Malignant hyperthermia is a potentially fatal pharmacogenetic disorder of skeletal muscle calcium regulation that affects animals including dogs, pigs, and other species. Triggering agents for malignant hyperthermia include all halogenated volatile anesthetics and depolarizing neuromuscular blocking agents (eg, succinylcholine and decamethonium). Clinical signs include rapid increase in body temperature, muscle fasciculation, muscle rigidity, tachypnea, tachycardia, arrhythmia, myoglobinuria, metabolic acidosis, acute kidney injury, and death. An in vitro contracture test or DNA analysis is used for diagnosis. Treatment involves discontinuation of the triggering agent and administration of dantrolene in combination with supportive care.
Malignant hyperthermia is a rare, subclinical, life-threatening pharmacogenetic disorder of skeletal muscle characterized by an uncontrolled hypermetabolic response in genetically susceptible animals.
Etiology of Malignant Hyperthermia
Susceptibility to MH is associated with a mutation in the ryanodine receptor 1 (RYR1) gene, which encodes the primary calcium-release channel of the skeletal muscle sarcoplasmic reticulum. This receptor is essential for excitation contraction coupling by regulating the release of calcium required for normal skeletal muscle contraction.
Additionally, variants in the CACNA1S gene, which encodes the dihydropyridine receptor ⍺-1 subunit, have also been identified as contributing factors in the development of MH (1, 2).
MH is most often triggered by exposure to halogenated inhalant anesthetics or a depolarizing neuromuscular blocking agent (3).
The most common triggering agents for MH are halogenated inhalant anesthetics. Although halothane has been implicated in numerous case reports, all currently available halogenated volatile anesthetics, including isoflurane, sevoflurane, and desflurane, can also trigger the syndrome in susceptible individuals (4, 5). Depolarizing neuromuscular blocking agents, particularly succinylcholine, have also been associated with the onset of MH (6).
In pigs, MH (also referred to as porcine stress syndrome), is an autosomal recessive disorder caused by mutations in the RyR1 receptor. The mutant allele must be inherited from both carrier parents for clinical expression to occur in the offspring. The disease can be precipitated not only by anesthetic triggers but also by environmental and physical stressors, such as transportation, high ambient temperatures, handling, and other stressful events (7).
In humans and dogs, susceptibility to MH is typically inherited as an autosomal dominant trait. Therefore, a single copy of the mutant allele inherited from either parent is sufficient to confer susceptibility, resulting in an approximately 50% chance that each offspring will inherit the disorder (8, 9).
In susceptible individuals, MH-like episodes can also be precipitated by stress or strenuous exercise in the absence of anesthetic exposure (10, 11, 12).
Epidemiology of Malignant Hyperthermia
Humans and pigs are considered the species with the greatest susceptibility to MH; however, the syndrome has also been described in horses (13), dogs (11, 12), and cats (14).
The incidence of MH during anesthesia in humans is estimated to be as high as 1 in 100,000 anesthetic procedures in adults (15) and approximately 1 in 30,000 anesthetic procedures in children (16). However, the incidence and prevalence of MH in veterinary medicine remain unknown.
In pigs, the breeds most susceptible to MH are Pietrain, Poland China, and Landrace; however, Large White, Yorkshire, Hampshire, and miniature pot-bellied pigs can also be affected (17, 18, 19).
In dogs, no breed predisposition has been established; however, MH has been reported in Bichon Frises, Border Collies, Golden Retrievers, Greyhounds, Labrador Retrievers, Pointers, Saint Bernards, and Springer Spaniels (10, 11, 12, 20, 21, 22).
Pathophysiology of Malignant Hyperthermia
Once an MH-susceptible patient is exposed to a triggering agent, the mutant RYR1 undergoes sustained, uncontrolled activation, resulting in excessive release of calcium (Ca2+) from the sarcoplasmic reticulum into the cytosol of skeletal muscle cells.
The accumulation of intracellular Ca2+ stimulates continuous activation of the sarcoplasmic/endoplasmic reticulum Ca2+ATPase (SERCA) pumps as they attempt to restore calcium homeostasis by returning Ca2+ to the sarcoplasmic reticulum (23). However, this compensatory response rapidly becomes insufficient, resulting in a marked increase in ATP utilization.
As energy requirements exceed cellular capacity, metabolism shifts toward anaerobic pathways, leading to increased oxygen (O2) consumption, excessive carbon dioxide (CO2) production, and the development of metabolic acidosis (6).
The accumulation of CO2 stimulates the sympathetic nervous system, resulting in tachycardia, hypertension, and other clinical signs of sympathetic activation. Concurrently, persistent elevations in intracellular Ca2+ promote sustained skeletal muscle contraction, while the excessive metabolic activity associated with increased ATP consumption generates substantial heat production, ultimately leading to hyperthermia (6).
As ATP stores become depleted, sustained skeletal muscle contraction leads to disruption of the sarcolemma, resulting in rhabdomyolysis and the release of intracellular components, including potassium (K+), creatine kinase (CK), and myoglobin, into the circulation. The resulting hyperkalemia can precipitate life-threatening cardiac arrhythmias, whereas the release of myoglobin and subsequent myoglobinuria can contribute to the development of acute kidney injury (6, 24).
Clinical Findings of Malignant Hyperthermia
Clinical signs of MH can develop at any time during anesthesia. In some patients, clinical signs occur shortly after exposure to a triggering agent, whereas in others the onset can be delayed, depending on the species and individual susceptibility.
In humans, MH can occur after the first exposure to a triggering anesthetic; however, some susceptible individuals might not experience a fulminant episode until after multiple anesthetic exposures, with as many as three exposures reported before clinical signs appear (4, 6, 25).
In animals, it remains unknown whether repeated exposure to triggering agents is required before MH is clinically expressed.
Clinical signs of MH during anesthesia include an unexpected increase in end-tidal carbon dioxide (ETCO2) that is unresponsive to increased ventilation followed by tachycardia, tachypnea, muscle fasciculations, muscle rigidity, hyperthermia, metabolic acidosis, cardiac arrhythmias, and, in severe cases, death. In patients that survive the acute crisis, rhabdomyolysiscan lead to myoglobinuria and subsequent acute kidney injury (6, 24, 25, 26).
In pigs, clinical signs of MH are characterized by an unexpected increase in ETCO2 followed by a rise in body temperature, muscle fasciculations, and generalized muscle rigidity, similar to that observed in humans (1, 27).
In humans, masseter muscle rigidity (jaw stiffness) is a characteristic early finding of MH (28). Additional clinical signs include tachypnea, red or blotched skin, tachycardia, cardiac arrhythmias, and metabolic acidosis with progression to myoglobinuria and subsequent acute kidney injury (3, 25). Without prompt treatment, MH can progress rapidly, with death occurring within 20 minutes. Body temperature can exceed 41°C (105.8°F), followed by the development of rigor mortis.
Pigs affected with MH are prone to developing pale, soft, exudative (PSE) meat, which decreases carcass quality and can result in substantial economic losses (27).
Unlike humans and pigs, dogs do not consistently develop marked muscle rigidity or severe lactic metabolic acidosis during MH, which can delay recognition of the syndrome. Comparative exercise studies suggest that dogs possess greater oxidative metabolic capacity, higher cardiac output, and more efficient acid–base and thermoregulatory regulation than pigs (29).
Pearls & Pitfalls
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A rapid and unexpected elevation in ETCO2 and tachycardia are typically the earliest and most prominent clinical indicators of MH in dogs during anesthesia. Increase in body temperature is often a later finding and can lag behind the onset of hypercapnia (8).
There have been limited case reports of MH in cats. In one case, a female domestic shorthair anesthetized with halothane developed clinical signs approximately 50 minutes after anesthetic induction, including arrhythmias, bradycardia, hypotension, and tachypnea, followed by hyperthermia, with a body temperature increase to 41.1°C (105.8°F), before cardiac arrest (14, 30). In another case, a neutered male domestic shorthair under isoflurane anesthesia developed tachycardia, tachypnea, ETCO2 elevation, and hyperthermia between 110 and 175 minutes after induction. Muscle rigidity became apparent when body temperature reached 42.5°C (108.5°F), and the patient died despite resuscitative efforts (14, 30).
A case of delayed onset of MH in cattle was described in an isoflurane-anesthetized Angus bull. At 75 minutes after induction, heart rate increased progressively from 55 to 70 beats per minute, and ETCO2 increased from 38 to 60 mm Hg. A decrease in PaO2 from 449 to 267 mm Hg was also observed. Heart rate and ETCO2 continued to increase even after discontinuation of isoflurane at 140 minutes, from 70 to 155 beats per minute and from 60 to 218 mm Hg, respectively. In addition, body temperature increased from 39.5°C (103.1°F) to 43.5°C (110.3°F). Muscle rigidity was not observed in this bull. Unfortunately, the bull developed ventricular fibrillation that progressed to asystole, and cardiopulmonary resuscitation was unsuccessful (31).
In horses, one case report described delayed onset of MH, with clinical signs developing approximately 3 hours after induction of halothane anesthesia. The episode was characterized by an unexpected increase in ETCO2, hyperthermia, hypertension, tachycardia, hyperkalemia, hypoxemia, and elevated CK. The horse responded successfully to treatment; however, after recovery, it developed hindlimb myopathy accompanied by pigmenturia (32).
Because many of the clinical findings reported in horses with MH overlap with those of hyperkalemic periodic paralysis (HYPP), distinguishing between these disorders can be challenging. HYPP, an inherited skeletal muscle sodium channelopathy, can also present with hypercarbia, hyperthermia, muscle rigidity, fasciculations, sweating, tachycardia, hypertension, hyperkalemia, and cardiac arrhythmias. Consequently, HYPP should be considered an important differential diagnosis in horses exhibiting clinical signs consistent with MH during anesthesia (33).
Diagnosis of Malignant Hyperthermia
In vitro contracture test
DNA analysis
Most cases of MH reported in veterinary medicine are recognized unexpectedly during anesthesia after exposure to halogenated inhalant anesthetics. However, susceptibility can be identified before anesthesia using diagnostic tests such as the in vitro contracture test (IVCT) and DNA analysis (10).
The IVCT evaluates abnormal skeletal muscle responses to triggering agents, while DNA analysis identifies genetic variants involving the RYR1 gene (10).
The IVCT is considered the gold standard for diagnosing MH susceptibility. The test requires a fresh skeletal muscle biopsy, which is exposed to halothane or caffeine to assess abnormal contractile responses. Because muscle biopsies are invasive and require specialized laboratory equipment, IVCT is performed only at a limited number of accredited centers worldwide (10).
Genetic screening by DNA analysis provides a specific alternative for identifying MH susceptibility. The test requires only a small blood sample, hair follicles, or oral swab, which can be submitted to an accredited veterinary diagnostic laboratory for detection of pathogenic mutations in the RYR1 gene. However, because not all disease-associated RYR1 gene variants have been identified, negative results of genetic testing do not completely exclude susceptibility.
Treatment and Prevention of Malignant Hyperthermia
Discontinue triggering agents
Dantrolene
Supportive care
Avoid triggers in susceptible patients
Treatment of Malignant Hyperthermia
The primary objectives of therapy are to rapidly halt the MH crisis and provide supportive management of the systemic complications resulting from the associated hypermetabolic state (25, 34).
Dantrolene is the only specific and effective treatment for MH, and it should be administered in conjunction with appropriate supportive therapy.
Immediate IV administration of dantrolene is the primary therapeutic intervention for MH. Dantrolene exerts its effect by decreasing calcium release through the RyR1 channel, thereby limiting the abnormal accumulation of intracellular Ca2+ within skeletal muscle cells. This decrease in calcium availability decreases actin–myosin interaction, alleviates sustained muscle contraction, and helps terminate the hypermetabolic response associated with the syndrome (35, 36, 37).
In dogs and pigs, dantrolene should be administered (3 mg/kg, IV) as soon as MH is diagnosed and repeated as needed, up to a total dose of 10 mg/kg (10, 21, 38).
Dantrolene sodium has historically been available as a lyophilized preparation containing 20 mg per vial. Because of its limited solubility, the powder must be dissolved immediately prior to use, requiring approximately 60 mL of sterile water for each vial. A formulation approved by the FDA in 2025 provides 250 mg of dantrolene sodium per ampule, and it can be reconstituted with only 5 mL of sterile water, yielding a concentration of 50 mg/mL. The enhanced solubility of this formulation greatly decreases the volume required for administration, allowing faster and more practical delivery during an acute MH event.
Concurrent with initiation of specific therapy, all sources of exposure to triggering agents should be immediately eliminated. The vaporizer should be turned off and removed from the anesthesia machine to prevent further delivery of volatile halogenated anesthetics. Fresh gas flow should be increased to the maximum available rate to facilitate the rapid removal of residual anesthetic gases from the breathing circuit (25).
Ventilatory support should be optimized by increasing minute ventilation to enhance CO2 elimination and correct hypercapnia. According to human literature, when available, activated charcoal filters should be placed on both the inspiratory and expiratory limbs of the rebreathing circuit to further decrease recirculation and minimize patient exposure to residual volatile anesthetic agents. Another option is to replace the anesthesia machine with a clean system that has not been exposed to volatile anesthetics, ensuring the absence of residual halogenated inhalant anesthetic contamination (25, 39).
Management of the hyperthermic state requires prompt initiation of active cooling measures. Cooling strategies can include administration of cold IV crystalloids and application of ice packs to highly vascularized regions (25).
Because hyperkalemia is one of the earliest and most life-threatening complications of malignant hyperthermia, serum potassium concentration should be assessed as soon as possible and treated without delay. Intravenous administration of 50% dextrose (0.5 mL/kg dilute with saline 1:4 IV slowly) combined with regular insulin (0.25–0.5 U/kg, IV slowly) can be used to promote the intracellular shift of potassium (40, 41).
In patients with both clinically severe metabolic acidosis (pH < 7.10) and persistent hyperkalemia despite first-line therapies, sodium bicarbonate (1–2 mEq/kg, IV over 15–20 minutes) can be administered to correct acid–base disturbances and further facilitate intracellular potassium movement (40, 42, 43, 44).
If ventricular arrhythmias persist despite correction of hyperkalemia, lidocaine (1–2 mg/kg, IV) can be administered for its antiarrhythmic activity (45). Once control of ventricular tachycardia is accomplished, a constant-rate infusion (50 mcg/kg/min, IV) is administered as needed (46).
In cats, esmolol can be considered as an alternative when there is concern for lidocaine-induced cardiotoxicity. Calcium chloride and calcium gluconate are commonly used to stabilize the myocardium during severe hyperkalemia; however, their use in MH remains controversial because of concerns that they can exacerbate intracellular calcium overload.
Pearls & Pitfalls
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Fluid resuscitation should be provided; however, there is no consensus in the literature regarding the optimal fluid for patients experiencing MH. Lactated Ringer’s solution has an electrolyte composition relatively similar to plasma; however, it contains calcium (approximately 3 mEq/L) and potassium (approximately 4 mEq/L). Its use should therefore be considered in the context of the pathophysiology of MH, which involves dysregulated intracellular calcium release, as well as the potential development of hyperkalemia during an MH crisis. Sodium chloride (0.9% NaCl) is an alternative that does not contain calcium or potassium; however, its high chloride concentration (154 mEq/L) can contribute to hyperchloremic metabolic acidosis, particularly when administered in large volumes.
After the initial resolution of an MH episode, continued intensive monitoring is required, because metabolic disturbances and clinical abnormalities can persist or reappear. Recommendations from human medicine support observation in an intensive-care environment for a minimum of 24 hours, allowing prompt identification of recurrent hypermetabolic activity and delayed complications, including potential organ dysfunction (25).
Prevention of Malignant Hyperthermia
For patients with known or suspected susceptibility to MH, avoidance of known triggering agents is a key component of prevention. In addition, minimizing stress associated with handling and procedures is recommended, with sedatives or tranquilizers used when appropriate to decrease physiological stress responses (25).
Various premedication protocols can be used in MH-susceptible patients, including phenothiazines, butyrophenones, alpha-2-adrenergic agonists, and benzodiazepines. These agents can be administered alone or combined with opioids to provide adequate sedation and analgesia, particularly when anesthesia is required for potentially invasive procedures (47, 48).
In susceptible Pietrain pigs, azaperone (0.5–2 mg/kg IM) has been used as a premedication agent to decrease stress responses. Acepromazine has also been reported to decrease the incidence of MH episodes in pigs (48, 49).
For induction of anesthesia in MH-susceptible patients, any currently available IV induction agent can be considered, including propofol, ketamine, alfaxalone, etomidate, and thiopental. These agents have not been identified as triggering drugs for MH and can be selected according to the patient’s clinical condition and anesthetic requirements.
For anesthetic maintenance in MH-susceptible patients, total IV anesthesia (TIVA) is a suitable alternative to avoid exposure to volatile triggering agents. Agents such as propofol and alfaxalone can be administered as constant-rate infusions (CRIs) to maintain an adequate plane of anesthesia. Intraoperative analgesia can be enhanced through the addition of opioids, alpha-2-adrenergic agonists, and IV lidocaine CRIs, providing multimodal analgesia while minimizing the need for inhalant anesthetics (50).
Regional anesthesia techniques using local anesthetics such as lidocaine, bupivacaine, and mepivacaine, including neuraxial approaches (eg, epidural or spinal anesthesia), can be incorporated into a multimodal anesthetic plan for MH-susceptible patients. These techniques provide effective analgesia, decrease the requirement for systemic anesthetic agents, and help minimize exposure to potential triggering drugs (51).
Airway protection should be considered during anesthesia, with endotracheal intubation providing a secure airway and decreasing the risk of vomiting, regurgitation, and potential aspiration. In addition, patients should be monitored closely for respiratory depression, and supplemental oxygen and mechanical ventilation should be available when indicated.
Patients undergoing anesthesia should receive appropriate monitoring to allow early detection of physiological abnormalities associated with MH. Capnography should be used to monitor ETCO2 continuously, as an unexpected increase can be an early indicator of a hypermetabolic state. Doppler monitoring can be used to assess pulse rate and systolic blood pressure, while invasive blood pressure monitoring should be considered for more complex or prolonged procedures.
Electrocardiographic monitoring is recommended for detection of cardiac arrhythmias, and continuous temperature monitoring should be performed to identify changes in body temperature. Active thermal support should be provided as needed. Pulse oximetry allows assessment of oxygenation, and reliable IV access should be established in all anesthetized patients to facilitate crystalloid fluid administration when indicated and administration of emergency medications if necessary (52).
Nonhalogenated anesthetic agents, such as the noble gas xenon, might represent an alternative option for anesthetic maintenance in patients susceptible to MH. Because xenon does not belong to the class of volatile halogenated anesthetics associated with triggering MH, it is a potential safer approach for anesthesia in these patients (53).
Key Points
Triggering agents for MH include all halogenated volatile anesthetics and depolarizing neuromuscular blocking agents (eg, succinylcholine and decamethonium).
Clinical onset of MH is variable and can occur at different times during anesthesia, depending on the species and individual susceptibility.
Early clinical signs of MH typically include a rapid increase in end-tidal carbon dioxide (ETCO2) despite adequate ventilation, followed by tachycardia and tachypnea, progressing to hyperthermia, muscle rigidity, metabolic acidosis, hyperkalemia, rhabdomyolysis, acute kidney injury, cardiac arrhythmias, and death.
Prompt administration of IV dantrolene, immediate discontinuation of the triggering agent, and aggressive supportive care are the cornerstones of treatment for MH.
Diagnosis of MH is on the basis of clinical suspicion and can be confirmed by the in vitro contracture test (IVCT) or DNA analysis for known pathogenic RYR1 mutations.
Prevention of MH involves identifying susceptible patients and avoiding exposure to triggering anesthetic agents while using safe anesthetic alternatives such as total IV anesthesia (TIVA) and regional anesthetic techniques when appropriate.
For More Information
Brunson DB, Hogan KJ. Malignant hyperthermia: a syndrome not a disease. Vet Clin North Am Small Anim Pract. 2004;34(6):1419-1433.
Gronert GA, Marshall BE. Malignant hyperthermia. Anesthesiology. 1980;53(5):395-423.
Hopkins PM. Malignant hyperthermia: pharmacology of triggering. Br J Anaesth. 2011;107(1):48-56.
Hopkins PM, Girard T, Dalay S, et al. Malignant hyperthermia 2020: guideline from the Association of Anaesthetists. Anaesthesia. 2021;76(5):655-664.
Nelson TE. Malignant hyperthermia in dogs. J Am Vet Med Assoc. 1991;198(6):989-994.
Malignant hyperthermia. UC Davis Veterinary Medicine, Veterinary Genetics Laboratory. Accessed September 13, 2026. https://vgl.ucdavis.edu/test/mh
Also see pet owner content regarding malignant hyperthermia in dogs, cats, and horses.
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