Malignant Hyperthermia in Animals

• Mutations in the ryanodine receptors (RYR1) and dihydropyridine receptors alter calcium regulation in skeletal muscle

• Onset and severity of clinical signs vary between species

Mutations in the ryanodine receptors (RYR1 locus) in humans, pigs, dogs, and horses, and in the dihydropyridine receptors (DHPR) in humans on the sarcoplasmic reticulum that surrounds myofibrils of skeletal muscles alter the function of calcium release channels. This results in massive release of calcium into the cytoplasm of the myofibrils. As a result, generalized, extensive skeletal muscle contraction occurs, leading rapidly to a potentially fatal hypermetabolic state. More than 400 RYR1 variants have been identified, and 34 of those mutations have been confirmed to cause MH according to the molecular genetic guidelines of the European Malignant Hyperthermia Group. Different mutation loci within the RYR1 receptors have been shown to be responsible for MH in different species.

Triggering agents include stress (eg, excitement, transportation, and preanesthetic handling), exercise, halogenated inhalation anesthetics (eg, halothane, isoflurane, sevoflurane, and desflurane), and depolarizing neuromuscular blocking drugs (eg, succinylcholine). Of the halogenated inhalation anesthetics, halothane is claimed to be the most potent triggering agent; although its use has generally been replaced by other inhalation anesthetics in many countries, halothane is still commonly used across the world. Use of succinylcholine, another potent triggering agent, has been gradually restricted by international anesthesia societies.

In pigs, MH is also referred to as porcine stress syndrome. In pigs, both parents must carry the mutant chromosome for the autosomal recessive gene to result in clinical expression in offspring. In the past, halothane was the most frequently reported trigger of MH in pigs. Isoflurane has been reported to trigger MH in pigs of susceptible breeds; however, only one instance of isoflurane-induced MH has been reported in a potbellied pig. Sevoflurane-induced MH also has been reported in purebred Poland China pigs. Episodes of MH induced by desflurane have been reported in Large White, Pietrain, and Pietran-mix pigs. In addition to halogenated inhalation anesthetics or succinylcholine, MH can be triggered by stress during transport or preslaughter conditions.

In humans and dogs, the mutant autosomal gene is dominant, so that a single copy of the mutant chromosome, carried by either parent, can result in clinical expression in the offspring (ie, 50% of offspring are susceptible to MH). In a study in which a colony of Doberman-German Shepherd Dog-Collie dogs were challenged with halothane/succinylcholine, the dogs that developed MH all had a mutation on the calcium-release channels in the RYR1 receptors. However, this mutation was identified on a different loci (T1640) than that responsible for MH in pigs (R614C) and in humans (CFA01). Another mutation, RYR1V547A, has also been shown to be involved in MH in dogs.

In humans, incidence rate has been estimated from 1 in 5,000 anesthetic events to 1 in 100,000 anesthetic events. The incidence rate of MH associated with anesthesia in dogs is reported to be 2.1% in Canada, 0.43% in the US, and 0.23% in England, with a mortality rate of 0.11% in both Canada and the US. Breed susceptibility varies in pigs, with Pietrain, Poland China, and Landrace pigs highly susceptible, and Large White, Yorkshire, and Hampshire pigs much less so. Possession of the gene is associated with heavily muscled or lean breeds. In dogs, MH has been reported in Pointers, Greyhounds, Labrador Retrievers, Saint Bernards, Springer Spaniels, Bichon Frises, Golden Retrievers, and Border Collies.

Most susceptible animals do not have signs of muscle disease in everyday life. Malignant hyperthermia can occur at any time during anesthesia or in the early postoperative period. Clinical signs are most often subtle to mild, with full-fledged episodes being less common. In humans, MH may develop at first exposure to an anesthetic triggering agent; in some cases, as many as three exposures must occur before a full-fledged MH crisis develops. In domestic animals, it is unclear whether multiple exposures to the triggering agent are required before developing a full-fledged episode. This uncertainty is because clinical signs of MH can be so subtle that a first episode may go unrecognized, and MH may be diagnosed only when severe clinical signs occur. Patients may remain normothermic. Fulminant episodes are characterized by a sudden and dramatic rise in body temperature and partial pressure of end-tidal CO₂ (ETCO₂), followed by muscle fasciculation, muscle rigidity, tachypnea, tachycardia, arrhythmias, myoglobinuria, metabolic acidosis, renal failure, and often death. Prognosis is usually poor once clinical signs are recognized.

Early clinical signs may include tachycardia, rapid rise in ETCO₂ in the presence of increased minute ventilation, and muscle rigidity. Elevation of body temperature is a notable, but often late, sign of MH. Progression may be very rapid and pronounced, particularly if precipitated by succinylcholine. In other cases, clinical signs appear much more slowly, not until several hours after anesthesia.

Clinical signs in pigs often include a sudden and pronounced rise in body temperature and ETCO₂ followed by muscle fasciculation, muscle rigidity, tachypnea, red and blotched skin, tachycardia, arrhythmias, myoglobinuria, metabolic acidosis, and renal failure. Death can occur within 20 minutes following exposure to the triggering agent, with rapid rigor mortis occurring when body temperature reaches 41ºC (105.8ºF). Prognosis is usually poor once the episode begins. Pigs affected by this mutation tend to develop pale, soft, exudative (PSE) meat, which is unsuitable can lead to substantial economic loss for producers.

There are distinct differences between clinical signs of MH in dogs and in pigs and humans. The first obvious indication of an imminent MH episode in dogs is the rapid and dramatic increase in CO₂ production, as evidenced by a sudden increase in ETCO₂. Body temperature may increase during the episode; however, this occurs much later than the increased ETCO₂.

In cats, it appears that different inhalation anesthetics play a major role in the onset of MH. In one reported case in a female domestic shorthair cat anesthetized with halothane, the first signs occurred 50 minutes after induction of anesthesia. Arrhythmia, bradycardia, hypotension, and tachypnea occurred, and later, hyperthermia, with a rapid rise in body temperature to 41.1ºC (105.8ºF) before cardiac arrest. In another case in a neutered male domestic shorthair cat, signs did not occur until long after the inhalation of isoflurane, increases in heart rate, respiratory rate, ETCO₂, and body temperature were observed sequentially from 110 to 175 minutes after anesthetic induction. Muscle rigidity was evident when body temperature reached 42.5ºC (108.5ºF). Intensive treatments and resuscitation were not successful.

Malignant hyperthermia is difficult to recognize in horses because it can easily be confused with other myopathies commonly associated with anesthesia. Unlike in pigs, dogs, and humans, signs of MH in horses tend to be slow to develop and often occur only after 3 hours of anesthesia. In addition to the clinical signs of anesthetic-related MH evident in other species, intraoperative cardiac arrhythmia (eg, premature ventricular contraction), postanesthetic myositis, and increased serum potassium concentration and CK activity occur in affected horses. Clinical signs similar to those of MH, such as hypercarbia, increased body temperature, and hyperkalemia, also occur in horses with hyperkalemic periodic paralysis, a genetic mutation of sodium channels. Prognosis for horses suffering an MH episode during or after anesthesia is usually poor because of the lack of response to symptomatic treatments and difficulty in managing complications such as myositis, fractures, or seizures.

• Definitive diagnosis via in vitro contracture test and DNA analysis

Currently, the gold standard for diagnosis of MH is an in vitro contracture test (IVCT), which is based on muscle fiber contracture in response to triggering agents such as halothane or caffeine. However, IVCT requires a surgical procedure (ie, muscle biopsy), is expensive, is available only at specialized testing centers, and may produce equivocal as well as false-positive and false-negative results.

Genetic screening using DNA analysis is an alternative to the IVCT; it requires only a small blood sample to be sent to an accredited diagnostic laboratory to screen for RYR1 mutation. An animal is diagnosed as MH susceptible if 1 of the 34 known causative mutations is detected. However, the diagnostic classification of many RYR1 mutations remains difficult because a mutation's pathophysiologic impact with regard to initiating an MH episode is not yet clear. Therefore, an IVCT is required to exclude MH susceptibility in case of an unclassified RYR1 mutation or if RYR1 mutation is absent.

Other minimally invasive diagnostic tests for identification of MH susceptibility are in development.

• Dantrolene is the only effective treatment for MH

• Inhalation anesthetics and succinylcholine should be avoided in susceptible patients; total IV anesthesia is an alternative

In susceptible animals, stress before anesthesia should be minimized and anesthetics that are known triggering agents should be avoided. Susceptible animals should be kept calm, with stress minimized by administering effective preanesthetic medication before induction and maintenance of anesthesia.

Total IV anesthesia or regional/local anesthetic techniques can be used as alternative procedures to allow surgery on susceptible animals. The following drugs have not been associated with MH and may be considered in susceptible animals:

• Phenothiazine derivatives (eg, acepromazine)

• Butyrophenone derivatives (eg, droperidol, azaperone)

• Benzodiazepine derivatives (eg, diazepam, midazolam, zolazepam)

• Alpha₂-agonists (eg, xylazine, detomidine, dexmedetomidine, romifidine)

• Dissociative anesthetics (eg, ketamine, tiletamine)

• Propofol

• Etomidate

• Opioids (eg, morphine, hydromorphone, fentanyl, butorphanol, buprenorphine)

• N₂O

• Nondepolarizing neuromuscular blocking drugs (eg, atracurium, vecuronium, rocuronium)

• Local anesthetics (eg, lidocaine, mepivacaine, bupivacaine)

Azaperone at 0.5–2 mg/kg, IM, has been shown to prevent MH due to halothane in susceptible Pietrain pigs. Acepromazine has also been shown to reduce the incidence of MH in pigs.

Treatment is most effective when signs of MH are recognized early and treated aggressively. Treatment is largely symptomatic and includes immediate discontinuation of inhalation anesthetic and use of ice packs and alcohol baths. Controlled ventilation using a machine flushed free of anesthetic agent should also be instituted as soon as possible to remove excessive CO₂ and maintain normal blood pH and acid-base status.

Dantrolene (a specific ryanodine receptor antagonist) has proved effective for treatment (1–3 mg/kg, IV) and prophylaxis (5–10 mg/kg, PO, prior to anesthesia). Two formulations of dantrolene are available. The conventional preparation contains 20 mg of a lyophilized form per vial. The drug is poorly soluble and requires 60 mL of sterile water to prepare; it should be reconstituted only before injection. A newer commercial formulation of dantrolene sodium, approved by the FDA, is available in 250-mg ampoules; it requires only 5 mL of sterile water (50 mg/mL) to reconstitute and has improved solubility. Therefore, a smaller volume of dantrolene is required for injection.

Animals with cardiac arrhythmias, such as tachycardia or severe premature ventricular contractions, can be treated with lidocaine (1–2 mg/kg, IV), if needed. Calcium chloride and calcium gluconate are contraindicated. Hyperkalemia should be treated with controlled ventilation, and 50% dextrose (0.5 mL/kg, IV) or insulin (0.25–0.5 U/kg, IV) can be administered to promote movement of extracellular potassium into cells. Sodium bicarbonate (1–2 mEq/kg, IV) can be administered to maintain normal blood pH in the presence of metabolic acidosis. Balanced electrolyte solutions, 5% dextrose in water, and normal saline (0.9% NaCl) solution are acceptable for supportive fluid therapy; lactated Ringer's solution with added calcium should not be used. Dantrolene should be administered to affected animals. Testing for disseminated intravascular coagulation, which often results when body temperature exceeds 41°C (105.8°F), is prudent, as well as observation of the urine for myoglobinuric renal failure due to severe muscle damage. Affected animals should be closely monitored for 48–72 hours because 25% may experience recrudescence.

The development of a DNA test for MH has allowed producers to accurately identify the MH mutation genotypes. Elimination of the MH mutation from breeding stock can reduce the amount of unsuitable PSE pork produced.

• Hopkins PM. Malignant hyperthermia: pharmacology of triggering.Br J Anaesth. 2011;107:48-56.

• McGrath C, Lee J, and Ashen M. (1984) Azaperone (Stresnil) in malignant hyperthermia (Mh) susceptible swine: determination of protective effects to halothane challenge and toxicity (Abstract). Vet Surg. 1964;14:75.

• McGrath C, Rempel W, Addis P, and Crimi A. Acepromazine and droperidol inhibition of halothane-induced malignant hyperthermia (porcine stress syndrome) in swine. Am J Vet Res. 1981;42:195–198.

• Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93.

• Also see pet health content regarding malignant hyperthermia in dogs, cats, and horses.