Overview of Malignant Hyperthermia
(Porcine stress syndrome)
Malignant hyperthermia (MH) is a rare, life-threatening, inherited disorder that can lead to metabolic disease of skeletal muscles in susceptible animals after exposure to triggering agents such as halogenated inhalation anesthetics, depolarizing neuromuscular blocking drugs, stress, and/or exercise. A mutation in the ryanodine receptors (RYR1 locus) on the sarcoplasmic reticulum that surrounds myofibrils of skeletal muscles alters the function of calcium release channels, which 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 known as an MH episode. More than 300 RYR1 variants have been identified, and 31 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 syndrome in different species.
MH is considered to be a clinical syndrome rather than a single disease, because research indicates that multiple environmental and genetic factors cause a complex of pathophysiologic events. Contrary to general belief, a full-fledged MH episode, with a sudden and rapidly progressive course of symptoms, does not occur frequently. In most cases, MH is a subtle disorder. Pigs and people seem to be most susceptible, but MH has also been reported in dogs, cats, and horses. In people and dogs, both parents must carry the mutant chromosome for the autosomal recessive gene to result in clinical expression in offspring. In pigs, 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.
Interestingly, most MH-susceptible animals, including people, do not suffer from signs of muscle disease in everyday life. In people, the incidence of MH episodes during anesthesia is between 1:5,000 and 1:50,000 per 100,000 anesthetic events. The MH episode may develop at first exposure to an anesthetic triggering agent, but 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 is because the clinical signs of MH can be so subtle that the episode goes unrecognized.
MH can occur at any time during anesthesia or in the early postoperative period. The clinical signs of MH are often a sudden and dramatic rise in body temperature and end-tidal CO2 (ETCO2), followed by muscle fasciculation, muscle rigidity, tachypnea, tachycardia, arrhythmias, myoglobinuria, metabolic acidosis, renal failure, and often death. The prognosis is usually poor once clinical signs are recognized. Triggering agents of MH 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, and it is no longer used in western countries. The 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. Breed susceptibility varies, with Pietrain, Portland China, and Landrace pigs very susceptible to MH, and Large White, Yorkshire, and Hampshire pigs much less so. 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, but 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-mixed pigs. There have been no reports of isoflurane- or sevoflurane-induced MH in cattle.
In dogs, MH syndrome has been reported in Pointers, Greyhounds, Labrador Retrievers, Saint Bernards, Springer Spaniels, Bichon Frises, Golden Retrievers, and Border Collies. There are distinct differences in the clinical signs of MH seen in dogs and those in pigs and people. 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 concentration. Body temperature may increase during the episode, but this occurs much later than the increased ETCO2. In a study in which a colony of Doberman-German Shepherd-Collie dogs were challenged with halothane/succinylcholine, the dogs that developed MH syndrome 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 syndrome in pigs (R614C) and in people (CFA01). Another mutation, RYR1V547A, has also been shown to be involved in MH syndrome in dogs. The incidence rate of MH syndrome associated with anesthesia in dogs is reported to be 2.1% in Canada, 0.43% in the USA, and 0.23% in England, with a mortality rate of 0.11% in both Canada and the USA.
MH syndrome in horses is difficult to recognize, because it can easily be confused with other myopathies commonly associated with anesthesia in horses. Unlike in pigs, dogs, and people, signs of MH syndrome in horses tend to be slow to develop and are often observed only after ≥3 hr of anesthesia. In addition to the clinical signs of anesthetic-related MH seen in other species, intraoperative cardiac arrhythmia (eg, premature ventricular contraction), postanesthetic myositis, and increased serum potassium and CK have also been seen in MH-affected horses. Clinical signs similar to those of MH syndrome such as hypercarbia, increased body temperature, and hyperkalemia, are also seen in horses with hyperkalemic periodic paralysis (see Hyperkalemic Periodic Paralysis), a genetic mutation of sodium channels. Thus, a definitive diagnosis should be confirmed by in vitro contracture test (IVCT) or DNA analysis. Prognosis of horses suffering an MH episode during or after anesthesia is usually poor because of the lack of response to symptomatic treatments and difficulty in management of complications such as myositis, fractures, and/or seizures.
Currently, the gold standard for diagnosis of MH is 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 and available only at specialized testing centers, and may produce equivocal as well as false-positive and false-negative results. 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 31 known causative mutations is detected. However, the diagnostic classification of many RYR1 mutations remains difficult because their 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
Because of few effective drugs available to treat MH, stress before anesthesia should be minimized, and using anesthetics that are known triggering agents should be avoided to prevent an MH episode in susceptible animals. Total IV anesthesia and/or regional/local anesthetic techniques can be safely used as alternative procedures to allow surgery on MH-susceptible animals. Drugs that can be safely administered to MH-susceptible animals include phenothiazine derivatives (eg, acepromazine), butyrophenone derivatives (eg, droperidol, azaperone), benzodiazepine derivatives (eg, diazepam, midazolam, zolazepam), α2-agonists (eg, xylazine, detomidine, dexmedetomidine, romifidine), dissociative anesthetics (eg, ketamine, tiletamine-zolazepam), propofol, etomidate, opioids (eg, morphine, hydromorphone, fentanyl, butorphanol, buprenorphine), N2O, nondepolarizing neuromuscular blocking drugs (eg, atracurium, vecuronium, rocuronium), and local anesthetics (eg, lidocaine, mepivacaine, bupivacaine). MH-susceptible animals should be kept calm and stress minimized by administering effective preanesthetic medication before induction and maintenance of anesthesia. Azaperone at 0.5–2 mg/kg, IM, provided 100% protection against MH in susceptible Pietrain pigs.
Treatment of MH is most effective when signs of MH (eg, muscle rigidity, sudden rise in body temperature and ETCO2) 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 mg/kg, PO, up to 10 mg/kg) of MH. 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 not recommended. Hyperkalemia should be treated with controlled ventilation, and 50% dextrose (0.5 mL/kg, IV) and/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 are acceptable for supportive fluid therapy; Ringer’s lactate 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 (131.4°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 signs of MH for 48–72 hr, because 25% may experience recrudescence.