Prevention of Malignant Hyperpyrexia

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1225 Prevention of Malignant Hyperpyrexia THE LANCET A RELATIVELY rare condition, malignant hyper- pyrexia, has given rise to a great deal of interest and research. There are two main reasons : firstly, it is a disease induced by doctors, the agent being administered by an anxsthetist; and, secondly, prevention may be possible by identifying susceptible individuals. The discovery of a dominant form of inheritance opened the way to counselling relatives,’ 1 and detection of raised creatine kinase in some relatives has indicated that susceptible individuals may have a subclinical myopathy. 2-5 Several groups have looked further into this possibility, and it is becoming clear that the syndrome of malignant hyperpyrexia may be a feature of several different diseases. BRI-IT and KALOW 6 concluded that there might be two diseases because two-thirds of patients became rigid while the remainder did not; the rigid group more often had pre-existing congenital muscle and skeletal disease. ISAACS and BARLOW now dispute this suggestion, having identified cases of both types in the same family. KING et al. investigated 18 families in which one or more propositi had had malignant hyperpyrexia. In nine cases serum-creatine- kinase activity was raised in other family members, and the inheritance appeared to be autosomal dominant. In three of these family members the raised creatine kinase was associated with a relatively specific myopathy, the remaining six having no clinical sign of muscle abnormality. The families of three other patients had normal creatine-kinase activities, suggesting mutation from the dominantly inherited subclinical variety. One patient had dominantly inherited myotonia congenita, and his serum-creatine-kinase was raised; but other members 1. Denborough, M. A., Forster, J. F. A., Lovell, R. H., Maplestone, P. A., Villiers, J. D. Br. J. Anœsth. 1962, 34, 395. 2. Britt, B. A., Locher, W. G., Kalow, W. Can. Anœsth. Soc. J. 1969, 16, 89. 3. Denborough, M. A., Forster, J. F. A., Hudson, M. C., Carter, N. G., Zapf, P. Lancet, 1970, i, 1137. 4. Isaacs, H., Barlow, M. B. Br. med. J. 1970, i, 275. 5. Zsigmond, E. K., Starkweather, W. H., Duboff, G. S., Flynn, K. Anesth. Analg. 1972, 51, 220. 6. Britt, B. A., Kalow, W. Can. Anœsth. Soc. J. 1970, 17, 293. 7. Isaacs, H., Barlow, M. B. J. Neurol. Neurosurg. Psychiat. 1973, 36, 228. 8. King, J. O., Denborough, M. A., Zapf, P. W. Lancet, 1972, i, 365. of his family with myotonia had normal levels-the occurrence of the two together may have been fortuitous, since many other patients with myotonia have had general anaesthesia without malignant pyrexia. Another five patients had families with normal creatine-kinase activities, and all these showed musculoskeletal abnormalities of various kinds, including short stature, cryptorchidism, pectus carinatum, lumbar lordosis, and thoracic kyphosis. This heterogeneity may explain some of the differ- ences between the results of groups who have looked into the myopathy. ELLIS et al. investigated seven relatives from 4 families with this syndrome and found that five had slight neurological abnormalities, five had raised creatine-kinase activities, five had biopsy specimens with " moth-eaten " fibres scattered throughout the muscle, and five had biopsy specimens showing contracture when exposed in vitro to a combination of halothane and suxamethonium. The moth-eaten fibres are, however, non-specific,1 and the " cores " in a biopsy specimen from a probably susceptible patient," and the various myopathic abnormalities illustrated in the review of ISAACS and BARLOW,7 must be looked upon with reserve. It is not unusual to see a few abnormal muscle-fibres in a normal individual, so it has to be proved that these abnormalities are more widespread in people suscept- ible to hyperpyrexia. Others who have investigated the light and electron-microscopic morphology of muscle, and the contracture induced in vitro by halothane and suxamethonium, have been unable to detect any real abnormality of muscle from sus- ceptible individuals, despite a raised serum-creatine- kinase. 12, 13 Prevention of malignant pyrexia rests on identi- fication of individuals at risk if subjected to general anaesthesia. BRADLEY and MURCHISON 12 rightly stress that, when advising relatives of patients with malignant hyperpyrexia, it is best to err on the side of caution. Operation under local or spinal anxs- thesia is better than chancing a death where the creatine kinase and other tests of muscle function are normal. Research must continue, to identify the different diseases underlying the syndrome, the different methods of identifying individuals at risk, the exact success-rate of these methods, and the best management for an attack. Until these efforts come to fruition, all relatives should be advised to avoid general anaesthesia with agents which can induce malignant hyperpyrexia, whether muscle tests are normal or not. 9. Ellis, F. R., Keaney, N. P., Harriman, D. G. F., Sumner, D. W., Kyei-Mensah, K., Tyrrell, J. H., Hargreaves, J. B., Parikh, R. K., Mulrooney, P. L. Br. med. J. 1972, iii, 559. 10. Bethlem, J., van Wijngaarden, G. K., de Jong, J. J. neurol. Sci. 1973, 18, 351. 11. Denborough, M. A., Dennett, X., Anderson, R. McD. Br. med. J. 1973, i, 272. 12. Bradley, W. G., Murchison, D. ibid. 1972, iv, 108. 13. Bradley, W. G., Ward, M., Murchison, D., Hall, L., Woolf, N. Proc. R. Soc. Med. 1973, 66, 67.

Transcript of Prevention of Malignant Hyperpyrexia

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1225

Prevention of Malignant Hyperpyrexia

THE LANCET

A RELATIVELY rare condition, malignant hyper-pyrexia, has given rise to a great deal of interest andresearch. There are two main reasons : firstly, it isa disease induced by doctors, the agent beingadministered by an anxsthetist; and, secondly,prevention may be possible by identifying susceptibleindividuals. The discovery of a dominant form ofinheritance opened the way to counselling relatives,’ 1and detection of raised creatine kinase in somerelatives has indicated that susceptible individualsmay have a subclinical myopathy. 2-5 Several groupshave looked further into this possibility, and it is

becoming clear that the syndrome of malignanthyperpyrexia may be a feature of several differentdiseases.

BRI-IT and KALOW 6 concluded that there might betwo diseases because two-thirds of patients becamerigid while the remainder did not; the rigid groupmore often had pre-existing congenital muscle andskeletal disease. ISAACS and BARLOW now disputethis suggestion, having identified cases of both typesin the same family. KING et al. investigated 18families in which one or more propositi had hadmalignant hyperpyrexia. In nine cases serum-creatine-kinase activity was raised in other family members,and the inheritance appeared to be autosomaldominant. In three of these family members theraised creatine kinase was associated with a relativelyspecific myopathy, the remaining six having no

clinical sign of muscle abnormality. The families ofthree other patients had normal creatine-kinase

activities, suggesting mutation from the dominantlyinherited subclinical variety. One patient had

dominantly inherited myotonia congenita, and hisserum-creatine-kinase was raised; but other members1. Denborough, M. A., Forster, J. F. A., Lovell, R. H., Maplestone,

P. A., Villiers, J. D. Br. J. Anœsth. 1962, 34, 395.2. Britt, B. A., Locher, W. G., Kalow, W. Can. Anœsth. Soc. J. 1969,

16, 89.3. Denborough, M. A., Forster, J. F. A., Hudson, M. C., Carter, N. G.,

Zapf, P. Lancet, 1970, i, 1137.4. Isaacs, H., Barlow, M. B. Br. med. J. 1970, i, 275.5. Zsigmond, E. K., Starkweather, W. H., Duboff, G. S., Flynn, K.

Anesth. Analg. 1972, 51, 220.6. Britt, B. A., Kalow, W. Can. Anœsth. Soc. J. 1970, 17, 293.7. Isaacs, H., Barlow, M. B. J. Neurol. Neurosurg. Psychiat. 1973,

36, 228.8. King, J. O., Denborough, M. A., Zapf, P. W. Lancet, 1972, i, 365.

of his family with myotonia had normal levels-theoccurrence of the two together may have been

fortuitous, since many other patients with myotoniahave had general anaesthesia without malignantpyrexia. Another five patients had families withnormal creatine-kinase activities, and all these

showed musculoskeletal abnormalities of various

kinds, including short stature, cryptorchidism, pectuscarinatum, lumbar lordosis, and thoracic kyphosis.This heterogeneity may explain some of the differ-ences between the results of groups who have lookedinto the myopathy. ELLIS et al. investigated sevenrelatives from 4 families with this syndrome andfound that five had slight neurological abnormalities,five had raised creatine-kinase activities, five had

biopsy specimens with " moth-eaten " fibres scatteredthroughout the muscle, and five had biopsy specimensshowing contracture when exposed in vitro to a

combination of halothane and suxamethonium. Themoth-eaten fibres are, however, non-specific,1 andthe " cores " in a biopsy specimen from a probablysusceptible patient," and the various myopathicabnormalities illustrated in the review of ISAACS and

BARLOW,7 must be looked upon with reserve. It isnot unusual to see a few abnormal muscle-fibres ina normal individual, so it has to be proved that theseabnormalities are more widespread in people suscept-ible to hyperpyrexia. Others who have investigatedthe light and electron-microscopic morphologyof muscle, and the contracture induced in vitro byhalothane and suxamethonium, have been unable todetect any real abnormality of muscle from sus-

ceptible individuals, despite a raised serum-creatine-kinase. 12, 13

Prevention of malignant pyrexia rests on identi-fication of individuals at risk if subjected to generalanaesthesia. BRADLEY and MURCHISON 12 rightlystress that, when advising relatives of patients withmalignant hyperpyrexia, it is best to err on the sideof caution. Operation under local or spinal anxs-thesia is better than chancing a death where thecreatine kinase and other tests of muscle functionare normal. Research must continue, to identifythe different diseases underlying the syndrome, thedifferent methods of identifying individuals at risk,the exact success-rate of these methods, and the bestmanagement for an attack. Until these efforts cometo fruition, all relatives should be advised to avoid

general anaesthesia with agents which can induce

malignant hyperpyrexia, whether muscle tests are

normal or not.

9. Ellis, F. R., Keaney, N. P., Harriman, D. G. F., Sumner, D. W.,Kyei-Mensah, K., Tyrrell, J. H., Hargreaves, J. B., Parikh, R. K.,Mulrooney, P. L. Br. med. J. 1972, iii, 559.

10. Bethlem, J., van Wijngaarden, G. K., de Jong, J. J. neurol. Sci.

1973, 18, 351.11. Denborough, M. A., Dennett, X., Anderson, R. McD. Br. med. J.

1973, i, 272.12. Bradley, W. G., Murchison, D. ibid. 1972, iv, 108.13. Bradley, W. G., Ward, M., Murchison, D., Hall, L., Woolf, N.

Proc. R. Soc. Med. 1973, 66, 67.