ANIMAL MODEL OF HUMAN DISEASE
Malignant Hyperthermia
Animal Model: Porcine Malignant Hyperthermia
Contributed by: T. E. Nelson, PhD, E. W. Jones, MRCVS, PhD, and 1. L. Anderson, BVSc, MS, College of Veterinary Medicine, Oklahoma State University, Stiltwater, Oklahoma 74074.
Biooc Featr
Malignant hyperthermia (MH) is an abnormal response to anesthetic agents which occurs in genetically susceptible strains of pigs among various breeds including Poland China,' Landrace,2 Pietrain,3 and Yorkshire.4 The primary pathophysiologic event in MH is an hypermetabolic state usually occurring with skeletal muscle rigidity. Once triggered, body temperature rapidly increases (1 degree centigrade per minute), reaching as high as 47 C."4 Anesthetic agents which trigger MH include several potent inhalation anesthetics (such as halothane, enflurane, isoflurane 1 3.5) and chloroform, diethylether, and cyclopropane.2 Skeletal muscle relaxants (e.g., succinylcholine) have been incriminated in some cases 26 but not in others.6 The etiologic factor(s) of MH remains unknown but abnormal metabolic and contracture responses in vitro of MH muscle to anesthetic agents incriminate abnormal skeletal muscle as the target tissue.7'8 Evidence for a neural component in the etiology of M H has been presented by La Cour et al.,9 who described both central and peripheral nervous svstem abnormalities in human survivors of M H episodes. An intact local spinal reflex has also been demonstrated to be necessary for development of the porcine M H syndrome.'0 Light and electron microscopic observations of M H muscle revealed evidence for sporadic myPublication sponsored by the Registrv of Comparative Pathologv of the Armed Forces Institute of Pathologx and supported bv Public Health Service Grant RR 003O1 from the Division of Research Resources, US Department of Health, Education and Welfare, under the auspices of Universities Associated for Research and Education in Pathology, Inc. 197
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American Journal of Pathology
opathv and examination of muscle from pigs after onset of NIH showed fibers with supercontraction associated with an increased density in the longitudinal elements of the sarcoplasmic reticulum." Susceptibility of the pig to MH may be assessed in vitro by measuring ATP and or lactate levels in muscle following exposure to halothane 2,7 or by the increase in isometric tension (contracture) response to halothane which occurs in NIH but not in normal skeletal muscle.8 Malignant hyperthermia may also be induced in the susceptible pig bv exercise and excitement ' and may share an identity with other porcine stress svndromes. 12
Comfarisons Wh Human Dises Nialignant hvperthermia is also a pharmacogenetic disease in man and the pathophysiology of porcine M H is similar if not identical to that observed in man. In man, MH is reportedly inherited as an autosomal dominant trait,14 as may be the case for pigs. lalignant hyperthermia occurs in 1 in 15,000 anesthetizations in man 13 but is of importance since it is often fatal and may occur in individuals in whom no anesthetic abnormality is expected. In man, MH is clinicallv associated with arrhv'thmias, acidosis, electrolyte disturbances, hvperkalemia, hvperthermia, and, often, skeletal muscle rigidity. Potent
Use
The clinical and pathophy-siologic similarity of porcine NIH to that in man provides a suitable model for investigating the etiology and diagnostic procedures, assessing the therapeutic and prophylactic potential of certain drugs, and determining safe and dan-gerous anesthetics. Avarlay
Pigs having malignant hyperthermia may be discovered by screening herds for animals which respond to halothane anesthesia with hyrperthermia and skeletal muscle rigidity. A high mortality is associated with this procedure, but littermates or parents may be subsequently tested by in vitro procedures. References 1. Jones EW, Nelson TE, Anderson IL, Kerr DD, Burnap TK:
NMalignant hyper-
thermia of swine. Anesthesiology 36:42-51, 1972 2. Harrison GG, Saunders SJ, Biebuvck JF, Hickman R. Dent DM, Weaver V. Terblanche J: Anaesthetic-induced malignant hyperpvrexia and a method for its prediction. Br J Anaesth 41:844-854, 1969
Vol. 84, No. 1 July 1976
MALIGNANT HYPERTHERMIA
199
3. Sybesma W, Eikelenboom G: Malignant hyperpyrexia syndrome in pigs. Neth J Vet Sci 2:155-160, 1969 4. Nelson TE: Unpublished observations 5. Murphy FL, Nelson TE, Strobel GE, Jones EW: Can isoflurane, enflurane or fluroxene trigger malignant hyperthermia? Anesthesiology (In press) 6. Nelson TE, Jones EW, Bedell DM: Porcine malignant hyperthermia: A study on the triggering effects of succinylcholine. Anesth Analg (Cleve) 52:908-911, 1973 7. Nelson TE, Jones EW, Venable JH, Kerr DD: Malignant hyperthermia of Poland China swine: Studies of a myogenic etiology. Anesthesiology 36:52-56, 1972 8. Nelson TE, Bedell DM, Jones EW: Porcine malignant hyperthermia: Effects of temperature and extracellular calcium concentration on halothane-induced contracture of susceptible skeletal muscle. Anesthesiology 42:301-36, 1975 9. La Cour D, Juul-Jensen P, Reske-Nielsen E: Central and peripheral mechanisms in malignant hyperthermia. Intemational Symposium on Malignant Hyperthermia. Edited by RA Gordon, BA Britt, W Kalow. Springfield, Ill., Charles C Thomas Publishers, 1973, pp 380-386 10. Kerr DD, Wingard DW, Gatz EE: Prevention of porcine malignant hyperthermia by epidural block. Anesthesiology 42:307-311, 1975 11. Venable JH: Skeletal muscle structure in Poland China pigs suffering from malignant hyperpyrexia.' pp 208-223 12. Nelson TE: Porcine stress syndromes.' pp 191-197 13. Britt BA, Kalow W: Malignant hyperthermia: A statistical review. Can Anaesth Soc J 17:293-315, 1970 14. Britt BA, Locher WG, Kalow W: Hereditary aspects of malignant hyperthermia. Can Anesth Soc J 16:89-98, 1969 This investigation is supported in part by Ayerst Laboratories Inc., New York, N.Y.
200
American Journal of Pathology
NELSON ET AL
[End of Article]
Malignant Hyperthermia
Animal Model: Porcine Malignant Hyperthermia
Contributed by: T. E. Nelson, PhD, E. W. Jones, MRCVS, PhD, and 1. L. Anderson, BVSc, MS, College of Veterinary Medicine, Oklahoma State University, Stiltwater, Oklahoma 74074.
Biooc Featr
Malignant hyperthermia (MH) is an abnormal response to anesthetic agents which occurs in genetically susceptible strains of pigs among various breeds including Poland China,' Landrace,2 Pietrain,3 and Yorkshire.4 The primary pathophysiologic event in MH is an hypermetabolic state usually occurring with skeletal muscle rigidity. Once triggered, body temperature rapidly increases (1 degree centigrade per minute), reaching as high as 47 C."4 Anesthetic agents which trigger MH include several potent inhalation anesthetics (such as halothane, enflurane, isoflurane 1 3.5) and chloroform, diethylether, and cyclopropane.2 Skeletal muscle relaxants (e.g., succinylcholine) have been incriminated in some cases 26 but not in others.6 The etiologic factor(s) of MH remains unknown but abnormal metabolic and contracture responses in vitro of MH muscle to anesthetic agents incriminate abnormal skeletal muscle as the target tissue.7'8 Evidence for a neural component in the etiology of M H has been presented by La Cour et al.,9 who described both central and peripheral nervous svstem abnormalities in human survivors of M H episodes. An intact local spinal reflex has also been demonstrated to be necessary for development of the porcine M H syndrome.'0 Light and electron microscopic observations of M H muscle revealed evidence for sporadic myPublication sponsored by the Registrv of Comparative Pathologv of the Armed Forces Institute of Pathologx and supported bv Public Health Service Grant RR 003O1 from the Division of Research Resources, US Department of Health, Education and Welfare, under the auspices of Universities Associated for Research and Education in Pathology, Inc. 197
NELSON ET AL
198
American Journal of Pathology
opathv and examination of muscle from pigs after onset of NIH showed fibers with supercontraction associated with an increased density in the longitudinal elements of the sarcoplasmic reticulum." Susceptibility of the pig to MH may be assessed in vitro by measuring ATP and or lactate levels in muscle following exposure to halothane 2,7 or by the increase in isometric tension (contracture) response to halothane which occurs in NIH but not in normal skeletal muscle.8 Malignant hyperthermia may also be induced in the susceptible pig bv exercise and excitement ' and may share an identity with other porcine stress svndromes. 12
Comfarisons Wh Human Dises Nialignant hvperthermia is also a pharmacogenetic disease in man and the pathophysiology of porcine M H is similar if not identical to that observed in man. In man, MH is reportedly inherited as an autosomal dominant trait,14 as may be the case for pigs. lalignant hyperthermia occurs in 1 in 15,000 anesthetizations in man 13 but is of importance since it is often fatal and may occur in individuals in whom no anesthetic abnormality is expected. In man, MH is clinicallv associated with arrhv'thmias, acidosis, electrolyte disturbances, hvperkalemia, hvperthermia, and, often, skeletal muscle rigidity. Potent
Use
The clinical and pathophy-siologic similarity of porcine NIH to that in man provides a suitable model for investigating the etiology and diagnostic procedures, assessing the therapeutic and prophylactic potential of certain drugs, and determining safe and dan-gerous anesthetics. Avarlay
Pigs having malignant hyperthermia may be discovered by screening herds for animals which respond to halothane anesthesia with hyrperthermia and skeletal muscle rigidity. A high mortality is associated with this procedure, but littermates or parents may be subsequently tested by in vitro procedures. References 1. Jones EW, Nelson TE, Anderson IL, Kerr DD, Burnap TK:
NMalignant hyper-
thermia of swine. Anesthesiology 36:42-51, 1972 2. Harrison GG, Saunders SJ, Biebuvck JF, Hickman R. Dent DM, Weaver V. Terblanche J: Anaesthetic-induced malignant hyperpvrexia and a method for its prediction. Br J Anaesth 41:844-854, 1969
Vol. 84, No. 1 July 1976
MALIGNANT HYPERTHERMIA
199
3. Sybesma W, Eikelenboom G: Malignant hyperpyrexia syndrome in pigs. Neth J Vet Sci 2:155-160, 1969 4. Nelson TE: Unpublished observations 5. Murphy FL, Nelson TE, Strobel GE, Jones EW: Can isoflurane, enflurane or fluroxene trigger malignant hyperthermia? Anesthesiology (In press) 6. Nelson TE, Jones EW, Bedell DM: Porcine malignant hyperthermia: A study on the triggering effects of succinylcholine. Anesth Analg (Cleve) 52:908-911, 1973 7. Nelson TE, Jones EW, Venable JH, Kerr DD: Malignant hyperthermia of Poland China swine: Studies of a myogenic etiology. Anesthesiology 36:52-56, 1972 8. Nelson TE, Bedell DM, Jones EW: Porcine malignant hyperthermia: Effects of temperature and extracellular calcium concentration on halothane-induced contracture of susceptible skeletal muscle. Anesthesiology 42:301-36, 1975 9. La Cour D, Juul-Jensen P, Reske-Nielsen E: Central and peripheral mechanisms in malignant hyperthermia. Intemational Symposium on Malignant Hyperthermia. Edited by RA Gordon, BA Britt, W Kalow. Springfield, Ill., Charles C Thomas Publishers, 1973, pp 380-386 10. Kerr DD, Wingard DW, Gatz EE: Prevention of porcine malignant hyperthermia by epidural block. Anesthesiology 42:307-311, 1975 11. Venable JH: Skeletal muscle structure in Poland China pigs suffering from malignant hyperpyrexia.' pp 208-223 12. Nelson TE: Porcine stress syndromes.' pp 191-197 13. Britt BA, Kalow W: Malignant hyperthermia: A statistical review. Can Anaesth Soc J 17:293-315, 1970 14. Britt BA, Locher WG, Kalow W: Hereditary aspects of malignant hyperthermia. Can Anesth Soc J 16:89-98, 1969 This investigation is supported in part by Ayerst Laboratories Inc., New York, N.Y.
200
American Journal of Pathology
NELSON ET AL
[End of Article]
