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WSAVA Hereditary Disease Committee:
Malignant Hyperthermia
Last updated on 08/01/2012, previously 11/13/2007.
Contributors:
Ned Patterson DVM, PhD, DACVIM (SAIM)
Linda Shell, DVM, DACVIM (Neurology)
Synonyms:
Canine Stress Syndrome
Disease description:
Malignant hyperthermia (MH) is the rapid, exaggerated, uncontrollable elevation of body
temperature, in animals susceptible to the syndrome, induced by an external stimuli. The
external stimuli may be psychological stress (excitement, fighting for dominance, etc.),
environmental stress (extreme heat, increased activity), other stresses, anesthetic agents
(halothane), depolarizing muscle relaxants (succinylcholine), and possibly toxicants. It
has been described in dogs, humans, pigs, horses and cats.
Genetic basis/mode of inheritance: A c.1640T>C mutation in the RYR1 gene which is
autosomal dominant has been identified in a colony of dogs15, but has not been yet found
in any dogs in the general dog population.
PATHOPHYSIOLOGY
The major calcium release channel in the skeletal muscle sarcoplasmic reticulum
membrane is the ryanodine receptor (RYRI). The gene that encodes this receptor has
been cloned and research has linked gene mutations to MH. 4 The physiologic mechanism
of MH is believed to be abnormal calcium hemostasis (specifically calcium release) that
results in prolonged increases in calcium concentrations and subsequently prolonged
muscle contractions. This results in extreme elevation of body temperature sometimes as
high as 110 F.
Severe hyperthermia results in increased metabolic activity and unreplenished oxygen
consumption. This will cause cell death and can result in multiple organ failure and
disseminated intravascular coagulation.
CLINICAL SIGNS
Clinical signs may include extreme hyperthermia, muscle fasciculations or spasms,
tachycardia, tachypnea, hyperventilation, blood pressure fluctuations, metabolic acidosis
and respiratory alkalosis, and cardiac arrest. The hypermetabolic state can produce
hypercarbia, rhabdomyolysis, generalized skeletal muscle contracture, cardiac
dysrhythmia, renal failure, disseminated intravascular coagulation, and death.
DIAGNOSIS
Diagnosis of MH and its related syndromes is often problematic. The neurologic and
physical examinations are usually within normal parameters.
In vitro contracture test (IVCT): This is the standard assay used to confirm a diagnosis
of MH in people after an anesthetic triggered episode, and to survey families for MH
susceptible individuals. (Kalow et. al., Lancet 1970). A muscle biopsy sample is
surgically removed from the patient and the degree to which it contracts when exposed to
caffeine or halothane is compared to normal muscle. The assay has considerable
variability, is invasive, and is difficult to perform, but does identify both heterozygotes
and homozygotes. IVCT can also be performed in dogs, but few in any labs are currently
able to perform this test on a commercial level.
Halothane exposure: Diagnosis can be based on halothane exposure, but this method is
less than ideal, as an adverse and serious reaction in a positive patient will likely result in
death. This approach is only appropriate if dantrolene (see treatment section) is available
to reverse the effects before significant damage is done.
Erythrocyte fragility testing: There is a defect in the erythrocytes of MH dogs and
swine such that they have increased susceptibility to hydrogen peroxide-induced
hemolysis. This is thought to be due to partial deficiencies of multiple antioxidant stem
enzymes, such as glucose-6-phosphate dehydrogenase, 6-phosphogluconate
dehydrogenase, and others. However, few commercial facilities are available that
routinely test erythrocyte fragility.
Disease description in this species:
MH has also been called Canine Stress Syndrome (CSS). 1 Although still under
investigation, it is known that at least some dogs inherit this condition as an autosomal
dominant trait, resulting in mutations in the calcium release channel of the sarcoplasmic
reticulum, also known as the ryanodine receptor (RYR1). 15 The mutated RYR1 causes
abnormal calcium homeostasis that results in prolonged increases in calcium
concentrations and muscle contraction. The prolonged and profound muscle contraction
then causes the rapid depletion of ATP, breakdown of muscle energy stores, and a lactic
acidosis.
Dogs were first clinically diagnosed with this disease in 1973. Some dogs were only
identified with this condition after the administration of halothane anesthesia. These
animals developed hypercarbia and increased carbon dioxide production within 10
minutes of induction. Tachycardia and hyperthermia followed usually within the first
hour of anesthesia. Death would result if anesthesia was not discontinued. It is still
possible that there continue to be rare events in dogs with inhalant anesthetics, but they
are infrequently recognized in dogs, since dogs may develop arrhythmias from MH and
die before their temperature elevates dramatically. There are not any documented cases of
dogs having true malignant hyperthermia causing a stress syndrome similar to pigs with
autosomal recessive mutations in the RYR1 gene causing porcine stress syndrome.
Etiology:
Amide local anesthetics
Anestheic agents
Genetic, hereditary
Hypercalcemia
Hypercarbia, increased CO
Hypoxemia
Idiopathic, unknown
Infection
Inhalants
Ketamine
Muscle relaxants
Muscular exertion
Succinylcholine hydrochloride
Sympathomimetics
Trauma
Breed predilection:
Border collie
Doberman pinscher
German shepherd X Doberman pinscher
Greyhound
Labrador retriever
Pointer
Saint Bernard
Spaniel
Springer spaniel
Clinical findings:
ANOREXIA, HYPOREXIA
Cachexia, weight loss
Dehydration
FEVER
Malaise
Oliguria
Polydipsia
TACHYCARDIA
Tachypnea, Hyperpnea, Hyperventilation
ZZZ INDEX ZZZ
Diagnostic procedures:
Blood bicarbonate of EDTA blood
Diagnostic results:
Blood bicarbonate decreased, metabolic acidosis
Serum chemistry
Creatine kinase (CK, CPK) increased
Urinalysis and Urine Sedimentation
Urine specific gravity increased
Blood pH on EDTA blood
Respiratory alkalosis
Blood pressure measurement
Blood pressure unstable
Electrocardiography
ELECTROCARDIOGRAPH ABNORMAL
Supraventricular tachycardia
Halothane-succinylcholine challenge
exposure test
Abnormal contraction response halothane
succinyl choline change
Caffeine induced contracture test on
muscle biopsies
Increased sensitivity to caffeine induced
contracture test
RBC fragility test
Increased fragility RBC
Treatment/Management/Prevention:
SPECIFIC
1) Dantrolene: 0.2 to 3.0 mg/kg IV. This skeletal muscle relaxant has been shown to be
very effective in treating an acute attack. The prophylactic benefit of daily administration
of dantrolene has not been determined.
2) The mainstay of therapy is aimed at avoiding stressful situations and maintaining a
quiet, cool environment.
Human Disease Homolog: Malignant Hyperthermia. Online Mendelian Inheritance in
Man (OMIM)# 145600 MIM# 180901.
Genetic Testing: Contact the canine and equine genetics lab at the University of
Minnesota College of Veterinary Medicine for possible genetic testing on a case by case
basis. http://www.cvm.umn.edu/vbs/faculty/Mickelson/lab/home.html
References:
1) Axlund TW: Exercise Induced Collapse in Dogs. Western Veterinary Conference
2004.
2) O'Brien PJ, Cribb PH, White RJ, et al: Canine malignant hyperthermia - Diagnosis of
susceptibility in a breeding colony. Can Vet J 1983 Vol 24 pp. 172-177.
3) O'Brien PJ, Forsyth GW, Olexon DW, et al: Canine malignant hyperthermia
susceptibility - Erythrocyte defects - Osmotic fragility, glucose-6-phosphate
dehydrogenase deficiency, and abnormal Ca2+ homeostasis. Can J Comp Med 1984
Vol 48 pp. 381-389.
4) O'Brien PJ, Pook HA, Klip A, et al: Canine stress syndrome/malignant hyperthermia
susceptibility: calcium-homeostasis defect in muscle and lymphocytes. Res Vet Sci
1990 Vol 48 (1) pp. 124-128.
5) Nelson TE: Malignant hyperthermia in dogs. J Am Vet Med Assoc 1991 Vol 198 (6)
pp. 989-994.
6) Cosgrove SB, Eisele PH, Martucci RW, Gronert GA: Evaluation of greyhound
susceptibility to malignant hyperthermia using halothane-succinylcholine anesthesia
and caffeine-halothane muscle contractures. Lab Anim Sci 1992 Vol 42 (5) pp. 482485.
7) Loke JL, MacLennan DH: Malignant hyperthermia and central core disease Disorders of Ca2+release channels. Am J Med 1998 Vol 104 pp. 470-486.
8) Denborugh M: Malignant hyperthermia. Lancet 1998 Vol 352 pp. 1131-1136.
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springer spaniel. J Am Vet Med Assoc 1987 Vol 190 (8) pp. 1013-1014.
15) Roberts MC, Mickelson JR, Patterson EE, et al: Autosomal dominant canine
malignant hyperthermia is caused by a mutation in the gene encoding the skeletal
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proteins. Curr Mol Med 2002 Vol 2 (4) pp. 347-369.
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