysis are hallmark features. Early detection is vital 1,2,3,4,5.
• Types: MH encompasses classic, mild, pediatric, and myopathy-associated variants, with clinical presentations varying by age and genetic background 2,3,8,10,13.
• Causes: MH is triggered by specific anesthetics in genetically susceptible people, most often due to RYR1 or CACNA1S mutations, and involves dysregulated calcium handling in muscle cells 2,10,11,12,13,14.
• Treatment: Immediate cessation of triggers, rapid administration of dantrolene, and aggressive supportive care are essential for survival. Preventive strategies and preparedness are equally important 1,2,3,4,5,13.

By staying informed and prepared, we can continue to reduce the risks and ensure the best outcomes for those susceptible to malignant hyperthermia.