Yet it may be no coincidence that one other mother observed by one author (K.M.) during the initial piloting of our study, who on her frequent visits simply stood next to her twin infants' isolettes and never interacted with them, subsequently neglected these babies. Both twins were readmitted to hospital at age 14 months, weighing 4.0 and 4.5 kg, respectively, and at a developmental age of 4 to 5 months. The developmental age of both increased by 6 weeks during their 21-day rehospitalization. We are presently collecting followup data on all the subjects of this study to search for correlations of motherinfant interactions in the nursery and at home. We have also begun to record our observations on a continuous basis rather than by a time-sampling procedure. This allows us to document particular sequences of behaviour between a mother or nurse and an infant much more accurately and can tell us which infant behaviours elicit which maternal responses and vice versa. Information gained from such work can then lead to manipulations of the premature infant's environment. For example, if eye opening and closing were a signal initiating a particular mothering behaviour, positioning the infant in such a way as to increase the frequency of observation of eye openings might enhance maternal attachment and thus contribute to a decrease in the incidence of later parenting disorders in prematurely born children. Once we have collected sufficient behavioural data on premature infants who have had a comparatively benign postnatal course we can turn our attention to special groups of infants such as those who have received extensive ventilatory assistance. We hope this will permit us to map out the contribution both the parents and these high-risk groups of infants make to the child's later emotional and cognitive development. This study could not have been done without the assistance of Drs. P.R. Swyer, G. Chance and P. Fitzhardinge of the department of neonatology of The Hospital for Sick Children, and Drs. C. Corter and S. Trehub of the department of psychology, University of Toronto. References 1. Ussiast R, MCLEAN F: Intrauterine growth of live born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks gestation. I Pedjair 74: 901, 1969 2. AMIEL-TISON C: Neurological evaluation of the maturity of newborn infants. Arch Dis Child 43: 89, 1968 3. USHER R, MCLEAN F, Scorr VE: Judgement of fetal age. Pediatr Clin North Am 13: 835, 1966 4. LUECHENCO LO, DELIVORIA-PAPADOPOULOS M, Sa.&ms D: Long-term follow-up studies of prematurely born infants. II. Influence of birthweight and gestational age on sequelae. I Pediatr 80: 509, 1972 5. DRILLIEN CM: The Growth and Development
of the Prematurely Born Infant, Baltimore. Williams and Wilkins, 1964, pp 177-316 6. NI5WANDER KR, FRIEDMAN EA, HOOVER DB: Total morbidity following potentially anoxiogenic obstetric conditions. I. Abruptio placentae. II. Placenta previa. III. Prolapse of the umbilical cord. Am I Obstet Gynecol 95: 838, 1966 7. WIENER G, RiDalt RV, OPPEL WC, et al: Correlates of low birthweight. Psychological status at 8 to 10 years of age. Pedtatr Res 2: 110, 1968 8. ELMk.R E, GREGG GS: Developmental characteristics of abused children. Pediatrics 40: 596, 1967 9. FANAROFF AH, KENNELL JH, KLAUS MH:
Follow-up of low birth weight infants, the predictive value of maternal visiting patterns. Pediatrics 49: 287, 1972 10. KLEIN M, STERN L: Low birthweight and the battered child syndrome.. Am I Dis Child 122: 15, 1971
11. KIAus MH, KENNELL JH: Mothers separated from their newborn infants. Pediatr Clin North Am 17: 1015, 1970 12. Laisaa AD, LEIDERMAN PH, BARNETr CR, et al: Effects of mother-infant separation on maternal attachment behaviour. Child Dev 43: 1203, 1972 13. SEAsHoRE MJ, LEIFER AD, BARNE1-r CR, et al: The effects of denial of early mother-
infant interactions on maternal self-confidence. J Person Soc Psychol 26: 369, 1973 14. POWELL LF: The effect of extra stimulation and maternal involvement in the development of low-birth weight infants and on maternal behaviour. Child Dev 45: 106, 1974 15. Lawis M, ROSENSLUM LA: The Effect of the Infant on its Caregiver, New York, Wiley, 1974, pp 21-48 16. KOaNER AF, GROBSTEIN R: Individual differences at birth: implications for motherinfant relationship and later development. J Am Acad Child Psychiatry 6: 676, 1967 17. CAPLAN 0, MASON EA, KAPLAN DM: Four studies of crisis in parents of prematures. Comm Mental Health 1: 149, 1965 18. SCARR-SALAPATEK 5, WILuAMs ML: The effects of early stimulation on low-birthweight infants. Child Dev 44: 94, 1973 19. BERNARD K: A program of stimulation for infants born prematurely. Paper presented at Society for Research in Child Development. Philadelphia, PA, March 1973
20. PARMALEE AH: Neurophysiological and behavioral organization of premature infants in the first months of life. Biol Psychiatry 1975 (in press) 21. KLAUS MH, KENNELL JH, PLUMB N, et al: Human maternal behaviour at the first contact with their young. Pediatrics 49: 287, 1970
Sudden unexpected death in children with congenital heart disease * P. THQRNBACK, MB, B CH, FRCP[C]; R.S. FOWLER, MD, FRCP[C]
Summary: Of 18000 children with organic heart disease evaluated at The Hospital for Sick Children, Toronto between 1940 and 1971, 33 died suddenly and unexpectedly between I and 21 years of age. Nine had discrete obstruction of the left ventricular outflow tract and five had muscular narrowing of the left ventricular outflow tract. Pulmonary vascular disease caused seven sudden deaths, and arrhythmias (usually due to atrioventricular block) caused seven more. Of the five other children who died suddenly three had transposition of the great arteries, one had a complex cyanotic heart defect and one had an anomalous course of the left coronary artery, which originated from the right sinus of Valsalva. With earlier investigation of aortic stenosis, earlier closure of ventricular septal defect to avoid pulmonary vascular disease, better design of artificial pacemakers and better investigation of patients with angina, many of these deaths will be avoided in the future. From the University of Toronto, faculty of medicine, and department of pediatrics, division of cardiology, The Hospital for Sick Children, Toronto *This paper was prepared for the Sept. 20, 1975 issue of the Journal commemorating the centennial of The Hospital for Sick Children, Toronto, but because of space limitations could not be included. Reprint requests to: Dr. R.S. Fowler, Department of pediatrics, Division of cardiology, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8
Resume: D.c.s soudain et inattendu chez des enfants souffrant de cardiopathies cong.nitaIes Des 18000 enfants souffrant de cardiopathies organiques examines au Hospital for Sick Children de Toronto de 1940 a 1971, 33 sont morts soudainement et de fa9on inattendue alors qu'ils avaient de I a 21 ans. Neuf avaient une obstruction discrete du tractus de sortie du ventricule gauche et cinq avaient un retrecissement musculaire du tractus de sortie du ventricule gauche. La maladie vasculopulmonaire a cause sept morts subites et des arythmies (habituellement attribuables a un blocage atrioventriculaire) ont entraine sept autres deces. Des cinq autres enfants morts subitement, trois avaient une transposition des grandes arteres, un avait une cardiopathie complexe cyanog.ne et un autre avait un trajet anormal de l'artere coronaire gauche, qui prenait naissance a partir du sinus de Valsalva droit. Grice a des examens plus precoces de Ia stenose aortique, a une fermeture plus precoce d'une communication interventriculaire pour eviter les troubles vasculopulmonaires, a une conception plus parfaite des stimulateurs artificiels et a une observation plus attentive des malades souffrant d'angine de poitrine, il est indeniable que nombre de ces deces pourront itre evites dans l'avenir.
CMA JOURNAL/OCTOBER 18, 1975/VOL. 113 745
Sudden unexpected death is unusual in children with congenital heart defects. We undertook a study in the cardiac division of The Hospital for Sick Chil¬ dren, Toronto to identify defects that may cause this tragic outcome, with the hope that therapeutic measures may be found. Some of the data were used in an international study by the pediatric council of the International Society of Cardiology (chairman, Dr. E.C. Lambert* of Buffalo). We studied children who had died a sudden natural "death occurring instantaneously within 24 hours of acute symptoms
or or
signs",1 including only ambulatory pa¬ tients who had died out of hospital and were aged 1 to 21 years to avoid the controversy surrounding "cot deaths" in infancy. Methods The clinical data of all children eval¬ uated in the cardiac division between 1940 and 1971 are recorded on digital tape; a computer review yielded num¬ bers of patients, all deaths and deaths resulting from surgery.2 The records of all patients of appropriate age who had not died as a result of surgery were personally reviewed by one of the au¬ thors (P.T.). Additional information was obtained by writing to the family physician or the patient's physician, his parents and the pathologist who per¬ formed the autopsy when it was not done at this institution. Results Of the 18 000 patients with organic heart disease evaluated over the 32 years 3055 died before age 21, an in¬ cidence of 169.7/1000. Of these deaths (in patients over 1 year old) 33 were sudden and unexpected by the above definition: 24 died instantly; the re¬ maining 9 died some hours after the onset of acute symptoms. Eight died during strenuous exercise, 14 died dur¬ ing routine daily activity and 3 died at rest; in the other 8 the relation of death to activity could not be ascertained. Fifteen of the children had had corrective surgery for their defect and in seven of them an arrhythmia had developed in the postoperative period.
Left ventricular outflow obstruction Fourteen children died as a result of left ventricular obstruction: nine had discrete left ventricular outflow ob¬ struction and the other five had idio¬ pathic hypertrophie subaortic stenosis. Of the nine with discrete obstruction five had aortic valve stenosis (uncom¬ plicated in four and associated with a ?Died in March 1974.
746 CMA JOURNAL/OCTOBER 18,
followed) after closure of a ventricular septal defect: in 3 of the 5 atrioventri¬ cular block developed in the immediate postoperative period and in the other 2 it developed 4 and 5 years later, re¬ spectively. Of the three who were furnished with pacemakers, death was at¬ were evaluated over the 31 years: 36% had cardiac catheterization and 16% tributed to pacemaker failure in each. had severe stenosis requiring valvulotomy; 37 have died, 9 suddenly. There¬ Other causes fore the incidence of sudden death in this group is only 1 %. Five of the nine Up to December 1971, 105 children patients who died suddenly had fainted underwent the Mustard procedure for after exertion some time before death. total correction of transposition of the Electrocardiograms (ECGs) were avail¬ great arteries; 30 have died, 3 suddenly able for eight of these patients: all and unexpectedly (4 years postopera¬ showed evidence of left ventricular hy¬ tively in one instance and 2 years post¬ pertrophy and four showed a typical operatively in two). None had do¬ pattern of left ventricular strain with cumented evidence of an arrhythmia or ST-segment depression in leads AVF, heart failure but all had required V4, V5 and V* and T-wave inver- digitalis in the immediate postopera¬ sion. The ECG of one patient did tive period. One child died after hemoptysis. She not show this pattern but did show the pattern of incomplete right bundle had a complicated cyanotic defect with branch block (RBBB) with reg¬ dextrocardia, transposition and septal ular sinus rhythm1 in Vi. This patient defects but had remained in relatively had subvalvular aortic stenosis; cardiac good health until 11 years of age. A 14-year-old boy had complained catheterization showed a peak pressure gradient across the valve of 67 mm of occasional fainting and anterior Hg. It is possible that the incomplete chest pain with exercise. Clinically RBBB masked the ST- and T-wave there were rio signs of heart disease and even with exercise his ECG was changes of left ventricular strain. In contrast, of the 30 children with normal. He collapsed and died suddiffuse muscular obstruction evaluated dently when playing football. The only over the 31 years 8 died, 5 (17% of abnormality found at autopsy was the the 30) suddenly. The risk of sudden anomalous course of the left coronary death in children with this form of artery, which originated at the right sinus of Valsalva in conjunction with cardiomyopathy is therefore high. All the died while undertaking moderate to right coronary artery and passed strenuous exercise two while riding anteriorly between the aorta and the bicycles, one while scrambling up a main pulmonary artery before dividriver bank and two while walking. ing; the vessel was somewhat narrowed at the point where it passed between the two great arteries. In all of the vascular disease Pulmonary other 21 children with anomalous co¬ Of 93 patients with pulmonary vas¬ ronary arteries evaluated in this hospi¬ cular resistance evaluated over the 31 tal the coronary artery originated from years 33 had primary pulmonary hy¬ the pulmonary artery. There were 13 pertension and in 60 the disease devel¬ deaths, only 1 of which was sudden. oped in association with a ventricular septal defect or a patent ductus arterio¬ Discussion sus with reverse shunting the EisenIn adults two thirds of all sudden menger reaction. Of the 29 patients who died before 21 years of age 7 nontraumatic deaths are due to athero¬ (7.5% of the 93) died suddenly: 1 had sclerotic heart disease,3 and appropriate primary disease and 6 the Eisenmenger preventive measures are being taken. In the report of a recent study of chil¬ reaction. During the 31 years 4160 children dren with congenital heart disease with ventricular septal defect were Lambert and colleagues4 emphasized evaluated; the only children to die sud¬ the important defects leading to sudden denly were those in whom pulmonary death. Although it was inevitable that vascular resistance increased or those many of the children assessed in our in whom an arrhythmia developed af¬ study would have died, there appear to be a number of situations in which ter surgical closure of the defect. increased awareness might have saved the child's life. Arrhythmias If in a child with a clinical diagnosis Seven patients died suddenly as a of aortic stenosis such symptoms and result of arrhythmia. Heart block was signs as effort syncope or dyspnea, an¬ congenital in 2 (of 88 patients being gina or pronounced decrease in exer¬ followed) and developed in 5 (of 31 cise tolerance, or electrocardiographic
previously resected coarctation in one), three had a subvalvular diaphragm and one had supravalvular stenosis com¬ plicated by mild infundibular and pul¬ monary artery stenosis. A total of 916 patients with such discrete obstruction
1975/VOL. 113
evidence of left ventricular strain or RBBB develop, he should be admitted to hospital for urgent cardiodynamic assessment. These symptoms and signs portend sudden death and indicate a dangerous pressure gradient across the stenotic outflow tract. Surgery, when indicated, may rapidly reverse the situation and relieve the strain on the myocardium. A child with complete atrioventricular block as a result of surgical repair of ventricular septal defect, tetralogy of Fallot or atrioventricularis communis needs a permanent demand pacemaker. If complete RBBB and left anterior hemiblock develop and there is even a temporary period of complete atrioventricular block the same treatment should be considered. A child with electrocardiographic evidence of atrioventricular block but no actual period of block should be observed closely because late block can occur as long as 14 years after surgery.5'6 The child who has symptoms of coronary artery insufficiency - either true angina pectoris or fainting spells after exertion - should be considered for cardiac catheterization. As in the 14-year-old boy whose case has been described, ischemic changes may not be apparent on the EGG, even with exercise. If no other remediable cause for the pain can be found, aortography or coronary arteriography should be undertaken; an anomalous coronary artery may be found and appropriate surgery may relieve the abnormality.7 No patient with a mild heart defect died suddenly in this series or another larger series.4'8 Parents should be encouraged to allow normal activity in their children with mild heart disease withodt fear of sudden death. We wish to thank Dr. Vera Rose for her help in reviewing the computer file. This work was partly supported by a grant from the Ontario Heart Foundation. References 1. PAUL 0, SCHATZ M: On sudden death (E). Circulation 43: 7, 1971 2. Rosa V, O'CONNOR JR, KEITH JD, et al: Computer-based data storage and retrieval in pediatric cardiology. Can Med Assoc J 107: 305, 1972 3. KULLER L: Sudden death in arteriosclerotic heart disease: the case for preventive medicine. Am J Cardiol 24: 617, 1969 4. LAMBERT EC, MENON VA, wAGNER HR, et al: Sudden unexpected death from cardiovascular disease in children: a cooperative international study. Am I Cardiol 34: 89, 1974 5. GOLDMAN MJ, RoBERTs NK, IZUKAwA T: Late postoperative conduction disturbances after repair of ventricular septal defect and tetralogy of Fallot: analysis of His bundle recordings. Circulation 49: 214, 1974 6. Moss AJ, KLYMAN G, EMMANOUSLIDES GC: Late onset complete heart block. Am J Cardiol 30: 884, 1972 7. CHEITLIN MD, DE CAsino CM, MCALLISTER HA: Sudden death as a complication of anomalous left coronary origin from the anterior sinus of Valsalva: a not-so-minor congenital anomaly. Circulation 50: 780, 1974
ALDOMET (methyldopa, MSD Std.)
Indications: Sustained moderate through severe hypertension. Dosage Summary: Start usually with 250 mg two or three times daily during the first 48 hours; thereafter adjust at intervals of not less than two days according to the patient's response. Maximal daily dosage is 3.0 g of methyldopa. In the presence of impaired renal function smaller doses may be needed. Syncope in older patients has been related to an increased sensitivity in those patients with advanced arteriosclerotic vascular disease and may be avoided by reducing the dose. Tolerance may occur occasionally between the second and third month after initiating therapy. Effectiveness can frequently be restored by increasing the dose or adding a thiazide. Contraindicatlons: Active hepatic disease such as acute hepatitis and active cirrhosis; known sensitivity to met hyldopa; unsuitable in mild or labile hypertension responsive to mild sedation or thiazides alone; pheochromocytoma; pregnancy. Use cautiously if there is a history of liver disease or dysfunction. Precautions: Acquired hemolytic anemia has occurred rarely. Hemoglobin and/or hematocrit determinations should be performed when anemia is suspected. If anemia is present, determine if hemolysis is present. Discontinue methyldopa on evidence of hemolytic anemia. Prompt remission usually results on discontinuation alone or the initiation of adrenocortical steroids. Rarely, however, fatalities have occurred. A positive direct Coombs test has been reported in some patients on continued therapy with methyldopa, the exact mechanism and significance of which is not established. Incidence has varied from 10 to 20%. If a positive test is to develop it usually does within 12 months following start of therapy. Reversal of positive test occurs within weeks to months after discontinuation of the drug. Prior knowledge of this reaction will aid in cross matching blood for transfusion. This may result in incompatible minor cross match. If the indirect Coombs test is negative, transfusion with otherwise compatible blood may be carried out. If positive, advisability of transfusion should be determined by a hematologist or expert in transfusion problems. Reversible leukopenia with primary effect on granulocytes has been seen rarely. Rare cases of clinical agranulocytosis have been reported. Granulocyte and leukocyte counts returned promptly to normal on discontinuance of drug. Occasionally fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in one or more liver function tests. Jaundice, with or without fever, may occur also, with onset usually within first 2 or 3 months of therapy. Rare cases of fatal hepatic necrosis have been reported. Liver biopsies in several patients with liver dysfunction showed a microscopic focal necrosis compatible with drug hypersensitivity. Determine liver function, leukocyte and differential blood counts at intervals during the first six to twelve weeks of therapy or whenever unexplained fever may occur. Discontinue if fever, abnormalitiesinliverfunctiontests, or jaundiceoccur. Methyldopa may potentiate action of other antihypertensive drugs. Follow patients carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on ALDOMET*. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. Hypertension occasionally noted after dialysis in patients treated with ALDOMET* may occur because the drug is removed by this procedure.
8. Sudden death in children with heart diqeasi' (E). Br Med 1 1: 1, 1975
748 CMA JOURNAL/OCTOBER 18, 1975/VOL. 113
Rarely involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, discontinue therapy. Fluorescence in urine samples at same wave lengths as catecholamines may be reported as urinary catecholamines. This will interfere with the diagnosis of pheochromocytoma. Methyldopa will not serve as a diagnostic test for pheochromocytoma. Usage in Pregnancy: Because clinical experience and follow-up studies in pregnancy have been limited, the use of methyldopa when pregnancy is present or suspected requires that the benefits of the drug be weighed against the possible hazards to the fetus. Adverse Reactions: Cardiovascular: Angina pectons may be aggravated; reduce dosage if symptoms of orthostatic hypotension occur; bradycardia occurs occasionally. Neurological: Symptoms associated with effective lowering of blood pressure occasionally seen include dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency. Sedation, usually transient, seen during initial therapy or when dose is increased. Similarly, headache, asthenia, or weakness may be noted as early, but transient symptoms. Rarely reported: paresthesias, parkinsonism, psychic disturbances including nightmares, reversible mild psychoses or depression, and a single case of bilateral Bells palsy. Gastrointestinal: Occasional reactions generally relieved by decrease in dosage: mild dryness of the mouth and gastrointestinal symptoms including distention, constipation, flatus, and diarrhea; rarely, nausea and vomiting. Hematological: Positive direct Coombs test, acquired hemolytic anemia, leukopenia and rare cases of thrombocytopenia. Toxic and Allergic: Occasional drug related fever and abnormal liver function studies with jaundice and hepatocellular damage, (see PRECAUTIONS) and a rise in BUN. Rarely, skin rash, sore tongue or black tongue, pancreatitis and inflammation of the salivary glands. Endocrine and Metabolic: Rarely, breast enlargement, lactation, impotence, decreased libido; weight gain and edema which may be relieved by administering a thiazide diuretic. If edema progresses or signs of pulmonary congestion appear, discontinue drug. Miscellaneous: occasionally nasal stuffiness, mild arthralgia and myalgia; rarely, darkening of urine after voiding. Detailed information available on request. How Supplied: Tablets ALDOMET* are yellow, filmcoated, biconvex shaped tablets, supplied as follows: Ca 8737 - each tablet containing 125 mg of methyldopa, marked MSD 135 on one side, supplied in bottles of 100 and 1000. Ca 3290 - each tablet containing 250 mg of methyldopa, marked MSD 401 on one side, supplied in bottles of 100 and 1000. Ca 8733 - each tablet containing 500 mg of methyldopa, marked MSD 516 on one side, supplied in bottles of 100 and 250. Also available: Ca 3293 - Injection ALDOMET* Ester hydrochloride, a clear colourless solution containing 250 mg methyldopate hydrochloride per 5 ml, supplied in 5 ml ampoules. (MC-949a)
C
ERCK I SHARP I & DOHME CANADA LIMITED/LIMIT.E
A Leader In Cardiovascular Medicine
of the Prematurely Born Infant, Baltimore. Williams and Wilkins, 1964, pp 177-316 6. NI5WANDER KR, FRIEDMAN EA, HOOVER DB: Total morbidity following potentially anoxiogenic obstetric conditions. I. Abruptio placentae. II. Placenta previa. III. Prolapse of the umbilical cord. Am I Obstet Gynecol 95: 838, 1966 7. WIENER G, RiDalt RV, OPPEL WC, et al: Correlates of low birthweight. Psychological status at 8 to 10 years of age. Pedtatr Res 2: 110, 1968 8. ELMk.R E, GREGG GS: Developmental characteristics of abused children. Pediatrics 40: 596, 1967 9. FANAROFF AH, KENNELL JH, KLAUS MH:
Follow-up of low birth weight infants, the predictive value of maternal visiting patterns. Pediatrics 49: 287, 1972 10. KLEIN M, STERN L: Low birthweight and the battered child syndrome.. Am I Dis Child 122: 15, 1971
11. KIAus MH, KENNELL JH: Mothers separated from their newborn infants. Pediatr Clin North Am 17: 1015, 1970 12. Laisaa AD, LEIDERMAN PH, BARNETr CR, et al: Effects of mother-infant separation on maternal attachment behaviour. Child Dev 43: 1203, 1972 13. SEAsHoRE MJ, LEIFER AD, BARNE1-r CR, et al: The effects of denial of early mother-
infant interactions on maternal self-confidence. J Person Soc Psychol 26: 369, 1973 14. POWELL LF: The effect of extra stimulation and maternal involvement in the development of low-birth weight infants and on maternal behaviour. Child Dev 45: 106, 1974 15. Lawis M, ROSENSLUM LA: The Effect of the Infant on its Caregiver, New York, Wiley, 1974, pp 21-48 16. KOaNER AF, GROBSTEIN R: Individual differences at birth: implications for motherinfant relationship and later development. J Am Acad Child Psychiatry 6: 676, 1967 17. CAPLAN 0, MASON EA, KAPLAN DM: Four studies of crisis in parents of prematures. Comm Mental Health 1: 149, 1965 18. SCARR-SALAPATEK 5, WILuAMs ML: The effects of early stimulation on low-birthweight infants. Child Dev 44: 94, 1973 19. BERNARD K: A program of stimulation for infants born prematurely. Paper presented at Society for Research in Child Development. Philadelphia, PA, March 1973
20. PARMALEE AH: Neurophysiological and behavioral organization of premature infants in the first months of life. Biol Psychiatry 1975 (in press) 21. KLAUS MH, KENNELL JH, PLUMB N, et al: Human maternal behaviour at the first contact with their young. Pediatrics 49: 287, 1970
Sudden unexpected death in children with congenital heart disease * P. THQRNBACK, MB, B CH, FRCP[C]; R.S. FOWLER, MD, FRCP[C]
Summary: Of 18000 children with organic heart disease evaluated at The Hospital for Sick Children, Toronto between 1940 and 1971, 33 died suddenly and unexpectedly between I and 21 years of age. Nine had discrete obstruction of the left ventricular outflow tract and five had muscular narrowing of the left ventricular outflow tract. Pulmonary vascular disease caused seven sudden deaths, and arrhythmias (usually due to atrioventricular block) caused seven more. Of the five other children who died suddenly three had transposition of the great arteries, one had a complex cyanotic heart defect and one had an anomalous course of the left coronary artery, which originated from the right sinus of Valsalva. With earlier investigation of aortic stenosis, earlier closure of ventricular septal defect to avoid pulmonary vascular disease, better design of artificial pacemakers and better investigation of patients with angina, many of these deaths will be avoided in the future. From the University of Toronto, faculty of medicine, and department of pediatrics, division of cardiology, The Hospital for Sick Children, Toronto *This paper was prepared for the Sept. 20, 1975 issue of the Journal commemorating the centennial of The Hospital for Sick Children, Toronto, but because of space limitations could not be included. Reprint requests to: Dr. R.S. Fowler, Department of pediatrics, Division of cardiology, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8
Resume: D.c.s soudain et inattendu chez des enfants souffrant de cardiopathies cong.nitaIes Des 18000 enfants souffrant de cardiopathies organiques examines au Hospital for Sick Children de Toronto de 1940 a 1971, 33 sont morts soudainement et de fa9on inattendue alors qu'ils avaient de I a 21 ans. Neuf avaient une obstruction discrete du tractus de sortie du ventricule gauche et cinq avaient un retrecissement musculaire du tractus de sortie du ventricule gauche. La maladie vasculopulmonaire a cause sept morts subites et des arythmies (habituellement attribuables a un blocage atrioventriculaire) ont entraine sept autres deces. Des cinq autres enfants morts subitement, trois avaient une transposition des grandes arteres, un avait une cardiopathie complexe cyanog.ne et un autre avait un trajet anormal de l'artere coronaire gauche, qui prenait naissance a partir du sinus de Valsalva droit. Grice a des examens plus precoces de Ia stenose aortique, a une fermeture plus precoce d'une communication interventriculaire pour eviter les troubles vasculopulmonaires, a une conception plus parfaite des stimulateurs artificiels et a une observation plus attentive des malades souffrant d'angine de poitrine, il est indeniable que nombre de ces deces pourront itre evites dans l'avenir.
CMA JOURNAL/OCTOBER 18, 1975/VOL. 113 745
Sudden unexpected death is unusual in children with congenital heart defects. We undertook a study in the cardiac division of The Hospital for Sick Chil¬ dren, Toronto to identify defects that may cause this tragic outcome, with the hope that therapeutic measures may be found. Some of the data were used in an international study by the pediatric council of the International Society of Cardiology (chairman, Dr. E.C. Lambert* of Buffalo). We studied children who had died a sudden natural "death occurring instantaneously within 24 hours of acute symptoms
or or
signs",1 including only ambulatory pa¬ tients who had died out of hospital and were aged 1 to 21 years to avoid the controversy surrounding "cot deaths" in infancy. Methods The clinical data of all children eval¬ uated in the cardiac division between 1940 and 1971 are recorded on digital tape; a computer review yielded num¬ bers of patients, all deaths and deaths resulting from surgery.2 The records of all patients of appropriate age who had not died as a result of surgery were personally reviewed by one of the au¬ thors (P.T.). Additional information was obtained by writing to the family physician or the patient's physician, his parents and the pathologist who per¬ formed the autopsy when it was not done at this institution. Results Of the 18 000 patients with organic heart disease evaluated over the 32 years 3055 died before age 21, an in¬ cidence of 169.7/1000. Of these deaths (in patients over 1 year old) 33 were sudden and unexpected by the above definition: 24 died instantly; the re¬ maining 9 died some hours after the onset of acute symptoms. Eight died during strenuous exercise, 14 died dur¬ ing routine daily activity and 3 died at rest; in the other 8 the relation of death to activity could not be ascertained. Fifteen of the children had had corrective surgery for their defect and in seven of them an arrhythmia had developed in the postoperative period.
Left ventricular outflow obstruction Fourteen children died as a result of left ventricular obstruction: nine had discrete left ventricular outflow ob¬ struction and the other five had idio¬ pathic hypertrophie subaortic stenosis. Of the nine with discrete obstruction five had aortic valve stenosis (uncom¬ plicated in four and associated with a ?Died in March 1974.
746 CMA JOURNAL/OCTOBER 18,
followed) after closure of a ventricular septal defect: in 3 of the 5 atrioventri¬ cular block developed in the immediate postoperative period and in the other 2 it developed 4 and 5 years later, re¬ spectively. Of the three who were furnished with pacemakers, death was at¬ were evaluated over the 31 years: 36% had cardiac catheterization and 16% tributed to pacemaker failure in each. had severe stenosis requiring valvulotomy; 37 have died, 9 suddenly. There¬ Other causes fore the incidence of sudden death in this group is only 1 %. Five of the nine Up to December 1971, 105 children patients who died suddenly had fainted underwent the Mustard procedure for after exertion some time before death. total correction of transposition of the Electrocardiograms (ECGs) were avail¬ great arteries; 30 have died, 3 suddenly able for eight of these patients: all and unexpectedly (4 years postopera¬ showed evidence of left ventricular hy¬ tively in one instance and 2 years post¬ pertrophy and four showed a typical operatively in two). None had do¬ pattern of left ventricular strain with cumented evidence of an arrhythmia or ST-segment depression in leads AVF, heart failure but all had required V4, V5 and V* and T-wave inver- digitalis in the immediate postopera¬ sion. The ECG of one patient did tive period. One child died after hemoptysis. She not show this pattern but did show the pattern of incomplete right bundle had a complicated cyanotic defect with branch block (RBBB) with reg¬ dextrocardia, transposition and septal ular sinus rhythm1 in Vi. This patient defects but had remained in relatively had subvalvular aortic stenosis; cardiac good health until 11 years of age. A 14-year-old boy had complained catheterization showed a peak pressure gradient across the valve of 67 mm of occasional fainting and anterior Hg. It is possible that the incomplete chest pain with exercise. Clinically RBBB masked the ST- and T-wave there were rio signs of heart disease and even with exercise his ECG was changes of left ventricular strain. In contrast, of the 30 children with normal. He collapsed and died suddiffuse muscular obstruction evaluated dently when playing football. The only over the 31 years 8 died, 5 (17% of abnormality found at autopsy was the the 30) suddenly. The risk of sudden anomalous course of the left coronary death in children with this form of artery, which originated at the right sinus of Valsalva in conjunction with cardiomyopathy is therefore high. All the died while undertaking moderate to right coronary artery and passed strenuous exercise two while riding anteriorly between the aorta and the bicycles, one while scrambling up a main pulmonary artery before dividriver bank and two while walking. ing; the vessel was somewhat narrowed at the point where it passed between the two great arteries. In all of the vascular disease Pulmonary other 21 children with anomalous co¬ Of 93 patients with pulmonary vas¬ ronary arteries evaluated in this hospi¬ cular resistance evaluated over the 31 tal the coronary artery originated from years 33 had primary pulmonary hy¬ the pulmonary artery. There were 13 pertension and in 60 the disease devel¬ deaths, only 1 of which was sudden. oped in association with a ventricular septal defect or a patent ductus arterio¬ Discussion sus with reverse shunting the EisenIn adults two thirds of all sudden menger reaction. Of the 29 patients who died before 21 years of age 7 nontraumatic deaths are due to athero¬ (7.5% of the 93) died suddenly: 1 had sclerotic heart disease,3 and appropriate primary disease and 6 the Eisenmenger preventive measures are being taken. In the report of a recent study of chil¬ reaction. During the 31 years 4160 children dren with congenital heart disease with ventricular septal defect were Lambert and colleagues4 emphasized evaluated; the only children to die sud¬ the important defects leading to sudden denly were those in whom pulmonary death. Although it was inevitable that vascular resistance increased or those many of the children assessed in our in whom an arrhythmia developed af¬ study would have died, there appear to be a number of situations in which ter surgical closure of the defect. increased awareness might have saved the child's life. Arrhythmias If in a child with a clinical diagnosis Seven patients died suddenly as a of aortic stenosis such symptoms and result of arrhythmia. Heart block was signs as effort syncope or dyspnea, an¬ congenital in 2 (of 88 patients being gina or pronounced decrease in exer¬ followed) and developed in 5 (of 31 cise tolerance, or electrocardiographic
previously resected coarctation in one), three had a subvalvular diaphragm and one had supravalvular stenosis com¬ plicated by mild infundibular and pul¬ monary artery stenosis. A total of 916 patients with such discrete obstruction
1975/VOL. 113
evidence of left ventricular strain or RBBB develop, he should be admitted to hospital for urgent cardiodynamic assessment. These symptoms and signs portend sudden death and indicate a dangerous pressure gradient across the stenotic outflow tract. Surgery, when indicated, may rapidly reverse the situation and relieve the strain on the myocardium. A child with complete atrioventricular block as a result of surgical repair of ventricular septal defect, tetralogy of Fallot or atrioventricularis communis needs a permanent demand pacemaker. If complete RBBB and left anterior hemiblock develop and there is even a temporary period of complete atrioventricular block the same treatment should be considered. A child with electrocardiographic evidence of atrioventricular block but no actual period of block should be observed closely because late block can occur as long as 14 years after surgery.5'6 The child who has symptoms of coronary artery insufficiency - either true angina pectoris or fainting spells after exertion - should be considered for cardiac catheterization. As in the 14-year-old boy whose case has been described, ischemic changes may not be apparent on the EGG, even with exercise. If no other remediable cause for the pain can be found, aortography or coronary arteriography should be undertaken; an anomalous coronary artery may be found and appropriate surgery may relieve the abnormality.7 No patient with a mild heart defect died suddenly in this series or another larger series.4'8 Parents should be encouraged to allow normal activity in their children with mild heart disease withodt fear of sudden death. We wish to thank Dr. Vera Rose for her help in reviewing the computer file. This work was partly supported by a grant from the Ontario Heart Foundation. References 1. PAUL 0, SCHATZ M: On sudden death (E). Circulation 43: 7, 1971 2. Rosa V, O'CONNOR JR, KEITH JD, et al: Computer-based data storage and retrieval in pediatric cardiology. Can Med Assoc J 107: 305, 1972 3. KULLER L: Sudden death in arteriosclerotic heart disease: the case for preventive medicine. Am J Cardiol 24: 617, 1969 4. LAMBERT EC, MENON VA, wAGNER HR, et al: Sudden unexpected death from cardiovascular disease in children: a cooperative international study. Am I Cardiol 34: 89, 1974 5. GOLDMAN MJ, RoBERTs NK, IZUKAwA T: Late postoperative conduction disturbances after repair of ventricular septal defect and tetralogy of Fallot: analysis of His bundle recordings. Circulation 49: 214, 1974 6. Moss AJ, KLYMAN G, EMMANOUSLIDES GC: Late onset complete heart block. Am J Cardiol 30: 884, 1972 7. CHEITLIN MD, DE CAsino CM, MCALLISTER HA: Sudden death as a complication of anomalous left coronary origin from the anterior sinus of Valsalva: a not-so-minor congenital anomaly. Circulation 50: 780, 1974
ALDOMET (methyldopa, MSD Std.)
Indications: Sustained moderate through severe hypertension. Dosage Summary: Start usually with 250 mg two or three times daily during the first 48 hours; thereafter adjust at intervals of not less than two days according to the patient's response. Maximal daily dosage is 3.0 g of methyldopa. In the presence of impaired renal function smaller doses may be needed. Syncope in older patients has been related to an increased sensitivity in those patients with advanced arteriosclerotic vascular disease and may be avoided by reducing the dose. Tolerance may occur occasionally between the second and third month after initiating therapy. Effectiveness can frequently be restored by increasing the dose or adding a thiazide. Contraindicatlons: Active hepatic disease such as acute hepatitis and active cirrhosis; known sensitivity to met hyldopa; unsuitable in mild or labile hypertension responsive to mild sedation or thiazides alone; pheochromocytoma; pregnancy. Use cautiously if there is a history of liver disease or dysfunction. Precautions: Acquired hemolytic anemia has occurred rarely. Hemoglobin and/or hematocrit determinations should be performed when anemia is suspected. If anemia is present, determine if hemolysis is present. Discontinue methyldopa on evidence of hemolytic anemia. Prompt remission usually results on discontinuation alone or the initiation of adrenocortical steroids. Rarely, however, fatalities have occurred. A positive direct Coombs test has been reported in some patients on continued therapy with methyldopa, the exact mechanism and significance of which is not established. Incidence has varied from 10 to 20%. If a positive test is to develop it usually does within 12 months following start of therapy. Reversal of positive test occurs within weeks to months after discontinuation of the drug. Prior knowledge of this reaction will aid in cross matching blood for transfusion. This may result in incompatible minor cross match. If the indirect Coombs test is negative, transfusion with otherwise compatible blood may be carried out. If positive, advisability of transfusion should be determined by a hematologist or expert in transfusion problems. Reversible leukopenia with primary effect on granulocytes has been seen rarely. Rare cases of clinical agranulocytosis have been reported. Granulocyte and leukocyte counts returned promptly to normal on discontinuance of drug. Occasionally fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in one or more liver function tests. Jaundice, with or without fever, may occur also, with onset usually within first 2 or 3 months of therapy. Rare cases of fatal hepatic necrosis have been reported. Liver biopsies in several patients with liver dysfunction showed a microscopic focal necrosis compatible with drug hypersensitivity. Determine liver function, leukocyte and differential blood counts at intervals during the first six to twelve weeks of therapy or whenever unexplained fever may occur. Discontinue if fever, abnormalitiesinliverfunctiontests, or jaundiceoccur. Methyldopa may potentiate action of other antihypertensive drugs. Follow patients carefully to detect side reactions or unusual manifestations of drug idiosyncrasy. Patients may require reduced doses of anesthetics when on ALDOMET*. If hypotension does occur during anesthesia, it usually can be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa. Hypertension occasionally noted after dialysis in patients treated with ALDOMET* may occur because the drug is removed by this procedure.
8. Sudden death in children with heart diqeasi' (E). Br Med 1 1: 1, 1975
748 CMA JOURNAL/OCTOBER 18, 1975/VOL. 113
Rarely involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, discontinue therapy. Fluorescence in urine samples at same wave lengths as catecholamines may be reported as urinary catecholamines. This will interfere with the diagnosis of pheochromocytoma. Methyldopa will not serve as a diagnostic test for pheochromocytoma. Usage in Pregnancy: Because clinical experience and follow-up studies in pregnancy have been limited, the use of methyldopa when pregnancy is present or suspected requires that the benefits of the drug be weighed against the possible hazards to the fetus. Adverse Reactions: Cardiovascular: Angina pectons may be aggravated; reduce dosage if symptoms of orthostatic hypotension occur; bradycardia occurs occasionally. Neurological: Symptoms associated with effective lowering of blood pressure occasionally seen include dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency. Sedation, usually transient, seen during initial therapy or when dose is increased. Similarly, headache, asthenia, or weakness may be noted as early, but transient symptoms. Rarely reported: paresthesias, parkinsonism, psychic disturbances including nightmares, reversible mild psychoses or depression, and a single case of bilateral Bells palsy. Gastrointestinal: Occasional reactions generally relieved by decrease in dosage: mild dryness of the mouth and gastrointestinal symptoms including distention, constipation, flatus, and diarrhea; rarely, nausea and vomiting. Hematological: Positive direct Coombs test, acquired hemolytic anemia, leukopenia and rare cases of thrombocytopenia. Toxic and Allergic: Occasional drug related fever and abnormal liver function studies with jaundice and hepatocellular damage, (see PRECAUTIONS) and a rise in BUN. Rarely, skin rash, sore tongue or black tongue, pancreatitis and inflammation of the salivary glands. Endocrine and Metabolic: Rarely, breast enlargement, lactation, impotence, decreased libido; weight gain and edema which may be relieved by administering a thiazide diuretic. If edema progresses or signs of pulmonary congestion appear, discontinue drug. Miscellaneous: occasionally nasal stuffiness, mild arthralgia and myalgia; rarely, darkening of urine after voiding. Detailed information available on request. How Supplied: Tablets ALDOMET* are yellow, filmcoated, biconvex shaped tablets, supplied as follows: Ca 8737 - each tablet containing 125 mg of methyldopa, marked MSD 135 on one side, supplied in bottles of 100 and 1000. Ca 3290 - each tablet containing 250 mg of methyldopa, marked MSD 401 on one side, supplied in bottles of 100 and 1000. Ca 8733 - each tablet containing 500 mg of methyldopa, marked MSD 516 on one side, supplied in bottles of 100 and 250. Also available: Ca 3293 - Injection ALDOMET* Ester hydrochloride, a clear colourless solution containing 250 mg methyldopate hydrochloride per 5 ml, supplied in 5 ml ampoules. (MC-949a)
C
ERCK I SHARP I & DOHME CANADA LIMITED/LIMIT.E
A Leader In Cardiovascular Medicine
