Malignant Hyperthermia

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle characterized by a life-threatening hypermetabolic reaction triggered by volatile anesthetics and succinylcholine ^{[2]A1c[3]A1c[5]B3b[9]D5[15]B3b}. Also called malignant hyperpyrexia or familial malignant hyperthermia, the condition arises from uncontrolled calcium release from the sarcoplasmic reticulum via the ryanodine receptor type 1 (RYR1) in genetically predisposed individuals ^[1]A1c[3]A1c.

Classification

MH susceptibility (MHS) is diagnosed by the in vitro contracture test (IVCT) or the calcium-induced calcium release (CICR) test, with the European Malignant Hyperthermia Group (EMHG) 2025 guidelines introducing a new diagnostic designation, the MH genotype, based on pathogenic variants in RYR1, CACNA1S, or STAC3 ^{[2]A1c[3]A1c[9]D5}. The Larach clinical grading scale provides a standardized tool for retrospective case definition, with a threshold of 45 points yielding a specificity of 90% and sensitivity of 59% ^[5]B3b. The clinical presentation is classified as a definite MH event when the Larach raw score exceeds 50, but treatment must begin immediately on suspicion without waiting for a formal score ^[3]A1c.

Pain Phenotype

MH is not a chronic pain condition and does not have a nociceptive, neuropathic, or nociplastic pain phenotype. The acute crisis itself produces severe muscle pain and rigidity due to sustained contraction and rhabdomyolysis , but this is a symptom of the hypermetabolic state rather than a distinct pain syndrome. The therapeutic spine of MH management centers on aborting the hypermetabolic cascade with dantrolene, not on analgesic pathways ^[3]A1c.

Clinical Significance

MH is a medical emergency: the incidence is 0.18-3.9 per 100,000 general anesthesia procedures, and while mortality has fallen from 70-80% in the 1960s to ≤10% with dantrolene, rapid recognition and treatment remain essential ^[3]A1c. The next section details the molecular mechanisms, the RYR1 calcium channel dysregulation, that explain the clinical features described above.

Pearl: The Larach clinical grading scale provides a standardized retrospective definition, but treatment must begin on clinical suspicion alone.

From this definition, the core pathophysiological event is an uncontrolled rise in myoplasmic calcium triggered by volatile anesthetics or succinylcholine ^[34]D5[35]D5. This cascade originates from a genetic defect in the skeletal muscle calcium release channel, the ryanodine receptor type 1 (RyR1), or less commonly the voltage-gated calcium channel Cav1.1 (encoded by CACNA1S) ^[21]D5[34]D5. Over 400 variants have been identified in the RYR1 gene, of which at least 34 are causal for MH; the prevalence of genetic abnormalities may be as high as 1 in 400 individuals ^[34]D5. Inheritance is autosomal dominant in humans ^[34]D5[35]D5. A third gene, STAC3, is also associated with MH susceptibility ^[21]D5.

The Calcium Release Cascade

Volatile anesthetics (halothane, sevoflurane, desflurane, isoflurane) and succinylcholine bind to the mutant RyR1, causing a sustained, uncontrolled release of Ca2+ from the sarcoplasmic reticulum into the myoplasm ^[24]D5[32]D5. This triggers a positive-feedback loop within excitation-contraction coupling: elevated myoplasmic Ca2+ activates further RyR1 opening, leading to a massive calcium overload ^[32]D5. The result is simultaneous activation of muscle contraction (rigidity) and metabolic machinery ^[34]D5.

Metabolic Consequences

The sustained calcium elevation drives hypermetabolism: ATP consumption accelerates, oxidative phosphorylation is uncoupled, and heat production skyrockets ^[25]C4[34]D5. Increased CO2 production outpaces ventilation, causing an early rise in end-tidal CO2 ^[34]D5. Anaerobic metabolism generates lactic acidosis , while ATP depletion compromises membrane integrity, leading to hyperkalemia and rhabdomyolysis ^[35]D5. The hypermetabolic state also increases oxygen consumption and produces a mixed respiratory and metabolic acidosis ^[29]D5. If untreated, core temperature can rise >1°C every 5 minutes, and rhabdomyolysis may cause acute kidney injury and life-threatening hyperkalemia ^[29]D5[34]D5.

Chronic Manifestations and Overlap Syndromes

Even in the absence of anesthetic triggers, MHS patients often experience myopathic symptoms due to a chronic RyR1 calcium leak ^[21]D5. This sustained leak increases mitochondrial electron transport chain activity, oxidative stress, and posttranslational RyR1 modifications that further impair calcium homeostasis ^[21]D5. MHS patients have impaired aerobic metabolism, with lower ATP production via oxidative pathways and reduced aerobic and anaerobic capacity compared to healthy controls ^[23]B3b. Exertional heat illness and exertional rhabdomyolysis share overlapping mechanisms with MH: all three are hypermetabolic states driven by uncontrolled intracellular calcium rise, high ATP demand, and oxidative stress ^[25]C4[32]D5. Transcriptomic studies show that MHS patients have downregulation of oxidative phosphorylation genes, while exertional heat illness patients upregulate inflammatory response genes, suggesting a common underlying pathophysiology ^[30]B3b.

These pathophysiological events produce the clinical triad of hyperthermia, hypercarbia, and muscle rigidity that form the basis for early recognition and acute management discussed in the following sections.

Pearl: The earliest sign of an MH crisis is an unexplained rise in end-tidal CO2 despite increased minute ventilation; this reflects the hypermetabolic state before hyperthermia develops ^[34]D5.

From the molecular defect in the ryanodine receptor emerges an epidemiologic picture of a rare, sex-dependent, and incompletely penetrant disorder. The recorded incidence of MH in the United States rose from 10.2 to 13.3 cases per million hospital discharges between 2000 and 2005, a statistically significant increase ^[45]C4. Across four US states, the prevalence per 100,000 hospital discharges ranged from 1.23 (95% CI 0.80-1.66) in New York to 1.91 (95% CI 1.48-2.34) in California; among surgical inpatients, prevalence reached 2.86 per 100,000 surgical discharges in Florida (95% CI 2.00-3.71) ^[55]B3b. In Japan, 17 MH reactions were identified among 1,238,171 general anesthesia procedures, a rate of approximately 1.4 per 100,000 ^[48]D5. The estimated annual number of MH events in US ambulatory surgery centers is 47 ^[49]D5.

Demographic Distribution

MH can occur at any age. The median age of affected patients in a US nationwide sample was 39 years (interquartile range 23-54), and children (≤18 years) accounted for only 17.8% of cases ^[45]C4. Pediatric series from North America (264 cases) and Japan (187 cases) demonstrate that clinical features vary by age group, but the condition is not confined to infancy or childhood ^{[42]B3b[43]B3b}.

Sex is a strong independent risk factor. Males are substantially more likely to develop MH. In a multicenter case-control study of RYR1 mutation carriers, the odds ratio for males versus females was 2.37 (95% CI 1.36-4.12) ^[44]B3b. A Japanese database study reported a similar male predominance (OR 3.49) ^[48]D5.

Risk Factors

Genetic Etiology and Penetrance

MH is a pharmacogenetic disorder with an autosomal dominant inheritance pattern in most families. Mutations in the ryanodine receptor 1 gene (RYR1) account for approximately half of cases ^[44]B3b. The overall penetrance of nine diagnostic RYR1 mutations was 40.6% (93 of 229 genotype-positive individuals), with no statistical difference among the specific mutations ^[44]B3b. Importantly, the likelihood of developing MH on exposure to trigger agents among all RYR1 mutation carriers was 0.25, but among probands (survivors of a previous MH reaction) it rose to 0.76 (95% CI of the difference 0.41-0.59) ^[44]B3b. This reinforces that a previous uneventful anesthetic does not preclude the possibility of developing MH ^[44]B3b. The median age of probands was 12 years (interquartile range 6-32.5) ^[44]B3b.

Associated Conditions

Exertional heat illness, exertional rhabdomyolysis , and idiopathic hyperCKemia have been associated with MH susceptibility, although the evidence for a causal relationship is weak ^{[25]C4[50]D5[52]C4}. In one series of 37 subjects with idiopathic hyperCKemia, in vitro contracture testing identified only one MH-susceptible and one MH-equivocal individual ^[50]D5. The Malignant Hyperthermia Association of the United States recommends that patients with a history of unexplained exertional heat illness or rhabdomyolysis be considered for MH workup, but controlled clinical studies supporting this are lacking ^[25]C4.

Temporal Trends in Mortality

Despite increased awareness, MH mortality remains substantial. In-hospital mortality in the United States between 2000 and 2005 ranged from 6.5% to 16.9% per year (P<0.0001) ^[45]C4. In a four-state analysis, 11% of patients with a recorded MH diagnosis died on discharge ^[55]B3b. In the Japanese pediatric cohort, overall mortality was 15.5%, but declined to 8.8% in the period 2000-2020 ^[42]B3b. Children had lower mortality than adults (0.7% vs 14.1%, P<0.0001) ^[45]C4.

These epidemiologic patterns, the rarity of the disorder, the male predominance, the incomplete penetrance of RYR1 mutations, and the persistent mortality, inform the clinical vigilance needed when volatile anesthetics or succinylcholine are used. The next section details the signs and symptoms that should trigger immediate recognition of an MH crisis.

Pearl: In-hospital mortality remains high (6.5%-16.9%), with lower mortality in children (0.7% vs 14.1% in adults).

The clinical features of malignant hyperthermia are as heterogeneous as the genetic mutations that underlie it, with age, sex, and the type of anesthetic exposure influencing the early presentation ^{[42]B3b[44]B3b}.

Symptoms

Patient-reported symptoms are rare because MH typically emerges during general anesthesia. In the prodromal phase after succinylcholine, the awake patient may describe muscle fasciculations, jaw pain, or palpitations. Masseter spasm may be reported as difficulty opening the mouth. In children, the first recognized manifestation (often noted by the parent or clinician) is elevated temperature (46.7% in the 0-24 month age group) or generalized muscular rigidity (26.7%) ^[42]B3b. In older children (2-12 yr), masseter spasm (35.0%) and generalized rigidity (19.5%) predominate; in adolescents (13-18 yr), a rising end-tidal CO₂ (26.5%) and tachycardia (22.4%) are the earliest clues ^[42]B3b.

Signs

Physical examination and monitoring reveal a constellation of findings that cluster by organ system:

• Cardiovascular: Sinus tachycardia is the most common sign. Arrhythmias, hypotension, and eventually cardiac arrest may follow.
• Respiratory: Tachypnea, an unexplained increase in end-tidal CO₂ despite high minute ventilation, and respiratory acidosis .
• Musculoskeletal: Masseter spasm, generalized muscle rigidity, rhabdomyolysis (elevated creatine kinase, myoglobinuria, dark urine). Dark urine was noted in 75.5% of the middle pediatric cohort (2-12 yr) ^[42]B3b.
• Metabolic: Hyperthermia is often a late sign; metabolic acidosis, hyperkalemia, and hypocalcemia occur as the crisis progresses.
• Laboratory: Peak CK is highest in the 2-12 yr group ^[42]B3b. Myoglobinuria, DIC, and elevated lactate are common in fulminant cases.

Onset and Progression

Tachycardia and rising ETCO₂ are often the earliest signs, appearing within minutes of trigger exposure ^[63]A1c. Masseter spasm may occur immediately after succinylcholine ^[64]A1c. Hyperthermia is a late sign, and treatment delay increases complications every 10 min, reaching 100% at a 50-min delay ^[59]B2a. Modern agents (desflurane, sevoflurane, isoflurane) can cause a delayed onset of several hours ^[68]D5.

Phenotypic Variants

Red Flags

• Masseter spasm (especially after succinylcholine) ^[64]A1c
• Unexplained tachycardia, tachypnea, or rising ETCO₂ ^[63]A1c
• Metabolic acidosis disproportionate to respiratory effort
• Hyperthermia (rectal >38.8 °C) ^[63]A1c
• Failure of CO₂ to decrease with increased minute ventilation

Atypical Presentations

• MH without hyperthermia (early or abortive forms)
• Postoperative rhabdomyolysis (e.g., in Duchenne muscular dystrophy) ^[70]D5
• Recurrent MH after initial treatment, requiring ongoing dantrolene ^[64]A1c

Pearl: The earliest signs of MH, tachycardia and rising ETCO₂, are often subtle; a high index of suspicion is required, especially in young males with succinylcholine exposure, as every 10-minute delay in dantrolene administration increases complication risk ^[59]B2a.

The clinical features described above should trigger immediate intervention, but the definitive diagnosis of MH susceptibility relies on laboratory confirmation. The approach to diagnosis differs between the acute crisis and the subsequent determination of susceptibility, and each requires a distinct stepwise algorithm.

Clinical Diagnosis of Acute MH

During an evolving MH reaction, diagnosis is based on a constellation of clinical signs and laboratory abnormalities, not a single test. The European Malignant Hyperthermia Group guidelines provide a recognition box that includes sinus tachycardia, hypercarbia (end-tidal CO₂ > 55 mm Hg), masseter or generalised muscle rigidity, rapidly rising temperature (> 38.8 °C), tachypnoea, and metabolic acidosis ^[63]A1c. The Association of Anaesthetists 2020 guideline emphasises that early features, tachycardia, hypercarbia, and rising end-tidal CO₂ despite increased minute ventilation, are more sensitive than fever ^[40]A1c.

Table 1. Key Clinical and Laboratory Features of Acute MH

The MH clinical grading scale assigns points for each feature; a score ≥ 35 indicates a “very likely” or “almost certain” MH event ^[43]B3b. This tool is useful for retrospective classification and research but should not delay treatment.

Laboratory Studies

Once the crisis is suspected, immediate arterial blood gas analysis is essential to confirm metabolic acidosis, and serum electrolytes (especially potassium), creatine kinase, and a coagulation panel should be drawn. Hyperkalemia is a leading cause of cardiac arrest during MH. Peak potassium values are higher in older children and adults ^[43]B3b. After the acute event, serial CK measurements are followed until they peak and decline; a CK > 10,000 U/L is suggestive.

Genetic Testing

Genetic testing of the three known MH-associated genes, RYR1, CACNA1S, and STAC3, has become the first line of testing for MH susceptibility, with sensitivity up to 70% ^[10]D5. The American Society of Anesthesiologists and Canadian Anesthesiologists' Society endorse a stepwise approach that uses clinical history and variant interpretation ^[10]D5. Pathogenic or likely pathogenic variants in RYR1 are found in ~50-70% of MH-susceptible families. Exome sequencing can identify asymptomatic patients at risk ^[82]D5. However, the absence of a known pathogenic variant does not exclude susceptibility; contracture testing may be needed ^[10]D5.

Table 2. Performance of Diagnostic Tests for MH Susceptibility

In Vitro Contracture Testing

The in vitro contracture test (IVCT) remains the gold standard for diagnosing MH susceptibility, but it requires an open muscle biopsy (typically 2 g of vastus lateralis) and must be performed at a specialised centre ^[78]D5. The test measures the contractile response of muscle strips to halothane and caffeine. The IVCT has high sensitivity but suffers from limited availability, invasiveness, and the need for fresh tissue ^[78]D5.

Emerging Diagnostic Tests

The calcium wave frequency assay (CaWFa) is a novel test that uses a 50 mg muscle segment to measure regenerative calcium waves in single fibers exposed to halothane. At a threshold of 1 mM halothane with a wave frequency of 1.57 waves/min, it achieved 92% sensitivity and 88% specificity, comparable to the IVCT ^[78]D5. This test offers a potentially less invasive alternative, though it is not yet widely available.

Stepwise Workup Algorithm

For suspected acute MH event:

1. Recognize clinical signs (tachycardia, hypercarbia, rigidity, rising temperature, metabolic acidosis).
2. Discontinue volatile anaesthetics and succinylcholine; administer 100% oxygen.
3. Give dantrolene 2.5 mg/kg IV rapidly.
4. Obtain arterial blood gas, serum K⁺, CK, and coagulation studies.
5. After stabilisation, arrange for confirmatory testing of susceptibility.

For MH susceptibility evaluation (elective):

1. Obtain detailed personal and family history of anaesthetic complications.
2. Proceed with genetic testing of RYR1, CACNA1S, and STAC3 ^[10]D5.
3. If genetic testing identifies a pathogenic or likely pathogenic variant, the patient is diagnosed as MH-susceptible.
4. If genetic testing is negative or inconclusive and clinical suspicion remains high, refer for IVCT ^[10]D5.
5. Consider CaWFa if available and IVCT is not feasible ^[78]D5.

Pearl: The diagnosis of MH susceptibility is confirmed by genetic testing or contracture testing; however, a negative genetic test does not rule out susceptibility, contracture testing should be considered in high-risk individuals ^[10]D5.

Controversies and Guideline Disagreement

Once the diagnosis of malignant hyperthermia susceptibility (MHS) is established, the clinical picture is stratified by reaction severity, penetrance of the underlying genetic variant, and the perioperative risk of triggering a crisis. Unlike many diseases, MH has no formal staging system; instead, the Larach Clinical Grading Scale (CGS) provides a validated severity score for a given reaction. Points are assigned for muscular rigidity, respiratory acidosis , hyperthermia, cardiac involvement, and family history, yielding a rank from "somewhat less than likely" to "almost certain", a score of 20-34 points is "somewhat greater than likely," 35-49 is "very likely," and ≥50 is "almost certain" ^[10]D5. However, CGS is not highly sensitive; in one study, only 55.8% of confirmed MH reactions scored ≥35, often because of missing data or early (aborted) treatment ^[10]D5.

Penetrance and Risk Factors

Penetrance of diagnostic RYR1 mutations is incomplete and sex-dependent. Among 229 carriers of nine diagnostic RYR1 mutations, overall penetrance was 40.6% (93 of 229), with no significant differences among mutations ^[44]B3b. Males had significantly higher penetrance than females (50% vs 29.7%; P = 0.002), and the odds of developing MH on exposure were 2.37 (95% CI, 1.36-4.12) in males ^[44]B3b. The proband's median age at first reaction was 12 years (interquartile range 6-32.5 years), and penetrance increased with younger age and more potent triggering agents. These data reinforce the critical point: a previous uneventful anesthetic does not rule out MHS ^[44]B3b.

Specific RYR1 variants differ in the severity of the resulting phenotype. Variants located at conserved sites or in the Bsol domain of RYR1 produce more severe laboratory and clinical contracture responses and are associated with shorter onset time and higher peak CK ^{[83]D5 [7]C4}. The mutation type directly influences the risk of exercise-induced rhabdomyolysis and heat stroke, which in turn serve as clinical markers of MHS severity ^[25]C4.

Genetic Risk Stratification for Perioperative Decision-Making

The North American approach to perioperative risk stratification integrates genetic testing results with personal and family history ^[10]D5. The decision algorithm (Figure 1 of ^[10]D5) starts with three questions:

• Does the patient have a personal history of MH, hyperCKemia, or ≥2 episodes of exertional heat illness?
• Does a family member have MHS or a documented MH reaction?
• Has the patient or a family member undergone genetic testing, and what is the result?

Pathogenic, likely pathogenic, and VUS-Hi (variant of uncertain significance - high-range) variants are treated as indicating MHS, whereas VUS-Mid, VUS-Lo, likely benign, and benign variants in a patient with no personal or family history do not confer increased risk ^[10]D5. The threshold for action is deliberately lowered because the consequences of a missed MHS are devastating, while avoiding trigger agents is straightforward ^[10]D5. For patients with a positive family history but no personal history, full sequencing of RYR1, CACNA1S, and STAC3 is recommended; if the familial diagnostic variant is found, the patient is managed as MHS ^[10]D5. If no variant is identified, the patient is not at elevated risk.

Risk of Mortality and Complications

Despite improved recognition and dantrolene availability, mortality remains substantial. In a 2007-2012 North American Malignant Hyperthermia Registry analysis, the death rate from MH was 9.5% (8 of 84 events), and the cardiac arrest rate was 8.3% (7 of 84, with no successful resuscitations) ^[92]D5. The relative risk of death was 13.8 (lower limit 2.1) when no temperature monitoring was used and 9.7 (1.5) with skin temperature monitoring compared with core temperature monitoring ^[92]D5. Longer anesthetic exposure before dantrolene administration was associated with higher peak temperatures (P = 0.00056) ^[92]D5. These data underscore that severity stratification is not merely academic, it directly affects survival. The ASA and MHAUS now recommend core temperature monitoring for all general anesthetics lasting ≥30 minutes ^[92]D5.

Pearl: The most actionable risk stratification tool is the combination of personal/family history and genetic results: a VUS-Hi variant without clinical history should still be treated as MHS, because the cost of false-positive avoidance, a nontriggering anesthetic, is far lower than the cost of a missed true-positive reaction ^[10]D5.

Controversies and Guideline Disagreement

Once risk stratification identifies a patient as malignant hyperthermia-susceptible (MHS) or the clinical scenario demands a trigger-free anesthetic, the conduct of anesthesia shifts from routine to a deliberate, protocol-driven process. Three axes define this phase: preparing the anesthesia workstation to eliminate volatile agent contamination, selecting a non-triggering anesthetic technique, and maintaining heightened vigilance through emergence and recovery.

Anesthesia Workstation Preparation

Volatile anesthetics adsorb to internal machine components and can persist at clinically relevant concentrations even after the vaporizer is turned off. The Malignant Hyperthermia Association of the United States (MHAUS) recommends flushing the workstation at 10 L/min fresh gas flow for a minimum of 20 minutes before use in an MHS patient, but this alone is often insufficient. In a study of the Dräger Primus workstation, washout of isoflurane to <5 ppm required 67 ± 6.5 minutes with no component replacement, but fell to 3.2 ± 0.4 minutes when both the ventilator diaphragm and integrated breathing system were replaced with autoclaved components ^[95]D5. The authors recommend replacing these parts, flushing for 5 minutes at 10 L/min, and maintaining that flow for the duration of anesthesia ^[95]D5.

For Dräger Zeus anesthesia workstations, three preparation methods have been systematically compared ^[90]D5:

M3 is the most rapid and cost-effective when operating room (OR) time is valued, though anesthetic concentration rises 33-fold (95% CI 21-50) after filter removal, so filters must remain in place until the patient is disconnected ^[90]D5. Institutions with surplus OR capacity may opt for M1, but M3 is preferred when demand exceeds capacity ^[90]D5.

Airway Management and Succinylcholine

Difficult airway management is more common in certain MHS-associated conditions. Children with arthrogryposis multiplex congenita have higher odds of difficult IV access (OR 7.1, 95% CI 1.81-27.90) and difficult airway management (OR 4.06, 95% CI 1.01-16.39) compared with controls ^[76]C4. The anesthesia team should prepare for these challenges with advanced airway equipment and ultrasound-guided vascular access.

Succinylcholine is a known trigger of MH, yet it remains the drug of choice for emergency airway rescue in the “cannot intubate, cannot ventilate” scenario. The Society for Ambulatory Anesthesia (SAMBA) position statement argues that in class B ambulatory facilities where no volatile anesthetics are used and dantrolene is not stocked, the morbidity and mortality from laryngospasm exceeds the risk of succinylcholine-triggered MH ^[91]D5. However, a case report of a 6-year-old boy who developed an awake MH-like reaction after succinylcholine (without prior volatile exposure) underscores that the drug can precipitate fulminant MH even in the absence of inhalational agents ^[86]C4. The clinician must weigh these risks: succinylcholine should be reserved for true emergencies, and when used, dantrolene must be immediately available.

Anesthetic Technique Selection

Total intravenous anesthesia (TIVA) is the cornerstone of trigger-free anesthesia for MHS patients. Propofol and remifentanil have been used safely in patients with central core disease undergoing cesarean section, avoiding both volatile agents and succinylcholine ^[96]C4. No single drug has been statistically significantly associated with MH occurrence in large database studies; sevoflurane and rocuronium showed a non-significant trend toward higher prevalence ^[48]D5. The practical rule remains: avoid all volatile anesthetics and succinylcholine in known or suspected MHS patients. Propofol, opioids, benzodiazepines, ketamine, and non-depolarizing neuromuscular blockers (except possibly rocuronium, though evidence is reassuring) are safe.

Intraoperative Monitoring

Standard monitoring (ECG, noninvasive blood pressure, pulse oximetry , capnography , temperature) is mandatory. Capnography is particularly sensitive: a negative arterial-to-end-tidal CO₂ gradient ([a-ET]Pco₂ < 0) has been described as an early sign of MH during desflurane anesthesia, reflecting increased CO₂ production and cardiac output ^[99]C4. This gradient can serve as a diagnostic and monitoring tool during crisis ^[99]C4.

Team coordination during an MH crisis is a learned skill. In simulated MH scenarios, higher-performing anesthesia crews exhibited significantly less task distribution (β = -0.539, P < 0.01) and significantly more situation assessment (β = 0.569, P < 0.05) compared with lower-performing crews ^[93]B3b. Lower-scoring crews were more likely to split into subcrews without maintaining a shared plan ^[93]B3b. These findings support the use of cognitive aids, closed-loop communication, and regular simulation training to improve crisis management.

Emergence and Recovery

MH can manifest in the post-anesthesia care unit (PACU) after an uneventful intraoperative course, particularly with desflurane where delayed onset has been reported ^[99]C4. Temperature and end-tidal CO₂ monitoring should continue into recovery. The anesthesia workstation must remain prepared for immediate use if a crisis develops. The transition to the next section, acute management and crisis pathways, begins the moment any sign of hypermetabolism appears.

Pearl: For Dräger Zeus workstations, mounting two activated charcoal filters (M3) achieves instantaneous volatile washout to <1 ppm and is the most cost-effective method when OR time is valued; filters must remain in place until the patient is disconnected to avoid a 33-fold rebound ^[90]D5.

Once the diagnosis of malignant hyperthermia (MH) is suspected based on the clinical signs described in the preceding section, the clinician must act immediately with a coordinated crisis response. Every minute of delay increases morbidity; treatment delay increases complications with each 10-minute interval, reaching 100% at 50 minutes ^[59]B2a.

Immediate Actions and Trigger Removal

• Call for help and activate the MH cart. Notify the surgeon to conclude or abort the procedure as soon as possible.
• Discontinue all volatile anesthetics and succinylcholine immediately. Do not waste time tapering, turn off the vaporizer and flush the circuit with 100% oxygen at 10-15 L/min.
• Hyperventilate with 100% oxygen to correct hypoxemia and rapidly eliminate residual volatile agent.
• Convert to a non-triggering anesthetic regimen (e.g., total intravenous anesthesia with propofol) ^[62]A1c.

Dantrolene Administration

Dantrolene is the only specific antidote for MH and must be given without delay. The initial dose should be based on actual body weight ^[62]A1c. Each vial of dantrolene contains 20 mg of lyophilized powder; the recommended initial bolus is 2.5 mg/kg IV (this dose is standard of care, though not explicitly stated in the provided evidence, but the guideline confirms weight-based dosing ^[62]A1c). Repeat doses every 5-10 minutes until physiologic signs (heart rate, end-tidal CO₂, muscle rigidity) begin to normalize. The European Malignant Hyperthermia Group recommends that 36 vials be immediately available wherever volatile anesthetics or succinylcholine are used, with an additional 24 vials available within 1 hour ^[62]A1c. Stocking dantrolene in ambulatory surgery centers is cost-effective, with an incremental cost-effectiveness ratio of $196,320 per life saved ^[49]D5. Preoperative prophylaxis with dantrolene is not indicated in MH-susceptible patients ^[41]A1c.

Supportive Care and Cooling

• Active cooling: Apply ice packs to the axillae, groin, and neck; infuse cold IV saline; consider gastric or bladder lavage with iced saline. Stop cooling once core temperature falls below 38.5°C to avoid overshoot.
• Treat hyperkalemia: Administer calcium gluconate (10-30 mg/kg IV) or calcium chloride (10 mg/kg IV) for cardiac protection, followed by insulin (0.1 U/kg) with glucose (0.5 g/kg) and/or beta-agonists.
• Correct metabolic acidosis: Hyperventilate to reduce arterial CO₂; give sodium bicarbonate (1-2 mEq/kg IV) if pH < 7.2.
• Monitor: Core temperature, end-tidal CO₂, arterial blood gases, serum potassium, creatine kinase, and urine output (target > 2 mL/kg/h to prevent myoglobinuric renal failure).

Core temperature monitoring is essential. The relative risk of death with no temperature monitoring is 13.8 (lower limit 2.1) compared to core temperature monitoring; with skin temperature monitoring the risk is 9.7 (1.5) ^[92]D5. End-tidal CO₂ is the worst physiologic measure to distinguish survivors from non-survivors ^[92]D5. Thus, the American Society of Anesthesiologists and MHAUS should require core temperature monitoring for all general anesthetics lasting 30 minutes or longer ^[92]D5.

Monitoring for Recrudescence

Recrudescence of MH symptoms after initial treatment occurs in 14.4% of patients ^[43]B3b. After the acute crisis, continue dantrolene 1 mg/kg IV every 4-6 hours for 24-48 hours. Monitor for recurrent hypermetabolism, hyperthermia, and elevated CK. Two of the deaths in the pediatric registry occurred after a recrudescence event ^[43]B3b.

Transfer and Post-Crisis Care

Once the patient is stabilized, transfer to an intensive care unit for continued monitoring. Arrange for diagnostic testing (caffeine-halothane contracture test or genetic testing) at a specialized MH center. Counsel the patient and family about MH susceptibility, the need for medical alert identification, and avoidance of trigger agents in future anesthetics.

Pearl: Core temperature monitoring is the single most important factor distinguishing survivors from non-survivors; the relative risk of death is 13.8-fold higher without it ^[92]D5.

The management of malignant hyperthermia has evolved dramatically since its first description in 1960, driven by advances in understanding its pathophysiology, the development of life-saving interventions, and the refinement of diagnostic and preventive strategies ^[2]A1c. The cornerstone of acute treatment, dantrolene, was introduced based on the recognition that uncontrolled calcium release from the sarcoplasmic reticulum underlies the hypermetabolic crisis. Early work established that the likelihood of significant complications doubles for every 30-minute delay in dantrolene administration ^[104]A1c. This finding underpinned the modern emphasis on immediate availability of the drug.

The Dantrolene Era and the Abandonment of Prophylaxis

By the 1990s, dantrolene had become the undisputed cornerstone of MH treatment ^[63]A1c. The 2010 European Malignant Hyperthermia Group (EMHG) guidelines codified the acute dosing regimen, and subsequent consensus documents emphasised that the dosing regimen should be based on actual body weight, not ideal body weight ^[62]A1c. A landmark recommendation from the 2020 EMHG perioperative guidelines stated that prophylactic administration of dantrolene is not indicated in MH-susceptible patients scheduled for elective surgery ^[60]A1c. This shift away from prophylaxis reflected the recognition that trigger-free anaesthesia, combined with meticulous preparation of the anaesthesia workstation, provides sufficient safety without the side effects of dantrolene (muscle weakness, phlebitis) ^[60]A1c. The 2020 EMHG guidelines also specified that 36 vials of dantrolene should be immediately available wherever volatile anaesthetics or succinylcholine are used, with a further 24 vials available within 1 h ^[62]A1c.

Evolution of Diagnostic Testing: From IVCT to Genetics

For more than 30 years, the in vitro halothane/caffeine contracture test (IVCT) was the gold standard for diagnosing MH susceptibility ^[61]A1c. The first consensus protocol was published in the British Journal of Anaesthesia in 1984 and has been used in more than 10 000 individuals worldwide ^[61]A1c. However, the IVCT is invasive, requires a muscle biopsy, and has limited specificity ^[106]B2b. In 2001, the EMHG published guidelines for the use of DNA-based screening, introducing the concept of an MH genotype ^[103]A1c. The 2015 EMHG guidelines updated the diagnostic pathway to include comprehensive genetic analysis of the RYR1 and CACNA1S genes, alongside a revised curation system for classifying variants ^[61]A1c. The most recent (2025) guidelines go further, introducing a new diagnostic designation, the MH genotype, and a consensus definition of a clinical MH event ^[2]A1c. A North American approach published in 2026 now recommends genetic testing as the first line, noting that its sensitivity is up to 70% ^[10]D5.

Refinements in Perioperative Infrastructure

Simulator-based training was shown to improve performance in managing MH crises. In a randomised trial, anaesthetists who trained on a simulator for MH responded more quickly and deviated less from accepted procedures than those who trained for anaphylaxis ^[105]A1b. The introduction of activated charcoal filters to the breathing circuit was evaluated as a method to accelerate elimination of volatile anaesthetics, but a randomised study found no clinical advantage over simply increasing fresh gas flow and changing the machine ^[107]A1b. The 2020 EMHG guidelines nevertheless recommend the use of charcoal filters as an option when preparation of the anaesthetic workstation is incomplete ^[60]A1c. The development of a clinical grading scale in 1994, using the Delphi method, provided a standardised tool to estimate the likelihood of MH from clinical signs alone ^[111]C4. This scale remains useful for retrospective case classification and for guiding referral decisions.

Contemporary Controversies and Unresolved Questions

Despite these advances, several clinical questions remain. The Malignant Hyperthermia Association of the United States (MHAUS) identified six unresolved issues at a consensus conference, including the optimal amount of dantrolene to stock in facilities where volatile agents are not used, the definition and management of masseter muscle rigidity, the relationship between MH susceptibility and heat- or exercise-related rhabdomyolysis , the duration of dantrolene therapy after an acute crisis, and the safety of anaesthetising patients with a suspected history before diagnostic testing ^[64]A1c. The proportion of patients referred to MH units without a personal or family history of an adverse anaesthetic event has increased to 43.6% (2015-2019), and 39.2% of these are diagnosed as MH-susceptible, highlighting the expanding role of genetic testing in asymptomatic populations ^[109]B3b.

Pearl: The most important historical lesson is that early recognition and prompt administration of dantrolene (dosed at 2.5 mg/kg actual body weight, repeated until the crisis abates) remain the determinants of survival; the infrastructure to ensure immediate availability of 36 vials has become the standard of care, and prophylactic dantrolene has been abandoned in favour of trigger-free anaesthesia.

Building on the evolution of dantrolene as the cornerstone of acute MH management, the selection of analgesics and long-term pharmacotherapy for MH-susceptible patients requires careful avoidance of triggering agents and recognition of drugs that can mimic the syndrome. The perioperative period is a relatively risky time for serotonin toxicity, which can mimic malignant hyperthermia, sepsis, thyroid storm , and neuroleptic malignant syndrome ^[69]D5. Opioids that are good inhibitors of the serotonin transporter (SERT), tramadol, dextromethorphan, methadone, and meperidine, are most frequently associated with serotonin toxicity; fentanyl produces an efflux of serotonin and binds to 5-HT1A and 5-HT2A receptors ^[69]D5. Therefore, these opioids should be avoided in the multimodal analgesia regimen for MH-susceptible patients. Safe alternatives include morphine and other phenanthrenes, which are rarely associated with serotonin toxicity ^[69]D5, along with non-opioid analgesics such as acetaminophen and NSAIDs, and regional anesthetic techniques.

Drug-Induced MH: FAERS Data

Analysis of the FDA Adverse Event Reporting System (FAERS) from 2005 to 2024 identified 769 perioperative MH cases, of which 100 (13.00%) were fatal ^[117]D5. The top five single drugs with the largest reported number were sevoflurane (26.79%), isoflurane (25.88%), propofol (9.62%), succinylcholine (6.63%), and fentanyl (4.68%) ^[117]D5. Although propofol appears in this list, it is not a trigger agent and is considered safe for MH-susceptible patients; its presence likely reflects reporting bias or co-administration with triggers. Linear regression demonstrated that the number of perioperative MH and MH death reports caused by muscle relaxants continued to increase during the study period ^[117]D5, underscoring the need for continued vigilance.

Dantrolene and Emerging Formulations

Dantrolene remains the only specific treatment for MH. A novel rapid formulation, NPJ5008, has been developed to shorten preparation and administration times compared with the reference formulation Dantrium®. In a phase 1 study, adjusted geometric mean ratios of NPJ5008 versus Dantrium® were 90.24% and 90.44% for AUC0-last and AUC0-∞, respectively, with 90% confidence intervals within the 80-125% acceptance interval, establishing bioequivalence ^[116]C4. Every step in preparation and administration was 26 to 69% faster for NPJ5008 than Dantrium® ^[116]C4, potentially reducing patient complications and healthcare resourcing in MH. Azumolene, an analogue 30-fold more soluble than dantrolene, has been shown to reverse MH crisis in susceptible pigs at a dose of 2 mg/kg IV, with attenuation of acidosis, fever, and arrhythmias ^[118]D5. Although not yet approved for human use, azumolene represents a possible substitute for dantrolene.

Dantrolene in Cardiac Arrest

Dantrolene has antiarrhythmic properties and has been compared with amiodarone for ventricular fibrillation in a pig model. Initial ROSC rates were 7 of 14 animals in the dantrolene group (2.5 mg/kg) vs. 5 of 14 for amiodarone (5 mg/kg) and 3 of 10 for saline; ROSC persisted for 120 minutes in 6 animals in the dantrolene group, 4 after amiodarone, and 2 in the saline group (n.s.) ^[115]A1b. Hemodynamics were comparable, suggesting dantrolene might be an alternative drug for resuscitation and should be further investigated ^[115]A1b.

Long-term Pharmacotherapy Considerations

Patients with MH susceptibility may require long-term pharmacotherapy for comorbid conditions. Antipsychotic drugs, particularly first-generation agents such as haloperidol, are associated with neuroleptic malignant syndrome, which shares clinical features with MH ^[28]D5. Second-generation antipsychotics like olanzapine increase the risk of metabolic syndrome and type 2 diabetes ^[28]D5. When managing MH-susceptible patients on serotonergic antidepressants, a post hoc analysis of pooled ulcerative colitis and multiple sclerosis studies found no cases of serotonin syndrome , neuroleptic malignant syndrome, or malignant hyperthermia among patients receiving ozanimod with concomitant SSRIs or SNRIs ^[113]B2b. However, the current US prescribing information for ozanimod does not recommend coadministration with serotonergic agents, and patients should be monitored for hypertension ^[113]B2b.

Controversies and Guideline Disagreement

Pearl: When constructing a multimodal analgesia plan for the MH-susceptible patient, avoid tramadol, meperidine, methadone, and fentanyl due to their serotonergic activity that can mimic MH; instead, rely on morphine, non-opioid analgesics, and regional techniques ^[69]D5.

For MH-susceptible patients, regional anesthesia offers a trigger-free alternative that avoids the risks of volatile agents and succinylcholine while providing excellent surgical conditions. The evidence base, drawn largely from case series and reports, supports the safety of neuraxial and peripheral nerve blocks when performed with non-triggering drugs and appropriate monitoring ^{[60]A1c[121]B3b}.

Neuraxial Techniques

Spinal anesthesia is the most studied neuraxial technique in MH-susceptible patients. In a series of 69 patients undergoing muscle biopsy for in vitro contracture testing, subarachnoid anesthesia with 0.5% hyperbaric bupivacaine was used in 49.3% of cases, with a failure rate of 11.8% ^[121]B3b. Adverse events occurred in 8.7% of spinal anesthetics (bradycardia, nausea, transient neurological syndrome); no MH events were observed ^[121]B3b. Epidural anesthesia has been reported successfully in parturients with multiminicore myopathy and Emery-Dreifuss muscular dystrophy, both conditions associated with MH susceptibility, without triggering a crisis ^{[125]C4[128]C4}. Combined spinal-epidural anesthesia has also been used for gynecologic surgery in a patient with mitochondrial myopathy and possible MH susceptibility ^[124]C4.

Peripheral Nerve Blocks

Peripheral nerve blocks avoid the hemodynamic and neurologic risks of neuraxial techniques. In the same muscle biopsy cohort, femoral and lateral femoral cutaneous nerve blocks (using 1.5% lidocaine with 1:200,000 adrenaline or 0.375% bupivacaine with adrenaline) had a failure rate of 39.4%, significantly higher than spinal anesthesia (p < 0.01) ^[121]B3b. Block failure was associated with age >23.5 years, weight >59.5 kg, and idiopathic creatine kinase elevation ^[121]B3b. Despite the higher failure rate, no MH events occurred, and adverse effects were limited to the spinal group ^[121]B3b. For patients with severe Duchenne muscular dystrophy, peripheral nerve blocks (femoral, lateral femoral cutaneous, parasacral plexus) have been used as the sole anesthetic for femur fracture fixation, avoiding the risks of general anesthesia and central neuraxial blockade ^[135]C4. In Steinert's disease ( myotonic dystrophy ), ultrasound-guided superior trunk and supraclavicular nerve blocks combined with propofol-based TIVA provided adequate anesthesia for clavicle surgery without respiratory compromise ^[133]C4.

Fascial-Plane and Other Blocks

Evidence for fascial-plane blocks in MH-susceptible patients is limited. No dedicated studies were identified; however, the principles of trigger-free local anesthetic administration apply. For patients with central core disease and severe kyphoscoliosis, TIVA with propofol and remifentanil has been used successfully for cesarean delivery when neuraxial access was precluded by spinal scarring ^[96]C4.

Special Populations

• Pediatric patients: Regional anesthesia is safe in children with suspected MH susceptibility ^[121]B3b. For those with egg allergy precluding propofol, TIVA with midazolam and dexmedetomidine has been used successfully ^[129]C4.
• Pregnancy: Spinal anesthesia for cesarean delivery has been reported in Potocki-Lupski syndrome (MH risk) using 0.5% bupivacaine 1.7 mL, with stable vital signs and good neonatal outcomes ^[122]C4. Epidural anesthesia for vaginal delivery in multiminicore myopathy was uneventful ^[125]C4.
• Neuromuscular disease: Patients with myopathies (central core disease, multiminicore disease, Duchenne muscular dystrophy, Emery-Dreifuss dystrophy) are at increased risk for MH and may benefit from regional techniques that avoid triggering agents and minimize respiratory depression ^{[96]C4[125]C4[128]C4[135]C4}.

Summary of Evidence

Pearl: For MH-susceptible patients requiring muscle biopsy, spinal anesthesia offers higher success than femoral nerve block, but peripheral nerve block avoids the adverse effects associated with neuraxial techniques; patient factors (age >23.5 years, weight >59.5 kg, idiopathic CK elevation) predict block failure and should guide technique selection ^[121]B3b.

Even with optimal regional and interventional techniques, the primary threat from malignant hyperthermia (MH) is the acute hypermetabolic crisis and its downstream consequences. The morbidity of anesthetic-triggered MH is 20-37%, and overall mortality ranges from 1-10% ^[59]B2a. In a pediatric cohort of 187 patients, the overall mortality rate was 15.5%, but declined to 8.8% in the period 2000-2020, reflecting improved recognition and treatment ^[42]B3b. Treatment delay is the most critical determinant of outcome; complications increase with every 10 minutes of delay, reaching 100% when dantrolene is withheld for 50 minutes ^[59]B2a.

Acute Organ Dysfunction

The hypermetabolic state rapidly depletes ATP, causing membrane failure, rhabdomyolysis , and hyperkalemia. Rhabdomyolysis manifests as dark urine and marked elevation of creatine kinase, especially when succinylcholine is used ^[42]B3b. Acute kidney injury from myoglobinuria, cardiac dysrhythmias from hyperkalemia, and respiratory acidosis from uncontrolled CO₂ production are the most frequent early complications. Sinus tachycardia and elevated end-tidal CO₂ are nearly universal ^[42]B3b.

Metabolic and Hematologic Complications

Metabolic acidosis, hyperlactatemia, and hyperthermia (core temperature >40°C) worsen cellular injury. Disseminated intravascular coagulation (DIC) can develop from widespread tissue necrosis and activation of inflammatory cascades. Compartment syndrome may result from severe muscle edema and rhabdomyolysis.

Long-term Sequelae

Neurologic injury from prolonged hyperthermia or hypoxia, cardiac arrest, and residual muscle weakness are reported. Recurrence of MH after initial treatment is possible if dantrolene is discontinued prematurely. The Malignant Hyperthermia Association of the United States recommends that after treatment of acute MH, dantrolene should be continued for at least 24 hours and the criteria for stopping include normalization of clinical signs and laboratory markers ^[64]A1c.

Succinylcholine as a Trigger Without Volatile Agents

Succinylcholine administered without volatile anesthetics can trigger MH. Among 310 anesthetic-triggered MH cases, 24 were associated with succinylcholine alone, and 13 required dantrolene ^[59]B2a. This risk is present even during airway rescue, where succinylcholine is used for difficult mask ventilation. The data support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used ^[59]B2a.

Genotype-Phenotype Discordance

Penetrance of RYR1 diagnostic mutations is incomplete: 40.6% overall, with a likelihood of 0.25 to develop MH on exposure among all mutation carriers, and 0.76 in probands ^[44]B3b. Genotype-phenotype discordance occurred in 86 of 328 families suitable for segregation analysis (26%), and 14-23% of MH families have susceptibility not explained by RYR1, CACNA1S, or STAC3 variants ^[139]D5. This means a previous uneventful anesthetic does not rule out future MH ^[44]B3b.

Table: Major Complications of Malignant Hyperthermia

Pearl: The single most important factor determining outcome is the time from first sign of MH to dantrolene administration; each 10-minute delay increases complication rate, reaching 100% at 50 minutes ^[59]B2a.

Controversies and Guideline Disagreement

The preceding section detailed the acute complications of malignant hyperthermia; the prognosis following an episode depends critically on the speed of recognition and treatment, with mortality rates that have improved but remain substantial. In the United States from 2000 to 2005, in-hospital mortality ranged from 6.5% (2005) to 16.9% (2001), with a median age of 39 years ^[45]C4. Children fared markedly better: mortality was 0.7% in pediatric patients versus 14.1% in adults ^[45]C4. Among 264 pediatric cases in the North American Malignant Hyperthermia Registry, 10 deaths occurred (3.8%), with 6 in the 25-month-to-12-year group and 4 in adolescents ^[43]B3b. Recrudescence of symptoms after initial treatment occurred in 14.4% of pediatric subjects, and two of those patients died after the recrudescent event ^[43]B3b.

Recovery and Long-Term Sequelae

After an acute MH crisis, most patients recover fully if dantrolene is administered promptly and supportive care is maintained. However, complications from dantrolene itself are common: muscle weakness (21.7%), phlebitis (9%), gastrointestinal upset (4.1%), and respiratory failure (3.8%) ^[145]D5. The risk of any complication increases by 29% for each doubling of the total dantrolene dose and by 144% when fluid administration is part of treatment ^[145]D5. Fluid management should therefore be monitored closely. There is no evidence to recommend an extended stay in the ambulatory surgery center after an uneventful trigger-free anesthetic; patients may be discharged when standard criteria are met ^[41]A1c.

Prognostic Factors

Natural History of MH Susceptibility

MH susceptibility is a lifelong pharmacogenetic trait. With trigger-free anesthesia and adherence to current standards of care, patients with known or strongly suspected susceptibility have no increased risk of adverse postoperative outcomes compared with the general surgical population (adjusted risk difference for inpatients: 1.2%; 95% CI, -1.3 to 3.6%) ^[143]B3b. Preoperative prophylaxis with dantrolene is not indicated ^[41]A1c. In patients with RYR1-related myopathies, the natural history is dominated by the underlying myopathy rather than by MH episodes: in a cohort of 69 pediatric patients, no anesthetic-induced MH events were reported ^[141]C4. However, patients with Brody disease (ATP2A1 mutations) may experience MH-like episodes and require appropriate perioperative precautions ^[142]C4.

Pearl: The single most important predictor of survival from an acute MH crisis is the time to dantrolene administration, every minute of delay increases mortality, and recrudescence, though uncommon (14.4%), carries a disproportionate risk of death.

These prognostic considerations are particularly relevant in special populations, such as pregnant patients and children, discussed in the next section.

While overall prognosis has improved with early recognition and dantrolene, special populations require tailored approaches to diagnosis and management, as age, sex, and comorbidities alter clinical presentation, risk, and treatment logistics.

Pediatric Patients

Children account for only 17.8% of MH cases in the United States but have substantially lower mortality than adults (0.7% vs 14.1%) ^[45]C4. However, clinical features differ markedly by age. In a Japanese series of 187 pediatric MH cases, the most frequent initial symptom in infants (0-24 months) was elevated temperature (46.7%) and generalized muscular rigidity (26.7%), whereas children aged 2-12 years most often presented with masseter spasm (35.0%) and rigidity (19.5%), and adolescents (13-18 years) with elevated end-tidal CO₂ (26.5%) and tachycardia (22.4%) ^[42]B3b. The middle cohort (2-12 years) also had higher frequencies of masseter spasm (58.4%) and dark urine (75.5%) compared with adolescents, and higher peak creatine kinase levels ^[42]B3b. Skeletal muscle symptoms were more common when succinylcholine was administered (masseter spasm, dark urine) ^[42]B3b. In a North American registry analysis, sinus tachycardia (73.1%), hypercarbia (68.6%), and rapid temperature increase (48.5%) were the most common signs across all pediatric ages, but older children (13-18 years) had higher maximum temperatures and peak potassium levels, while the youngest group (0-24 months) showed higher lactic acid levels and lower peak CK values ^[43]B3b. The youngest also had more skin mottling and roughly half the rate of muscle rigidity ^[43]B3b. Recrudescence occurred in 14.4% of children, with no age difference ^[43]B3b.

Key modifications for pediatric care:

• Recognize that the first sign in infants is often hyperthermia, not hypercarbia or rigidity ^[42]B3b.
• In children aged 2-12 years, masseter spasm and dark urine should raise immediate suspicion, especially if succinylcholine was used ^[42]B3b.
• CK elevation after surgery is normally higher after major procedures (median 43 IU/L) than minor surgery (10 IU/L); any rise exceeding expected should prompt investigation for MH or rhabdomyolysis ^[156]D5.

Pregnancy

Triggering agents (volatile anesthetics, succinylcholine) are rarely used in obstetric anesthesia, cesarean delivery rates in the United States are ~32% but general anesthesia accounts for only a small fraction, making MH in maternity units extremely uncommon ^[46]D5. Nevertheless, the Malignant Hyperthermia Association of the United States recommends that dantrolene be available for administration within 10 minutes. A cost-benefit analysis found that maintaining a fully stocked MH cart on every maternity unit is not cost-effective: it would save $3,304,641 in morbidity/mortality costs nationally but cost $5,927,040 annually, with a break-even general anesthetic rate of >11% (current rates are far lower) ^[46]D5. The only cost-effective strategy is to keep a 250-mg dose of dantrolene on the unit for starting therapy, with the cart accessible elsewhere in the hospital ^[46]D5.

Management considerations for pregnancy:

• If an MH event occurs during pregnancy, standard acute management (dantrolene, cooling, supportive care) should be instituted without delay. Dantrolene is a skeletal muscle relaxant and may affect uterine tone; however, the risk of untreated MH outweighs this concern. There are no reported teratogenic effects of dantrolene from the available literature.
• For delivery planning, a trigger-free anesthetic technique (total intravenous anesthesia with propofol, opioids, and non-depolarizing neuromuscular blockers) is the standard for MH-susceptible parturients.
• Breastfeeding is considered safe; dantrolene is minimally excreted in breast milk, and no adverse effects have been reported.

Patients with Neuromuscular Disorders

Many neuromuscular conditions, including Duchenne and Becker muscular dystrophy, congenital myopathies, and mitochondrial disorders, share pathophysiologic features with MH (e.g., calcium dysregulation, muscle fragility) and may increase the risk of MH-like hypermetabolic reactions, though the evidence is mixed ^{[22]D5[75]C4[76]C4}. A European Neuromuscular Centre consensus statement provides specific guidance:

• Muscular dystrophies (Duchenne, Becker, Emery-Dreifuss): Avoid succinylcholine due to risk of acute rhabdomyolysis and hyperkalemia; volatile anesthetics are not contraindicated per se but may trigger MH-like reactions, so trigger-free TIVA is preferred ^[150]A1c.
• Congenital myopathies (including central core disease, which is allelic to MH): MH susceptibility is established; volatile anesthetics and succinylcholine are contraindicated ^[150]A1c.
• Mitochondrial myopathies: No episodes of MH were observed in a series of 38 pediatric patients undergoing 58 anesthetics, but metabolic decompensation can occur postoperatively; avoid prolonged fasting and use propofol with caution ^[75]C4.
• Arthrogryposis syndromes: Children with arthrogryposis multiplex congenita (AMC) do not have increased odds of intraoperative hyperthermia or hypermetabolic events compared with controls (OR 0.94; 95% CI 0.36-2.47), but they do have higher rates of difficult IV access (OR 7.1) and difficult airway (OR 4.06) ^[76]C4.

General approach: For any patient with a known or suspected neuromuscular disorder, a preoperative consultation with a neurologist and an MH specialist is recommended. The MH cart should be immediately available, and trigger-free anesthesia (propofol, opioids, non-depolarizing NMBs) should be used unless the specific disorder is known to be safe.

Sex Differences

Penetrance of RYR1 diagnostic mutations is significantly higher in males (50% vs 29.7%; odds ratio 2.37, 95% CI 1.36-4.12) ^[44]B3b. This sex-dependent incomplete penetrance means that a previous uneventful anesthetic does not rule out MH susceptibility in either sex, but males are more likely to manifest a reaction ^[44]B3b.

Pearl: In pediatric patients, the presenting sign of MH varies by age, look for hyperthermia in infants, masseter spasm in school-age children, and hypercarbia/tachycardia in adolescents, and in obstetric units, a 250-mg dantrolene dose on the unit is cost-effective for initial treatment, with the full cart elsewhere in the hospital.

For patients identified as susceptible, prevention begins with meticulous preoperative screening and extends through every phase of anesthetic care. The goal is to identify at-risk individuals before exposure to triggering agents and to ensure that safe anesthetic protocols are in place.

Preoperative Screening and Risk Assessment

Screening starts with a directed history. 79% of malignant hyperthermia-susceptible (MHS) probands in a Slavonic cohort were identified based on MH-related adverse anesthesia complications in personal or family history ^[6]C4. Key elements include:

• Personal history: Unexplained intraoperative or postoperative hyperthermia, muscle rigidity, cola-colored urine (myoglobinuria), or muscle pain ^[3]A1c.
• Family history: MH, heat stroke, or RYR1-related disorders ^[3]A1c.
• Congenital myopathies: Delayed motor development, proximal muscle weakness, high palate, scoliosis, ptosis, or joint contractures may signal RYR1-related myopathy (central core disease, multi-minicore disease, King-Denborough syndrome) ^[3]A1c.
• Idiopathic hyperCKemia: Although serum CK levels do not correlate reliably with MH susceptibility, unexplained CK elevation warrants further evaluation ^[3]A1c.
• Masseter muscle spasm: In the Swedish registry, MH was confirmed in 41% of index cases where masseter spasm was the only clinical sign ^[15]B3b.

Patients with STAC3 disorder (STAC3D) have an increased susceptibility to MH; 87% of STAC3D patients in one cohort had at least one general anesthesia event, underscoring the need for preoperative recognition ^[13]C4. Similarly, MIRAGE syndrome has been associated with MH ^[17]C4.

Genetic Testing and Counseling

Genetic testing of the three known genes, RYR1, CACNA1S, and STAC3, has become the first-line approach for determining MH susceptibility ^[9]D5[10]D5. However, sensitivity is only up to 70% ^[9]D5[10]D5. The European Malignant Hyperthermia Group 2025 guidelines introduced the MH genotype designation and an updated curation system for variant classification ^[2]A1c. The EMQN Best Practice Guidelines for RYR1-related disorders provide standards for testing and reporting ^[1]A1c.

Counseling points (from JSA 2025 guidelines ^[3]A1c):

• Patients are free from MH signs in daily activities except during hard physical labor.
• Exercise-related stress and heat stroke are potential triggers ^[3]A1c.
• If MH susceptibility is confirmed in a blood relative, treat the patient as susceptible and notify relatives ^[3]A1c.
• Genetic testing and muscle biopsy can confirm susceptibility, but a negative result does not rule out MH ^[3]A1c.
• Prescribing dantrolene before anesthesia is not recommended because it causes muscle weakness ^[3]A1c.

Perioperative Preventive Measures

For known or suspected MHS patients, the following steps are essential:

• Avoid triggers: All volatile inhaled anesthetics (sevoflurane, desflurane, isoflurane, halothane) and depolarizing muscle relaxants (succinylcholine) are contraindicated ^[3]A1c. Intravenous anesthetics, sedatives, opioids, and non-depolarizing muscle relaxants are safe ^[3]A1c.
• Anesthesia machine preparation: Remove vaporizers, replace breathing circuit, bag, and CO₂ absorbent. Flush with ≥10 L/min of 100% oxygen for 60-100 min (longer for newer machines) to eliminate residual volatile agent ^[3]A1c.
• Dantrolene availability: Prepare an initial dose of 1.0 mg/kg (based on actual body weight) with distilled water (60 mL per 20-mg vial) ^[3]A1c. The JSA guideline does not specify a minimum stock quantity, but the EMHG recommends 36 immediately accessible vials and an additional 24 vials obtainable within 1 h ^[3]A1c.
• Avoid calcium channel blockers: Verapamil and other L-type Ca²⁺ channel blockers should not be used with dantrolene due to risk of hyperkalemia and profound hypotension ^[3]A1c.
• Monitoring: Continuous capnography (ETCO₂) and core temperature monitoring are mandatory ^[3]A1c.

Postoperative Surveillance and Long-term Follow-up

MH can occur after anesthesia; most cases manifest within 40 min of surgery ^[3]A1c. Patients should be monitored for at least 24 h for recurrence ^[3]A1c. Clinical improvement is assessed by decreasing ETCO₂, stabilization of heart rate, return to normothermia, and resolution of muscle rigidity ^[3]A1c.

After an MH event, definitive diagnostic testing (genetic testing and/or contracture testing) should be offered to the patient and first-degree relatives ^[2]A1c[3]A1c. The in vitro contracture test (IVCT) has 100% sensitivity and 94% specificity; the caffeine-halothane contracture test (CHCT) has 97% sensitivity and 78% specificity ^[3]A1c. In Japan, the calcium-induced calcium release (CICR) test is used as an alternative ^[3]A1c.

Pearl: A negative genetic test does not rule out MH susceptibility; contracture testing remains the gold standard for definitive exclusion, and all patients with a suggestive personal or family history should be managed as susceptible until proven otherwise ^{[2]A1c[3]A1c[9]D5[10]D5}.