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Anesthetic-induced malignant hyperpyrexia in children
]uly, 1973 T h e ]ournal o/ P E D I A T R I C S
37
Anesthetic-induced malignant byperpyrexia in children Malignant hyperpyrexia is an often fatal complication of anesthesia occurring in individuals with underlying muscle disease. One clinical myopathy associated with malignant hyperpyrexia occurs in young boys who are small/or age and have undescended testes, lumbar lordosis, thoracic kyphosis, and pectus carinatum. They also have an unusual facial appearance with a small chin, low-set ears, and antimongoloid obliquity of the palpebral fissures. When these physical abnormalities are noticed the clinician should suspect that the patient may be susceptible to malignant hyperpyrexia and should took [or clinical and biochemical evidence of muscle disease.
j. o . King, M.D., M.R.A.C.P., and M. A. Denborough, M.D., D.Phil., F.R.A.C.P., M.R.C.P., ~" Victoria, Australia
S I N C ~ malignant hyperpyrexia was first described in 1960,1 more than 200 cases have been reported; the case fatality rate has been approximately 65 per cent. The syndrome is characterized by a rapid and extreme rise in body temperature during anesthesia and may be associated with muscular rigidity, cyanosis, tachypnea, and tachycardia. The patients are always severely acidotic. These clinical features probably result from an increased concentration 'of calcium ions in the myoplasm!, 3; it is now known that all individuals who are susceptible to malignant hyperpyrexia have an underlying disease of muscle, which may be subclinical. 4-G At teast three clinical types of imyopathy predispose to malignant hyperpyrexiafi The From the Department of Medicine, University of Melbourne, and The Royal Melbourne Hospital. *~Reprint address: Department o[ Medicine, Royal dl'lelbourne Hospital, Victoria 3050 Australia.
present report emphasizes one of these clinical myopathies which is found in young boys and is associated with striking physical abnormalities., which should alert the clinician or anesthesiologist to the possibility that the child may be susceptible to malignant hyperpyrexia.
METHODS All known cases of malignant hyperpyrexia in Australia and New Zealand were studied. If the patient had died of the reaction, information of the past medical history was obtained from relatives and medical attendants. The relatives of all propositi and the survivors were examined when possible, and serum creatine phosphokinase levels were obtained.
RESULTS Four of the 19 individuals who suffered an unequivocal episode of malignant hyperVol. 83, No. 1, pp. 37-40
38
King and Denborough
The Journal o[ Pediatrics July 1973
T a b l e I. Characteristics of four patients with physical abnormalities
Case No. Features
'12131+
Male sex + + Small build + + Cryptorchidism + + Pectus carinatum + + Kyphosis + + Lordosis + + Hypoplastie mandible + + Crowded lower teeth + ~ Antimongoloid obliquity of palpebral fissures + + Low attachment of ears + + Webbed neck + ? Ptosis + Weakness of serrati + ? + = Present, - = absent, ? = not known.
+ + + + + + + +
+ + + + + + + -
+ ? ~
+ + + + +
pyrexia h a d strikingly similar physical abnormalities. T h e y were all young boys, ages 13, 11, 10, a n d 10 years, respectively; three died from m a l i g n a n t hyperpyrexia, and one is still living. T h e details of the physical features of the four patients are given in T a b l e I. All boys were small for age. T h e y were all of n o r m a l intelligence. Case 1 weighed 3~5t5 G m . at birth, but at 13 years his height a n d weight were below the third percentile. Case 2 weighed 2,608 Gm. at birth and was below the third percentile for weight at 11 years. Case 3 h a d a birth weight of 3,431 Gm., b u t at 4 years of age was below the t e n t h percentile for weight and just above the tenth percentile for height. Case 4 weighed 2,728 Gm. at birth; at one year he was below the tenth percentile for weight a n d height, a n d at 11 years he was below the twenty-fifth percentile for weight. Cryptorchidism was present in all four boys; in three of them orchiopexies had been performed. E a c h of the boys h a d a l u m b a r lordosis, thoracic kyphosis, a n d pectus carin a t u m . T h e spinal deformities were first noted at 4 ~ years in one a n d at 4 years in another. Case 3 h a d congenital fusion of the second, third, and fourth l u m b a r vertebrae. T h e facial appearances of the four boys were strikingly similar. E a c h had hypoplasia of the m a n d i b l e and m a l a r bones. Two of t h e m h a d been seen by a dentist because of
crowding of the lower teeth; Case 3 h a d a speech defect due to a "short p a l a t e with nasal escape." T h e a t t a c h m e n t of the ears was probably lower t h a n n o r m a l in each of t h e m but was p a r t i c u l a r l y obvious in Cases 1 and 4, both of w h o m also h a d webbed necks. T h r e e of the four h a d antimongoloid obliquity of tile p a l p e b r a l fissures. This gave rise to the a p p e a r a n c e of ptosis, but in Case 4 definite left ptosis was present as well (Fig. 1). Case 1 also h a d winging of the scapulae and h i g h - a r c h e d feet, a n d Case 4 h a d recurrent dislocation of the patellae as well as weakness and wasting of the quadriceps and serrati. T h e mothers of the boys h a d h a d uneventful pregnancies with no known d r u g ingestion or infections. Physical milestones were passed slowly in all of tile boys; they walked at 13, 18, 16, a n d 23 months, respectively. T h e karyotypes of two boys were n o r m a l male *46,XY, a n d a third was c h r o m a t i n negative on a buccal smear. T h e only survivor (Case 4) h a d a slowly progressive weakness involving principally the shoulder girdle a n d thigh muscles. His serum creatine phosphokinase level was eIevated at 212 I.U. p e r liter (normal range 0 to 4 0 ) ; a muscle biopsy taken at the age of 10 years showed great variation in the diameters of muscle fibers; there were m a n y giant fibers, occasional necrotic foci w i t h , phagocytosis, and an increase in fat. These changes are consistent with m u s c u l a r dystrophy. 7 T h e four boys were each r e g a r d e d as unique in their families. Clinical e x a m i n a tion and serum creatine phosphokinase screening of their families has failed to reveal any affected relatives. DISCUSSION T h e physical features of the four young boys presented are so similar t h a t it seems probable that they all h a d the same underlying disease. All boys developed m a l i g n a n t hyperpyrexia d u r i n g general anesthesia between the ages of 10 and 13 years. T h e y were all small for their age a n d h a d undescended testes a n d the same spinal a n d thoracic deformities. All had hypoplasia of
Volume 83 Number 1
the lower face and three had antimongoloid obliquity of the palpebral fissures. The only survivor appears to have a slowly progressive congenital myopathy, which from retrospective information was probably present in the other three. The syndrome described here in association with malignant hyperpyrexia may account for about 25 per cent of all individuals who develop this reaction under general anesthesia. Although this clinical problem is uncommon, the physical features are sufficiently distinctive to alert physicians to the syndrome before anesthesia is administered. If clinical examination of the patient raises the possibility of susceptibility to maligant hyperpyrexia, a serum creatine phosphokinase value should be obtained to look for an underlying myopathy. The only survivor in the present survey has a markedly elevated creatine phosphokinase value. If the serum creatine phosphokinase level is elevated in a patient with the physical abnormalities which are described in this report, he should be regarded as being at risk of developing malignant hyperpyrexia. If possible any operative procedure for him should be done under local, spinal, or regional anesthesia. If general anesthesia is unavoidable thiopentone sodium, nitrous oxide, and d-tubocurarine could be used, but these are the only general anesthetic agents which at present are known to be safe. If the serum creatine phosphokinase value is normal, the patient should not be susceptible to malignant hyperpyrexia. If the serum creatine phosphokinase result is equivocal the only way to exclude susceptibility to malignant hyperpyrexia that is at present available is to examine the in vitro response of the patient's muscle to halothane, s, ~ If facilities for performing this test are not available the safest procedure would be to regard the child as being at risk from malignant hyperpyrexia Should an anesthetic be necessary. Histologic studies on muscle in malignant hyperpyrexia have not been very helpful in the past but may be more useful in the future, in view of the recent observation of
Anesthetic-induced malignant hyperpyrexia
39
\ Fig. 1. Case 4, at 2 years of age, prior to surgical correction of left ptosis.
an association between malignant hyperpyrexia and the rare inyopathy known as central core disease, ~~ which has a characteristic histochemical and electron microscopic appearance. We are indebted to the followiug colleagues who supplied information: Drs. D. M. Danks, J F. Mainland, H. J. Sinn, and H. P. Taft (Melbourne); N. M. Dilworth (Perth); P. Hinchley (Albany); and A. J. Newson and Mr. B. M. Hay (New Zealand), We also thank Mr. K. W. Radford of Kevron Photographies for the photograph. REFERENCES
1. Denborough, M. A., and Lovell, R. R. H.: Anaesthetic deaths in a family, Lancet 2: 45, 1960. 2. Britt, B. A., and Kalow, W.: Malignant hyperpyrexia. Aetiology unknown, Can. Anaesth. Soc. J. 17: 316, 1970. 3. Denborough, M. A., Hird, F. J. R., King,
40
King and Denborough
J. O., Marginson, M. A., Mitchelson, K. R., Nayler, W. G., Rex, M. A., Zapf, P. W., and Condron, R. J.: Mitochondrial and other studies in Australian Landrace pigs affected with malignant hyperthermia, proceedings of the International Symposium on Malignant Hyperthermia, Toronto, 1971. In press. 4. Denborough, M. A., Ebeling, P., King, J. O., and Zapf, P. W.: Myopathy and malignant hyperpyrexia, Lancet 1: 1138, 1970. 5. Isaacs, H., and Barlow, M. B.: Malignant hyperpyrexia during anaesthesia: Possible association with subclinical myopathy, Br. Med. J. 1: 275, 1970.
The Journal o[ Pediatrics July 1973
6. King, J. O., Denborough, M. A., and Zapf, P. W.: Inheritance of malignant hyperpyrexia, Lancet 1: 365, 1972. 7. Dilworth, N. M.: Personal communication, 1971. 8. Kalow, W., Britt, B. A., Terreau, M. E., and Haist, C.: Metabolic error of muscle metabolism after recovery from malignant hyperthermia, Lancet 2: 895, 1970. 9. Moulds, R. F. W., and Denborough, M. A.: Procaine in malignant hyperpyrexia, Br. Med. J. 4: 526, 1972. 10. Denborough, M. A., Dennett, X., and Anderson, R. M.: Brit. Med. J. In press.
37
Anesthetic-induced malignant byperpyrexia in children Malignant hyperpyrexia is an often fatal complication of anesthesia occurring in individuals with underlying muscle disease. One clinical myopathy associated with malignant hyperpyrexia occurs in young boys who are small/or age and have undescended testes, lumbar lordosis, thoracic kyphosis, and pectus carinatum. They also have an unusual facial appearance with a small chin, low-set ears, and antimongoloid obliquity of the palpebral fissures. When these physical abnormalities are noticed the clinician should suspect that the patient may be susceptible to malignant hyperpyrexia and should took [or clinical and biochemical evidence of muscle disease.
j. o . King, M.D., M.R.A.C.P., and M. A. Denborough, M.D., D.Phil., F.R.A.C.P., M.R.C.P., ~" Victoria, Australia
S I N C ~ malignant hyperpyrexia was first described in 1960,1 more than 200 cases have been reported; the case fatality rate has been approximately 65 per cent. The syndrome is characterized by a rapid and extreme rise in body temperature during anesthesia and may be associated with muscular rigidity, cyanosis, tachypnea, and tachycardia. The patients are always severely acidotic. These clinical features probably result from an increased concentration 'of calcium ions in the myoplasm!, 3; it is now known that all individuals who are susceptible to malignant hyperpyrexia have an underlying disease of muscle, which may be subclinical. 4-G At teast three clinical types of imyopathy predispose to malignant hyperpyrexiafi The From the Department of Medicine, University of Melbourne, and The Royal Melbourne Hospital. *~Reprint address: Department o[ Medicine, Royal dl'lelbourne Hospital, Victoria 3050 Australia.
present report emphasizes one of these clinical myopathies which is found in young boys and is associated with striking physical abnormalities., which should alert the clinician or anesthesiologist to the possibility that the child may be susceptible to malignant hyperpyrexia.
METHODS All known cases of malignant hyperpyrexia in Australia and New Zealand were studied. If the patient had died of the reaction, information of the past medical history was obtained from relatives and medical attendants. The relatives of all propositi and the survivors were examined when possible, and serum creatine phosphokinase levels were obtained.
RESULTS Four of the 19 individuals who suffered an unequivocal episode of malignant hyperVol. 83, No. 1, pp. 37-40
38
King and Denborough
The Journal o[ Pediatrics July 1973
T a b l e I. Characteristics of four patients with physical abnormalities
Case No. Features
'12131+
Male sex + + Small build + + Cryptorchidism + + Pectus carinatum + + Kyphosis + + Lordosis + + Hypoplastie mandible + + Crowded lower teeth + ~ Antimongoloid obliquity of palpebral fissures + + Low attachment of ears + + Webbed neck + ? Ptosis + Weakness of serrati + ? + = Present, - = absent, ? = not known.
+ + + + + + + +
+ + + + + + + -
+ ? ~
+ + + + +
pyrexia h a d strikingly similar physical abnormalities. T h e y were all young boys, ages 13, 11, 10, a n d 10 years, respectively; three died from m a l i g n a n t hyperpyrexia, and one is still living. T h e details of the physical features of the four patients are given in T a b l e I. All boys were small for age. T h e y were all of n o r m a l intelligence. Case 1 weighed 3~5t5 G m . at birth, but at 13 years his height a n d weight were below the third percentile. Case 2 weighed 2,608 Gm. at birth and was below the third percentile for weight at 11 years. Case 3 h a d a birth weight of 3,431 Gm., b u t at 4 years of age was below the t e n t h percentile for weight and just above the tenth percentile for height. Case 4 weighed 2,728 Gm. at birth; at one year he was below the tenth percentile for weight a n d height, a n d at 11 years he was below the twenty-fifth percentile for weight. Cryptorchidism was present in all four boys; in three of them orchiopexies had been performed. E a c h of the boys h a d a l u m b a r lordosis, thoracic kyphosis, a n d pectus carin a t u m . T h e spinal deformities were first noted at 4 ~ years in one a n d at 4 years in another. Case 3 h a d congenital fusion of the second, third, and fourth l u m b a r vertebrae. T h e facial appearances of the four boys were strikingly similar. E a c h had hypoplasia of the m a n d i b l e and m a l a r bones. Two of t h e m h a d been seen by a dentist because of
crowding of the lower teeth; Case 3 h a d a speech defect due to a "short p a l a t e with nasal escape." T h e a t t a c h m e n t of the ears was probably lower t h a n n o r m a l in each of t h e m but was p a r t i c u l a r l y obvious in Cases 1 and 4, both of w h o m also h a d webbed necks. T h r e e of the four h a d antimongoloid obliquity of tile p a l p e b r a l fissures. This gave rise to the a p p e a r a n c e of ptosis, but in Case 4 definite left ptosis was present as well (Fig. 1). Case 1 also h a d winging of the scapulae and h i g h - a r c h e d feet, a n d Case 4 h a d recurrent dislocation of the patellae as well as weakness and wasting of the quadriceps and serrati. T h e mothers of the boys h a d h a d uneventful pregnancies with no known d r u g ingestion or infections. Physical milestones were passed slowly in all of tile boys; they walked at 13, 18, 16, a n d 23 months, respectively. T h e karyotypes of two boys were n o r m a l male *46,XY, a n d a third was c h r o m a t i n negative on a buccal smear. T h e only survivor (Case 4) h a d a slowly progressive weakness involving principally the shoulder girdle a n d thigh muscles. His serum creatine phosphokinase level was eIevated at 212 I.U. p e r liter (normal range 0 to 4 0 ) ; a muscle biopsy taken at the age of 10 years showed great variation in the diameters of muscle fibers; there were m a n y giant fibers, occasional necrotic foci w i t h , phagocytosis, and an increase in fat. These changes are consistent with m u s c u l a r dystrophy. 7 T h e four boys were each r e g a r d e d as unique in their families. Clinical e x a m i n a tion and serum creatine phosphokinase screening of their families has failed to reveal any affected relatives. DISCUSSION T h e physical features of the four young boys presented are so similar t h a t it seems probable that they all h a d the same underlying disease. All boys developed m a l i g n a n t hyperpyrexia d u r i n g general anesthesia between the ages of 10 and 13 years. T h e y were all small for their age a n d h a d undescended testes a n d the same spinal a n d thoracic deformities. All had hypoplasia of
Volume 83 Number 1
the lower face and three had antimongoloid obliquity of the palpebral fissures. The only survivor appears to have a slowly progressive congenital myopathy, which from retrospective information was probably present in the other three. The syndrome described here in association with malignant hyperpyrexia may account for about 25 per cent of all individuals who develop this reaction under general anesthesia. Although this clinical problem is uncommon, the physical features are sufficiently distinctive to alert physicians to the syndrome before anesthesia is administered. If clinical examination of the patient raises the possibility of susceptibility to maligant hyperpyrexia, a serum creatine phosphokinase value should be obtained to look for an underlying myopathy. The only survivor in the present survey has a markedly elevated creatine phosphokinase value. If the serum creatine phosphokinase level is elevated in a patient with the physical abnormalities which are described in this report, he should be regarded as being at risk of developing malignant hyperpyrexia. If possible any operative procedure for him should be done under local, spinal, or regional anesthesia. If general anesthesia is unavoidable thiopentone sodium, nitrous oxide, and d-tubocurarine could be used, but these are the only general anesthetic agents which at present are known to be safe. If the serum creatine phosphokinase value is normal, the patient should not be susceptible to malignant hyperpyrexia. If the serum creatine phosphokinase result is equivocal the only way to exclude susceptibility to malignant hyperpyrexia that is at present available is to examine the in vitro response of the patient's muscle to halothane, s, ~ If facilities for performing this test are not available the safest procedure would be to regard the child as being at risk from malignant hyperpyrexia Should an anesthetic be necessary. Histologic studies on muscle in malignant hyperpyrexia have not been very helpful in the past but may be more useful in the future, in view of the recent observation of
Anesthetic-induced malignant hyperpyrexia
39
\ Fig. 1. Case 4, at 2 years of age, prior to surgical correction of left ptosis.
an association between malignant hyperpyrexia and the rare inyopathy known as central core disease, ~~ which has a characteristic histochemical and electron microscopic appearance. We are indebted to the followiug colleagues who supplied information: Drs. D. M. Danks, J F. Mainland, H. J. Sinn, and H. P. Taft (Melbourne); N. M. Dilworth (Perth); P. Hinchley (Albany); and A. J. Newson and Mr. B. M. Hay (New Zealand), We also thank Mr. K. W. Radford of Kevron Photographies for the photograph. REFERENCES
1. Denborough, M. A., and Lovell, R. R. H.: Anaesthetic deaths in a family, Lancet 2: 45, 1960. 2. Britt, B. A., and Kalow, W.: Malignant hyperpyrexia. Aetiology unknown, Can. Anaesth. Soc. J. 17: 316, 1970. 3. Denborough, M. A., Hird, F. J. R., King,
40
King and Denborough
J. O., Marginson, M. A., Mitchelson, K. R., Nayler, W. G., Rex, M. A., Zapf, P. W., and Condron, R. J.: Mitochondrial and other studies in Australian Landrace pigs affected with malignant hyperthermia, proceedings of the International Symposium on Malignant Hyperthermia, Toronto, 1971. In press. 4. Denborough, M. A., Ebeling, P., King, J. O., and Zapf, P. W.: Myopathy and malignant hyperpyrexia, Lancet 1: 1138, 1970. 5. Isaacs, H., and Barlow, M. B.: Malignant hyperpyrexia during anaesthesia: Possible association with subclinical myopathy, Br. Med. J. 1: 275, 1970.
The Journal o[ Pediatrics July 1973
6. King, J. O., Denborough, M. A., and Zapf, P. W.: Inheritance of malignant hyperpyrexia, Lancet 1: 365, 1972. 7. Dilworth, N. M.: Personal communication, 1971. 8. Kalow, W., Britt, B. A., Terreau, M. E., and Haist, C.: Metabolic error of muscle metabolism after recovery from malignant hyperthermia, Lancet 2: 895, 1970. 9. Moulds, R. F. W., and Denborough, M. A.: Procaine in malignant hyperpyrexia, Br. Med. J. 4: 526, 1972. 10. Denborough, M. A., Dennett, X., and Anderson, R. M.: Brit. Med. J. In press.