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MALIGNANT HYPERPYREXIA AND SUDDEN INFANT DEATH SYNDROME
Br. J. Anaesth. (1988), 60, 28-30
MALIGNANT HYPERPYREXIA AND SUDDEN INFANT DEATH SYNDROME F. R. ELLIS, P. J. HALSALL AND D. G. F. HARRIMAN
SUBJECTS, MATERIALS AND METHODS
SUMMARY This paper reports three investigations of the suggested relationship between sudden infant death syndrome (SIDS) and malignant hyperpyrexia (MH). In the first study 151 MHsusceptible families completed a questionnaire designed to identify the incidence of SIDS within their own pedigree. In the second study 106 SIDS families completed a questionnaire designed to identify the incidence of anaesthetic related problems. In the third study, 14 SIDS parents were subjected to muscle biopsy and in vitro halothane contracture and caffeine contracture screening for susceptibility to MH. From the results of the three studies it can be concluded that there is no association between SIDS and MH.
Second study
Another more elaborate questionnaire was sent to 106 consecutive SIDS parents, through the A simple questionnaire was sent to 195 patients Foundation for the Study of Infant Deaths. This previously biopsied in this department who had questionnaire asked for details of the death of the been shown to be susceptible to MH (MHS) who child, including ambient temperatures and clothwere in or above child-bearing age. ing, etc., and the anaesthetic histories of both parents and their respective families. SIDS The questions included: parents were also asked to provide details of any How many pregnancies have you had? neuromuscular abnormalities including strabisWhat was the outcome of these pregnancies ? mus, ptosis, joint dislocations, hernia, kyphoHow many miscarriages ? scoliosis, muscle pains and cramps and the effects How many stillbirths ? How many children died in the first year of of strenuous exercise they experienced. life ? (Please give dates of birth, death, cause of death as written on the death certificate.) Third study Following the publicity in the media, 14 SIDS F . R . E L L I S , M.B., CH.B., PH.D., F.F.A.R.C.S.; P. J. HALSALL, parents volunteered to undergo a biopsy of the left M.B., CH.B.; D . G. F. HARRIMAN, M.D., F.R.C.P., F.R.C.PATH.; vastus medialis muscle. These studies were acThe Leeds Malignant Hyperpyrexia Investigation Unit, cepted by the Research Ethical Committees of University Department of Anaesthesia, Clinical Sciences Building, St James's University Hospital, Leeds, Yorks. both Leeds East and Leeds West Health Authorities. Halothane and caffeine contracture tests were Accepted for Publication: August 7, 1987. First study
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on March 14, 2015
In 1982 Denborough, Galloway and Hopkinson [1] stated that three of nine Australian families susceptible to malignant hyperpyrexia (MH) had also suffered the loss of a child through sudden infant death syndrome (SIDS). Until this time there had been no clinical suspicion of an association between these two conditions. This suggested association was avidly promoted by the media and in this country caused concern amongst both the MH and the SIDS families. A further study [2] described "positive medical family histories" in relation to anaesthesia among SIDS families. We felt it was important to validate this association, studying both the incidence of SIDS in the MH families and the incidence of MH in the SIDS families. A further study was designed in which SIDS parents were asked to submit to a muscle biopsy similar to those performed as part of the routine screening procedure for members of MH families [3].
MALIGNANT HYPERPYREXIA AND SUDDEN INFANT DEATH SYNDROME performed in vitro using the European MH Group procedure [4, 5] and muscle histology was undertaken. The clinical management of these subjects was identical to that given to patients referred to this Unit for screening for MH susceptibility [3].
29
replied to the questionnaire. There were no deaths attributed to anaesthesia and five families recorded a problem which was not suspected to be MH at the time by their medical attendants. Scanty details of these complications were as follows:
Subject 1. A father had experienced an increase in postoperative temperature on several occasions. Subject 2. A mother was pyrexial for 7 days First study following Caesarean section on two occasions. One hundred and fifty-one (76%) of the Subject 3. A mother reported a postoperative questionnaires were returned, recording 511 preg- respiratory depression and slow recovery. nancies with 456 live births. The outcome of these Subject 4. A mother described postoperative stiffness for 24 h following the removal of a live births is summarized in table I. There were 16 deaths in children younger than benign papilloma from the soft palate. 1 year of age, of which three were described as Subject 5. A maternal uncle was "packed in ice" "cot deaths" occurring in apparently healthy following an acute appendicectomy. infants. The cause of the infant deaths is sumThe only case which could have been MH was marized in table II and details of the SIDS are in Subject 5, although it should be noted he was table III. undergoing surgery for an infected lesion, the Using the binomial theorem the incidence of mobilization of which can cause acute pyrexia. In SIDS amongst the MH live births does not differ our experience of over 500 proband investigations significantly from the incidence of SIDS in the for MH screening, postoperative pyrexia has not general population (P < 0.05), which is taken to been found to be a presenting sign of MH. Also, be 1.96 per 1000 live births [6] (but see discussion we have never encountered a case of MH later). presenting as a 7-day postoperative pyrexia. Subject 4 resembles a post suxamethonium myoSecond study sitis. There were no consistent reports of neuroA total of 278 anaesthetics had been recalled musculoskeletal problems. amongst the 106 pairs of SIDS parents who Third study TABLE I. Outcome of pregnancies in MH families The laboratory tests conducted on live muscle tissue taken from the normal SIDS parents were Total pregnancies 511 Live births 456 all within normal limits (MHN) as denned by the Miscarriage 46 European protocol. Stillbirth 5 In order to compare our studies with those of Therapeutic termination 3 Denborough, Galloway and Hopkinson [1], Ectopic pregnancy 1 muscle specimens were also exposed to 3 % halothane, a test not recognized in the European TABLE II. Causes of infant death in MH families MH Group procedure. One of the 14 parents produced an insignificant increase in the baseline Perinatal unspecified 6 muscle tension of 0.1 g on exposure to 3 % Congenital heart disease 4 halothane. 2 Gastroenteritis No patient displayed any abnormal histology, Convulsions 1 and preoperative resting serum creatinekinase 3 SIDS (CK) activity was consistently within normal limits for our laboratory. TABLE III. Details of SIDS in MH families RESULTS
3 months old 5 months old 4 months old
6th pregnancy 17th pregnancy 4th pregnancy
DISCUSSION
It was not until 1971 that cot death or sudden death became accepted as a registrable cause of
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on March 14, 2015
Case 1. 1962 Case 2. 1971 Case 3. 1978
30
[3], although differing patterns of inheritance have been described previously [11]. Should SIDS correlate with MH, the muscle abnormality should also be dominantly inherited and each SIDS parent should have a 0.5 probability for the muscle abnormality. Using sequential analysis it can be inferred that, with the 14 negative findings, the probability of a muscle defect occurring similar to that found in MHS patients is less than 0.05. We considered that further biopsy studies, with their attendant risks, would be unethical. The apparent discrepancy between our laboratory results and those of Denborough and colleagues [1] can be explained by the method of case selection used by the latter group. In particular they encouraged SIDS families with a family history of an anaesthetic mishap to be investigated preferentially (Denborough, 1987 personal communication), thus biasing their findings in favour of an association between SIDS and MH, which we have been unable to substantiate.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on March 14, 2015
death in England and Wales. The term sudden infant death syndrome (SIDS) came into use in 1979. The incidence of SIDS in the general population is difficult to ascertain precisely and is variously quoted as 0.62 per 1000 live births in 1971 to 2.13 in 1982 and currently is 1.96 (vide supra). Before 1971, unexpected deaths were reported as "sudden respiratory deaths" and as acute tracheobronchitis, bronchiolitis or bronchopneumonia, despite lack of conclusive pathological evidence. However, virological evidence has been found by Downham and colleagues [7] in some sudden respiratory deaths and some "cot deaths". Since 1971 the number of sudden deaths attributed to "respiratory causes" has declined from 1.63 in 1971 to 0.46 in 1981 whereas the combined rate of SIDS and respiratory problems has stayed at a steady 2.4 per 1000 live births over the period 1971-81 [8]. The problem is compounded further because of controversy over the exact definition of SIDS, some applying the term regardless of postmortem findings [9], thus making epidemiological studies difficult. Becroft, Beckwith and Ray in 1970 [10] suggested the definition to be: " the sudden death of an infant or young child, which is unexplained by history, and in which a thorough postmortem examination fails to demonstrate an adequate cause of death". Because of these difficulties, cases described as "cot deaths" occurring in MH families before 1971, were included. This gives an overall incidence in the MH families of three cot deaths per 456 live births as compared with 2.4 per 1000 live births for the combined SIDS and respiratory deaths in the general population. If these two cases are excluded because they could not have been registered as a SIDS or cot death on the death certificate, the incidence becomes 1 SIDS per 456 live births compared with 1.96 per 1000 live births in the general population; the latter incidence excludes the "respiratory causes" group. The number of cases of SIDS reported in this study is too small for there to be a significant and specific link between MH and SIDS. The incidence of anaesthetic mortality in the SIDS group was zero and the morbidity of 5 in 278 anaesthetics is gratifyingly low. With the possible but unlikely exception of Subject 5, none could be considered to be MH reactions. From a recent study in this laboratory, MH is inherited as a Mendelian dominant characteristic
BRITISH JOURNAL OF ANAESTHESIA
REFERENCES 1. Denborough MA, Galloway GJ, Hopkinson, KC. Malignant hyperpyrexia and sudden infant death. Lancet 1982; ii: 1068. 2. Peterson DR, Davis, N. Malignant hyperthermia diathesis and sudden infant death syndrome. Anesthesia and Analgesia 1986; 65: 209. 3. Ellis FR, Halsall PJ, Harriman DGF. The work of the Leeds Malignant Hyperpyrexia Unit 1971-1984. Anaesthesia 1986; 41: 809-815. 4. European Malignant Hyperpyrexia Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. British Journal of Anaesthesia 1984; 56: 1267-1269. 5. European Malignant Hyperpyrexia Group. Laboratory diagnosis of malignant hyperpyrexia susceptibility. British Journal of Anaesthesia 1985; 57: 1038. 6. Limerick SR. The Foundation for the Study of Infant Deaths. 15, Belgrave Sq., London SW1X 8PS. 1986. 7. Downham MAPS, Gardner PS, Mcquillin J, Ferris JAS. Role of respiratory viruses in childhood mortality. British Medical Journal 1975; i: 235-239. 8. Gardner A. The history of certification of sudden infant death syndrome is reviewed and methods of establishing statistics of conditions are discussed. Studies in sudden infant deaths. Office of Population Censuses and Surveys. Studies on Medical and Population Subjects, 1982; no. 45. 9. Editorial. Cot deaths. Lancet, 1975; U: 1024-1025. 10. Becroft AB, Beckwith JB, Ray CG. Sudden Infant Death Syndrome. University of Washington Press, 1970: 18. 11. Gronert GA. Malignant hyperthermia. Anesthesiology 1980; 53: 395-423.
MALIGNANT HYPERPYREXIA AND SUDDEN INFANT DEATH SYNDROME F. R. ELLIS, P. J. HALSALL AND D. G. F. HARRIMAN
SUBJECTS, MATERIALS AND METHODS
SUMMARY This paper reports three investigations of the suggested relationship between sudden infant death syndrome (SIDS) and malignant hyperpyrexia (MH). In the first study 151 MHsusceptible families completed a questionnaire designed to identify the incidence of SIDS within their own pedigree. In the second study 106 SIDS families completed a questionnaire designed to identify the incidence of anaesthetic related problems. In the third study, 14 SIDS parents were subjected to muscle biopsy and in vitro halothane contracture and caffeine contracture screening for susceptibility to MH. From the results of the three studies it can be concluded that there is no association between SIDS and MH.
Second study
Another more elaborate questionnaire was sent to 106 consecutive SIDS parents, through the A simple questionnaire was sent to 195 patients Foundation for the Study of Infant Deaths. This previously biopsied in this department who had questionnaire asked for details of the death of the been shown to be susceptible to MH (MHS) who child, including ambient temperatures and clothwere in or above child-bearing age. ing, etc., and the anaesthetic histories of both parents and their respective families. SIDS The questions included: parents were also asked to provide details of any How many pregnancies have you had? neuromuscular abnormalities including strabisWhat was the outcome of these pregnancies ? mus, ptosis, joint dislocations, hernia, kyphoHow many miscarriages ? scoliosis, muscle pains and cramps and the effects How many stillbirths ? How many children died in the first year of of strenuous exercise they experienced. life ? (Please give dates of birth, death, cause of death as written on the death certificate.) Third study Following the publicity in the media, 14 SIDS F . R . E L L I S , M.B., CH.B., PH.D., F.F.A.R.C.S.; P. J. HALSALL, parents volunteered to undergo a biopsy of the left M.B., CH.B.; D . G. F. HARRIMAN, M.D., F.R.C.P., F.R.C.PATH.; vastus medialis muscle. These studies were acThe Leeds Malignant Hyperpyrexia Investigation Unit, cepted by the Research Ethical Committees of University Department of Anaesthesia, Clinical Sciences Building, St James's University Hospital, Leeds, Yorks. both Leeds East and Leeds West Health Authorities. Halothane and caffeine contracture tests were Accepted for Publication: August 7, 1987. First study
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on March 14, 2015
In 1982 Denborough, Galloway and Hopkinson [1] stated that three of nine Australian families susceptible to malignant hyperpyrexia (MH) had also suffered the loss of a child through sudden infant death syndrome (SIDS). Until this time there had been no clinical suspicion of an association between these two conditions. This suggested association was avidly promoted by the media and in this country caused concern amongst both the MH and the SIDS families. A further study [2] described "positive medical family histories" in relation to anaesthesia among SIDS families. We felt it was important to validate this association, studying both the incidence of SIDS in the MH families and the incidence of MH in the SIDS families. A further study was designed in which SIDS parents were asked to submit to a muscle biopsy similar to those performed as part of the routine screening procedure for members of MH families [3].
MALIGNANT HYPERPYREXIA AND SUDDEN INFANT DEATH SYNDROME performed in vitro using the European MH Group procedure [4, 5] and muscle histology was undertaken. The clinical management of these subjects was identical to that given to patients referred to this Unit for screening for MH susceptibility [3].
29
replied to the questionnaire. There were no deaths attributed to anaesthesia and five families recorded a problem which was not suspected to be MH at the time by their medical attendants. Scanty details of these complications were as follows:
Subject 1. A father had experienced an increase in postoperative temperature on several occasions. Subject 2. A mother was pyrexial for 7 days First study following Caesarean section on two occasions. One hundred and fifty-one (76%) of the Subject 3. A mother reported a postoperative questionnaires were returned, recording 511 preg- respiratory depression and slow recovery. nancies with 456 live births. The outcome of these Subject 4. A mother described postoperative stiffness for 24 h following the removal of a live births is summarized in table I. There were 16 deaths in children younger than benign papilloma from the soft palate. 1 year of age, of which three were described as Subject 5. A maternal uncle was "packed in ice" "cot deaths" occurring in apparently healthy following an acute appendicectomy. infants. The cause of the infant deaths is sumThe only case which could have been MH was marized in table II and details of the SIDS are in Subject 5, although it should be noted he was table III. undergoing surgery for an infected lesion, the Using the binomial theorem the incidence of mobilization of which can cause acute pyrexia. In SIDS amongst the MH live births does not differ our experience of over 500 proband investigations significantly from the incidence of SIDS in the for MH screening, postoperative pyrexia has not general population (P < 0.05), which is taken to been found to be a presenting sign of MH. Also, be 1.96 per 1000 live births [6] (but see discussion we have never encountered a case of MH later). presenting as a 7-day postoperative pyrexia. Subject 4 resembles a post suxamethonium myoSecond study sitis. There were no consistent reports of neuroA total of 278 anaesthetics had been recalled musculoskeletal problems. amongst the 106 pairs of SIDS parents who Third study TABLE I. Outcome of pregnancies in MH families The laboratory tests conducted on live muscle tissue taken from the normal SIDS parents were Total pregnancies 511 Live births 456 all within normal limits (MHN) as denned by the Miscarriage 46 European protocol. Stillbirth 5 In order to compare our studies with those of Therapeutic termination 3 Denborough, Galloway and Hopkinson [1], Ectopic pregnancy 1 muscle specimens were also exposed to 3 % halothane, a test not recognized in the European TABLE II. Causes of infant death in MH families MH Group procedure. One of the 14 parents produced an insignificant increase in the baseline Perinatal unspecified 6 muscle tension of 0.1 g on exposure to 3 % Congenital heart disease 4 halothane. 2 Gastroenteritis No patient displayed any abnormal histology, Convulsions 1 and preoperative resting serum creatinekinase 3 SIDS (CK) activity was consistently within normal limits for our laboratory. TABLE III. Details of SIDS in MH families RESULTS
3 months old 5 months old 4 months old
6th pregnancy 17th pregnancy 4th pregnancy
DISCUSSION
It was not until 1971 that cot death or sudden death became accepted as a registrable cause of
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on March 14, 2015
Case 1. 1962 Case 2. 1971 Case 3. 1978
30
[3], although differing patterns of inheritance have been described previously [11]. Should SIDS correlate with MH, the muscle abnormality should also be dominantly inherited and each SIDS parent should have a 0.5 probability for the muscle abnormality. Using sequential analysis it can be inferred that, with the 14 negative findings, the probability of a muscle defect occurring similar to that found in MHS patients is less than 0.05. We considered that further biopsy studies, with their attendant risks, would be unethical. The apparent discrepancy between our laboratory results and those of Denborough and colleagues [1] can be explained by the method of case selection used by the latter group. In particular they encouraged SIDS families with a family history of an anaesthetic mishap to be investigated preferentially (Denborough, 1987 personal communication), thus biasing their findings in favour of an association between SIDS and MH, which we have been unable to substantiate.
Downloaded from http://bja.oxfordjournals.org/ at University of Michigan on March 14, 2015
death in England and Wales. The term sudden infant death syndrome (SIDS) came into use in 1979. The incidence of SIDS in the general population is difficult to ascertain precisely and is variously quoted as 0.62 per 1000 live births in 1971 to 2.13 in 1982 and currently is 1.96 (vide supra). Before 1971, unexpected deaths were reported as "sudden respiratory deaths" and as acute tracheobronchitis, bronchiolitis or bronchopneumonia, despite lack of conclusive pathological evidence. However, virological evidence has been found by Downham and colleagues [7] in some sudden respiratory deaths and some "cot deaths". Since 1971 the number of sudden deaths attributed to "respiratory causes" has declined from 1.63 in 1971 to 0.46 in 1981 whereas the combined rate of SIDS and respiratory problems has stayed at a steady 2.4 per 1000 live births over the period 1971-81 [8]. The problem is compounded further because of controversy over the exact definition of SIDS, some applying the term regardless of postmortem findings [9], thus making epidemiological studies difficult. Becroft, Beckwith and Ray in 1970 [10] suggested the definition to be: " the sudden death of an infant or young child, which is unexplained by history, and in which a thorough postmortem examination fails to demonstrate an adequate cause of death". Because of these difficulties, cases described as "cot deaths" occurring in MH families before 1971, were included. This gives an overall incidence in the MH families of three cot deaths per 456 live births as compared with 2.4 per 1000 live births for the combined SIDS and respiratory deaths in the general population. If these two cases are excluded because they could not have been registered as a SIDS or cot death on the death certificate, the incidence becomes 1 SIDS per 456 live births compared with 1.96 per 1000 live births in the general population; the latter incidence excludes the "respiratory causes" group. The number of cases of SIDS reported in this study is too small for there to be a significant and specific link between MH and SIDS. The incidence of anaesthetic mortality in the SIDS group was zero and the morbidity of 5 in 278 anaesthetics is gratifyingly low. With the possible but unlikely exception of Subject 5, none could be considered to be MH reactions. From a recent study in this laboratory, MH is inherited as a Mendelian dominant characteristic
BRITISH JOURNAL OF ANAESTHESIA
REFERENCES 1. Denborough MA, Galloway GJ, Hopkinson, KC. Malignant hyperpyrexia and sudden infant death. Lancet 1982; ii: 1068. 2. Peterson DR, Davis, N. Malignant hyperthermia diathesis and sudden infant death syndrome. Anesthesia and Analgesia 1986; 65: 209. 3. Ellis FR, Halsall PJ, Harriman DGF. The work of the Leeds Malignant Hyperpyrexia Unit 1971-1984. Anaesthesia 1986; 41: 809-815. 4. European Malignant Hyperpyrexia Group. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. British Journal of Anaesthesia 1984; 56: 1267-1269. 5. European Malignant Hyperpyrexia Group. Laboratory diagnosis of malignant hyperpyrexia susceptibility. British Journal of Anaesthesia 1985; 57: 1038. 6. Limerick SR. The Foundation for the Study of Infant Deaths. 15, Belgrave Sq., London SW1X 8PS. 1986. 7. Downham MAPS, Gardner PS, Mcquillin J, Ferris JAS. Role of respiratory viruses in childhood mortality. British Medical Journal 1975; i: 235-239. 8. Gardner A. The history of certification of sudden infant death syndrome is reviewed and methods of establishing statistics of conditions are discussed. Studies in sudden infant deaths. Office of Population Censuses and Surveys. Studies on Medical and Population Subjects, 1982; no. 45. 9. Editorial. Cot deaths. Lancet, 1975; U: 1024-1025. 10. Becroft AB, Beckwith JB, Ray CG. Sudden Infant Death Syndrome. University of Washington Press, 1970: 18. 11. Gronert GA. Malignant hyperthermia. Anesthesiology 1980; 53: 395-423.