Malignant hyperthermia (MH) is a hypermetabolic syndrome involving skeletal muscle characterized by hyperthermia, tachycardia, tachypnea, increased oxygen consumption, cyanosis, cardiac dysrhythmias, metabolic acidosis, respiratory acidosis, muscle rigidity, unstable arterial blood pressure, and death. There also may be electrolyte abnormalities, myoglobinuria, CK elevation, impaired blood coagulation, renal failure, and pulmonary edema. Although MH was initially recognized as a fatal syndrome in people, the term describing its occurrence in swine is porcine stress syndrome. MH is most prevalent in swine, but this syndrome has also been reported in dogs (especially Greyhounds), cats, and horses.
MH is a heritable disease in people. Questions regarding unexplained anesthetic deaths are part of a family history preanesthetic questionnaire filled out by human patients and should be included on history forms for veterinary patients as well. In addition, whenever a suspected case of MH occurs, it is prudent for veterinarians to notify owners of siblings and breeders if applicable. However, MH can occur sporadically without any pedigree history. Many times, MH has occurred after a previous anesthetic procedure, but because of subtle signs that might go unrecognized, the syndrome was not suspected or diagnosed.
Porcine stress syndrome has been reported in most swine breeds. Prevalence varies, with incidence >90% in some strains. Incidence is higher in lean, heavily muscled breeds, eg, Pietrain, Poland China, Landrace, Duroc, and Large White. Mortality in finishing pigs was reported to be 3.2% but could be considerably higher in susceptible herds.
An autosomal recessive gene that has variable penetrance determines susceptibility to MH. The causative mutation has been localized to a C-to-T transition in the gene that controls the Ca2+ release channel (ryanodine receptor) of sarcoplasmic reticulum in skeletal muscle. Loss in regulation of muscle cell Ca2+ is believed to be the primary etiologic event for induction of MH. It is consistently triggered in genetically susceptible animals by excitement, apprehension, exercise, or environmental stress. This is particularly true in pigs, but exercise-induced MH has also been reported in dogs, suggesting the existence of canine stress syndrome. Exposure to volatile anesthetics or depolarizing neuromuscular blocking agents will consistently trigger MH in susceptible animals. In fact, careful testing with halothane can be used as a screening method.
Subsequent to the initial challenge or stress, the hypersensitive ryanodine receptor floods the myoplasm of skeletal muscle with Ca2+. Muscle contracture and hypermetabolism develop rapidly as a direct result of this uncontrolled and sustained increase in myoplasmic Ca2+. ATP in skeletal muscle is depleted as energy requirements for contracture exceed supply. Increased aerobic and anaerobic metabolism results in excessive CO2 and lactic acid production, while thermogenesis and peripheral vasoconstriction increase core body temperature. As the MH episode progresses, the combination of increased temperature, acidosis, and ATP depletion eventually results in rhabdomyolysis. Myoplasmic enzymes and electrolytes are released from the cells, and additional Ca2+ enters the myoplasm. Contracture and its subsequent energy requirements are further enhanced and eventually, because of temperature and pH changes, proceed independently of myoplasmic Ca2+ levels. Death occurs due to an increase in serum K+, which causes cardiac dysrhythmia and arrest.
The rapidity with which clinical signs develop varies. Signs include muscle stiffness or fasciculation that progresses to muscle rigor. Ventricular tachycardia develops early and continues until serum K+ reaches cardiotoxic levels. In unanesthetized animals, open-mouthed breathing, tachypnea, and hyperventilation may progress to apnea. Blanching and erythema followed by blotchy cyanosis are seen in the skin of light-colored animals. Core body temperature rapidly increases and can reach 113°F (45°C) antemortem. In anesthetized animals, the CO2 absorbant is rapidly depleted, and the breathing circuit canister is hot to touch. Because hypothermia is an expected consequence during general anesthesia, detection of hyperthermia is a key sign, along with the presence of tachycardia and tachypnea. The disease is usually fatal. Rigor mortis develops within minutes, and muscle temperature is significantly increased. Affected muscles from an animal that dies acutely are pale and soft and appear exudative or wet. Pale, soft exudative pork syndrome is often linked to MH.
Clinical diagnosis is based on development of clinical signs in an animal exposed to a volatile anesthetic and/or stressful event. The acute nature of the disease and its relationship to a stressor enables differentiation of MH from other fatal disorders. Numerous laboratory tests have been developed to aid in the identification of MH-susceptible animals, but none enables rapid diagnosis of MH in an acute situation. Most screening tests lack the sensitivity and specificity to identify MH-susceptible animals or carriers. The caffeine contracture test involves in vitro exposure of extracted muscle tissue to caffeine and halothane. Muscle from MH-susceptible subjects will contract when exposed to lower concentrations of caffeine and halothane, compared with normal muscle. This test has limited application in animals because special laboratory facilities are required and the test must be run within minutes after the specimen is obtained. A molecular genetic test is specific for the MH gene. This DNA-based assay is performed on a small sample of anticoagulated blood to detect mutation in the ryanodine receptor gene and can identify homozygous MH-resistant and MH-susceptible animals as well as heterozygous carriers. It has been reported to more accurately predict both the homozygous and heterozygous forms of the MH gene than does the halothane challenge test.
Often, MH episodes are not detected until it is too late. During anesthesia, early detection is essential for a successful outcome. Exposure of the animal to the volatile anesthetic must stop. Breathing tubes and CO2 canisters must be changed, and dantrolene sodium given at 4–5 mg/kg, IV. It is essential that dantrolene be administered early in the course of the disease because muscle blood flow is significantly reduced as the disease progresses. Additional doses of dantrolene may be given as needed. Supportive treatment includes fluid therapy and management of acidosis through ventilatory support and administration of sodium bicarbonate. Increases in core body temperature can be managed by surface cooling and/or chilled saline lavages. If an MH anesthetic event is detected in northern climates during winter, moving an animal outside to a snow bank may be a life-saving maneuver. Other supportive measures include oxygen enrichment of inspired gases and treatment of cardiac dysrhythmias.
Reducing the prevalence of MH within the swine population requires genetic selection against the trait. With the advent of DNA-based assays, it is possible to cull MH-susceptible animals and carriers. Prevention of MH episodes in individual animals requires that management practices to minimize stress be followed.
If a documented MH survivor or a suspected susceptible animal requires anesthesia and surgery, dantrolene should be given at 3–5 mg/kg, PO, 1–2 days before anesthesia. A tranquilizer/opioid combination can be given as preanesthetic medication, and propofol used to induce anesthesia. Acepromazine inhibits development of MH, and propofol has not been reported to trigger the syndrome. Volatile anesthetic agents must be avoided. The CO2 canister of the unit should be cleaned, and new absorbant used along with a new breathing circuit and endotracheal tube. An alternative is to use a semi-open system for delivery of oxygen. Amide local anesthetics are safe to use in MH-susceptible animals. Finally, the procedure must be kept as short as possible, because MH happens most often when anesthesia exceeds 1 hr. All of these maneuvers help reduce the possibility of but may not prevent an MH crisis.
Last full review/revision July 2011 by Donald C. Sawyer, DVM, PhD