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The childrens hospital medical center, Boston, Mass.
CLINICAL
PATHOLOGICAL
CONFERENCE
THE
CHILDREN'S
BOSTON,
HOSPITAL
MEDICAL
CENTER,
MASS.
Sidney Farber, M.D., Editor Gordon F. Vawter, M.D., Assistant Editor
T H I S 1 1 - Y E A R - O L D boy was admitted to The Children's Hospital Medical Center because of growth failure and restriction of activity. T h e child was first admitted at 3 days of age because of cyanosis noted on the first day of life. H e was born at term after the first pregnancy of a 28-year-old mother who had had fever and diarrhea in the third gestational month. T h e birth weight was 7 pounds, 7 ounces. T h e umbilical cord was around his neck at delivery, and he was generally cyanotic but improved greatly when in oxygen. T h e respiratory rate was 38 per minute and the pulse 120. T h e liver was palpable 1 cm. below the costal margin; the spleen was normal. The lungs were clear. A Grade 4 systolic cardiac m u r m u r obscured the first sound along the left sternal border with maximal intensity at the fifth intercostal space. O n roentgenographic examination, the heart appeared slightly large but had a narrow waist; the pulmonary artery was not visible and the pulmonary vasculature was descreased; the apex was slightly lifted and there was a prominent right-sided bulge. A barium contrast roentgenograph was normal. An electrocardiogram demonstrated a P-R interval of 0.12; rate 120 per minute; axis plus 30; the R wave in lead V~ was 19 mm. in height; P,, was 2 mm. T h e infant was discharged from the hospital to be followed in the Outpatient Department. At 7 months of age, frequent upper res-
piratory tract infections were noted. T h e patient had no cyanotic spells. Slight clubbing of the fingers and toes was evident. T h e weight was 20 pounds and height 28 inches, both at the ninetieth percentile. There was a history of squatting at 18 months which did not continue after this age. T h e patient had had no hypoxic spells. T h e heart rhythm was irregular and a third sound was present. Fluoroscopy demonstrated a large globular heart with a very large right atrium and definite right ventricular action. A n electrocardiogram showed a P-R interval of 0.15 (normal = 0.125); the P wave measured 4 mm. in lead I and 8 mm. in V1. At 2 8 9 years of age, the patient had a Grade 2 harsh systolic murmur, maximal at the fourich left intercostal space. The liver was palpable 3 cm. below the costal margin. An electrocardiogram demonstrated a P-R interval of 0.20; axis plus 155 degrees; tall, slurred P waves; and ventricular premature beats. At 3 years and 7 months of age, the boy was active but tired more easily than his peers. His weight was 39 pounds (at the ninetieth percentile) and height 39 inches (between the twenty-fifth and fiftieth percentiles). The blood pressure was 115 systolic, 65 diastolic. T h e systolic m u r m u r was Grade 4 at the left sternal border and apex and was poorly transmitted. T h e diastolic rumble was Grade 2. 817
8 18
Clinical pathological con[erence
W h e n the patient was 4 years and 2 months of age, a phonocardiogram demonstrated a late first sound; decreased second sound with no splitting; a third sound; a fourth sound after the P waves; variable medium-frequency systolic m u r m u r at the fourth left intercostal space; low-frequency presystolic m u r m u r at the second right intercostal space; and adventitial sounds. At 7 years of age, an anterior chest deformity was apparent. T h e patient's weight was 51~2 pounds (between the: fiftieth and seventy-fifth percentiles) and his height 46 inches (between the tenth and twenty-fifth percentiles). Clubbing of fingers and toes was 2 to 3 plus. T h e cardiac impulse was diffuse. G r o w t h failure became manifest between 7 and 9 years of age. He was given digitalis but tired easily and had shortness of breath on exertion. T h e systolic venous wave in the neck was 3 cm. at 30 degrees. T h e spleen and liver were both palpable 3 cm. below the costal margin. By ear oximetry, the oxygen saturation was 59 per cent of normal. Successively during the winter prior to his second admission, he had "flu" and required antibiotic therapy for streptococcal pharyngitis, measles, and several episodes of upper respiratory tract infection. T h e patient's second admission was at 11 years of age for cardiac catheterization and possible surgery. He was cyanotic and had severe clubbing of the fingers and toes and a bilateral precordial bulge. T h e heart rate was 118. T h e blood pressure was 120 systolic, 80 diastolic. T h e neck veins were distended at 30 degrees with the A wave. T h e liver was palpable 6 era. and the spleen 3 cm. below the costal margin. T h e lungs were clear. T h e cardiac apex was at the fourth left intercostal space at anterior axillary line (AAL) with a left ventricular impulse. Sj was normal and $2 single; Sa was audible at the apex and $4 at the lower left sternal border. A Grade 1 protodiastolic rumble was present at the left sternal border and apex; Grade 1 ejection systolic m u r m u r was heard at the left sternal border. Laboratory studies showed: hematocrit, 88 per cent; white blood cell count 6,650, with
May 1966
57 per cent polymorphonuclear cells, 39 per cent leukocytes, 2 per cent monocytes, and 2 per cent eosinophils. T h e platelet count was 98,000 per cubic millimeter. Urinary p H was 5.5, specific gravity 1.012, protein 175 mg. per cent, and there were 5 red blood cells per high-power field. A vectorcardiogram was obtained. Catheterization of the right side of the heart revealed a saturation of 57 per cent in the superior vena cava, right atrium, and right ventricle, except for one right atrial determination of 72 per cent. Brachial arterial saturation was 72 per cent. I n the superior vena cava, the pressures showed an "a" value of 7 and a mean value of 5. I n the right atrium, the "a" value was 7, "v" was 6, and the m e a n was 5. T h e right ventricular pressure was 20 and the brachial arterial pressure 92/66. T h e calculated pulmonary output was 1.2 1 per minute per square meter and systemic output 3.2 1 per minute per square meter, with respective stroke volumes of 12 and 35 c.c. T h e patient died with bradycardia and cardiac dilatation during cardiac surgery. DR. ALEXANDER NADAS."x" This child was admitted at 3 days of age because of cyanosis noted on the first day of life. This finding is not unusual and does not necessarily indicate the presence of a congenital cardiac malformation. The respiratory, cardiac, and central nervous systems are the three principal origins of pathologic cyanosis in the newborn. In addition, some newborn infants who later are perfectly all right, may be cyanotic, presumably from inadequate expansion of the lungs. Another curious syndrome of the newborn is profound cyanosis during the first 24 to 36 hours without obvious cardiac, pulmonary or central nervous system disease. In 48 to 72 hours, this cyanosis disappears completely and the infant becomes normal. This may possibly represent temporary persistence of the fetal circulation--a lack of expansion and relaxation of the pulmonary vascular bed which thus maintains the right-to-left shunt through the ductus arteriosus for a longer period than is physiologic. Differentiating among respiratory, cardiac, and *Cardiologist, The Children's Hospital Medical Center, Boston, Mass.
Volume 68
Number 5
central nervous system origins of cyanosis can tax the pediatrician's ingenuity. Sometimes this differentiation is impossible without waiting at least 24 hours to see the response to oxygen. Persistence of cyanosis in oxygen would not exclude conditions of central nervous system origin, but episodic cyanosis is more suggestive of central nervous system causes, while persistent cyanosis is more indicative of cardiac or respiratory origin. This boy was born at term to a 28-year-old mother who had had fever and diarrhea in the third gestational month. This maternal illness may have been viral and may have some bearing on any ensuing congenital malformation. Dr. Thomas Weller has been able to find high antibody titers against rubella in babies over 6 months of age who have congenital malformations similar to those associated with maternal rubella. No information of this sort is available for today's patient. The loud murmur at 3 days of age usually means stenosis of one of the semilunar valves, either aortic or pulmonic, because these are the orifices through which blood has to flow on the first day of life. In contrast, in a ventricular septal defect, no significant flow of blood occurs very early because the pressures within the two ventricles are equal. Hence, a patient who has a loud m u r m u r in the first 2 or 3 days of life is not likely to have a ventricular septal defect; those murmurs occur at 1 week or even at 1 or 2 months of age, when the pressure-volume characteristics of the right ventricle assume the pattern that allows a sizable left-to-right shunt. Atrial septal defects do not produce any murmurs within the first 2 days of life. Tricuspid or mitral regurgitation may cause a loud murmur this early in life because, from the very beginning of life, atrial pressures are significantly lower than ventricular systolic pressures. I am wary of taking very seriously the description of the murmur at 3 days of age with a heart rate of possibly 132. However, if the first sound really is obscured, atrioventricular valve regurgitation seems more likely than semilunar stenosis, because the ejection murmurs of the latter usually start an appreciable interval after the first sound. The roentgenogram shows that the heart was slightly large, with a narrow waist. This may not be significant; nor can I take very seriously the comments about no visible pulmonary artery and a decreased pulmonary vasculature. "'The apex
Clinical pathological con[erence
8 19
was slightly lifted" is also indefinite information, but the finding of a prominent right-sided bulge is tangible, usable information. One chooses from a protocol, as from a Thanksgiving fruit bowl, what one likes. The electrical axis of the electrocardiogram is given in the protocol as plus 30 degrees. Dr. Hugenholtz recalculated it for me as minus 90 degrees. T h e average axis in the newborn is about 116 degrees, but the range is from minus 5 to plus 190. This axis of minus 90 degrees is certainly abnormal but probably not highly significant for diagnostic purposes. The R wave in V 1 is 19 m m . : This is just below the maximal, but considerably above the average. The P2 of 2 mm. indicates atrial hypertrophy. The statement that the infant was discharged to be followed in the Outpatient Department is interesting, for this was 13 years ago. Today we would not send a baby of this sort home to come back in 6 months. Instead, we would attempt, by catheterization and angiography, to make an anatomic diagnosis. We are pursuing a much more aggressive policy, attempting an accurate diagnosis and instituting treatment on much younger infants than we did 13 years ago. At the end of this infant's first admission, one could not be sure that he had congenital heart disease, but the persistent cyanosis, the murmur, and abnormal cardiac silhouette with a large right atrium are strongly suggestive of cyanotic congenital heart disease. The likely diagnoses would be pulmonic stenosis alone or, more probably, within the syndrome of tetralogy of Fallot (pulmonic stenosis in association with ventricle septal defect). None of the other cyanotic lesions, such as transposition of the great arteries or more complex abnormalities, can be excluded on the basis of the first portion of this case record. The only strong clue is the description of the roentgenogram, which indicates a large right atrium; this is also suggested by the electrocardiogram, with large P waves in lead 2, and by the possible tricuspid regurgitation. The last is suggested by the early appearance of a loud, regurgitant murmur at the lower left sternal border. F r o m the information given about the patient at 7 months of age, the most catastrophic types of cyanotic congenital heart disease, such as hypoplastic left heart syndrome and complete transposition of the great arteries, can be excluded. Squatting at age 18 months, but not after" this time, is mentioned. Most babies barely get
820
Clinical pathological con[erence
up on their feet at this time, or in other words, all squat at this age. This may be an echo from the mother coming from a suggestion thrown out by the physician. The irregular cardiac rhythm, an indefinite finding in itself, might be related to the premature ventricular beats noted later. On fluoroscopy, the right atrium seemed impressively large. The lack of definite right ventricular action is also a fluoroscopic observation. This child had two fluoroscopic examinations within 18 months, which would probably not be done today. We are more cautious in using radiation and rely on plain films if possible. Dr Neuhauser suggested the policy of using plain films rather than fluoroscopy for follow-up. DR. SIDNEY FARBER. Dr. Neuhauser, what is the difference in radiation between fluoroscopy and plain roentgenography? DR. E. B. D. NEUHAUSER. Ten years ago the difference in amount of radiation was considerable. With the use of image amplifiers, the difference is less, but fluoroscopy still involves more radiation than plain roentgenography. For follow-up, the latter can give most of the required information, provided the data from the initial examination were adequate. Cardiac catheterization involves much more radiation than simple fluoroscopy. DR. NADAS. The difference between 0.I5 seconds and the normal of 0.125 seconds in the P-R interval on the electrocardiogram is not too impressive as a single observation, but makes sense in retrospect, for the P-R interval becomes longer and longer. An atrioventricular conduction distnrbance is developing, which at this early stage is slight and of only possible significance. The P wave in lead V 1 of 8 ram. is extremely high and unquestionably represents right atrial enlargement and hypertrophy. The progressive right atrial hypertrophy, both on roentgenograms and electrocardiograms and the appearance of a diastolic rumble at 2~/~ years of age exclude, for all practical purposes, one of the most likely diagnoses for a cyanotic baby--the tetralogy of Fallot. The phonocardiogram made when the patient was 2 years of age shows that the systolic murmur begins with the first sound, which, I believe, is both obscured by the murmur and diminished in amplitude. In addition, the murmur is a plateau" all through systole. The hug e P waves, third sound, diminished and single second sound, and perhaps a fourth sound indi-
May 1966
cating atrial activity are also noteworthy. In a new tracing with a newer machine, there is a jugular venous tracing with a big A wave corresponding to the fourth sound and to atrial activity. A large V wave tends to be superimposed on the A wave, which, with the fourth sound, means considerable tricuspid regurgitation, atrial activity, and right atrial hypertension. By age 11 years, the patient's growth disturbance is apparent. Why patients with congestive heart failure do not gain and grow normally remains to be investigated. A number of factors are involved: increased oxygen consumption, poor appetite, increased work in breathing, inefficient working of the heart, visceral congestion, and poor absorption. This patient must have been in congestive failure because he was digitalized, had exertional shortness of breath, and a systolic venous wave of 3 cm. at 30 degrees was visible in the neck when the second phonogram was made. The spleen and liver were both palpable beIow the costal margi n . Ear oximetry is not a very accurate way to determine arterial oxygen saturation, but it certainly indicates that this boy's blood was severely unsaturated. This may be an appropriate time to see the x-ray films. DR. NEUI-IAUS~R. The first examination was at age 7 days (Fig. 1). The cardiac silhouette is very large and grossly abnormal in contour with a high, prominent bulge on the right side, which, at that time, was interpreted as an enlarged right atrium. No right ventricle can be seen with any clarity and the lateral view has no shadow that could be interpreted as a large right ventricle. The left apex is elevated. The left cardiac waist is not especially narrow, and the border is fairly straight. The lungs are unduly clear with ahnost no visible vascular markings, and they are increased in volume. The liver may have been slightly increased in size even at this early age. Over the years, the heart becomes progressively larger but does not change in cortour, nor does the vascular pattern in the lungs alter noticeably. By 4 years of age, a few vessels in the lungs are apparent but are diminished out of proportion to the size of the heart (Fig. 2). The aorta is on t h e left and appears relatively small with possibly a slight engorgement of the right vena cava on the right side. DR. NADAS. The electrocardiograms show tall, abnormally shaped P waves, and no significant degree of right ventricular hypertrophy is present. A discrepancy exists between the hypertrophy in
Volume 68
Number 5
Fig. 1. At age 7 days, the cardiac silhouette is large and abnormal. The lungs are increased in volume and unduly clear.
Fig. 2. By age 4 years, the heart is larger but unchanged in contour. A few vessels in the lungs are apparent but diminished in size. the right atrium and the lack of it in the right ventricle. In the second part of this protocol, from the time the child is 7 months old, the situation is clarified considerably. First, this child has cyanotic congenital heart disease with diminished arterial oxygen saturation. Second, the condition is not one of the common kinds of cyanotic congenital heart disease. It is not pure pulmonic stenosis because evidence of ventricular hypertrophy is lacking. It certainly is not tetralogy of Fallot because the heart is too large, nor is it likely to be a hypoplastic left heart or pulmonary atresia because the patient lived to 11 years of age. Tricuspid atresia is unlikely because the electrical axis does not fit that diagnosis. Transposition of the great arteries is unlikely because of the decreased pulmonary vasculature and the long survival. Trans-
Clinical pathological con/erence
821
position of the pulmonary veins is unlikely because of the absence of right ventricular hypertrophy. One uncommon type of cyanotic congenital heart disease which would fit the whole picture is Ebstein's malformation of the tricuspid valve, a downward displacement of the valve that can give atrial trouble plus a right-to-left shunt at the atrial level. The second admission at 11 years of age for cardiac catheterization and possible surgery clearly resulted from his clinical deterioration as reflected in the history, physical findings, and laboratory data. DR. PAUL HUGENHOLTZ. The electrocardiogram showed a striking bundle branch block, and the electrical axis remained around minus 90 degrees. DR. NADAS. The axis remaining at minus 90 degrees is important in the embryologic aspects of this malformation. The right heart catheterization reveals a saturation of 57 per cent in the superior vena cava, the right atrium, and the right ventricle. One right atrial determination is 72 per cent as is the brachial arterial saturation; this sample probably represents left atrial saturation, since in the large atrial cavity it might be difficult to know exactly the placement of the catheter tip. On the assumption that the pulmonary veins are 98 per cent saturated, the brachial artery saturation shows a large right-to-left shunt at the atrial level, The pressures in the superior vena cava and in the right atrium are only modestly increased; more interesting, the right ventricular pressure is only 20, which is normal. The brachial artery pressure is normal with the narrow pulse pressure characteristic of congestive heart failure. Calculated cardiac output shows a small pulmonary flow and a normal systemic flOW. The patient died following bradycardia and cardiac dilatation during cardiac surgery. To my knowledge, he could have had only one anomaly --Ebstein's anomaly, with an atrial defect and a patent foramen ovale. In many instances in the past, patients with this rare anomaly have died during catheterization. Before the advent of the monitor and defibrillating systems, the cause of death at catheterization was primarily an arrhythmia. Although today the occurrence of arrhythmia may be as frequent and as severe, we have available the equipment and knowledge to counteract it. DR. GORDON VAWTER. The extraordinary dilatation of the heart which was apparent at autopsy made one wonder how the child had
8 2 2 Clinical pathological con[erence
survived as long as he did. The heart virtually filled the entire chest cavity. The dilatation is especially marked in the right atrium and ventricle, which chambers had approximately six times greater volume than the left atrium and ventricle. There is marked insufficiency of the tricuspid valve resulting both from cardiac dilation and from the so-called downward displacement of the posterior cusp, characteristic of Ebstein's anomaly of the tricuspid valve. The malattachment of the valve, as in this child, is frequently marked externally by a shallow groove. Cephalad to these landmarks, the right ventricular wall is continuous with that of the right atrium, the whole compound chamber having a thin and probably relatively ineffectual musculature. As is common in Ebstein's anomaly, there is a prominent Chiari network in the right atrium. The right-to-left shunt at the atrial level in this instance occurs through a patent foramen ovale, enlarged considerably by the massive atrial dilatation. Most examples of Ebstein's anomaly have been described as having a small, thick-walled pulmonary conus more suggestive of stenosis than dominant insufficiency, but, in this heart, the pulmonary conus is so hugely dilated and thin walled that there appears to be dilatation of the pulmonary valve ring, incompetence of the pulmonary valve, and an element of supravalvular pulmonary stenosis. While the pulmonic valve is said to be normal in most instances of Ebstein's anomaly and the abnormalities seen here may be secondary to tricuspid incompetence, they may have ultimately contributed to the circulatory aberration. It is of interest that pressure gradients are commonly reported at the pulmonic valve in published cardiac catheterization studies. The pulmonary arteries have a modest volume, walls of one-fifth normal thickness, and proximally show medial fibrosis and degeneration, perhaps related to histologically similar lesions found in the aortas of some cyanotic patients: The bundle branch block may be in part related to the stretching and thinning of the moderator band as well as to mild myocardial fibrosis found here. Syndromes associated with Ebstein's anomaly, in addition to those already mentioned (cardiac arrhythmias, conduction defects, and shdden death) include a high incidence of perlcarditis, often hemorrhagic, for which we have evidence here; encephalomalacia, not found in this patient
May 1966
who did, however, have healed renal and splenic infarcts; and systemic hypertension, not clearly established in this instance. Of those forms of cyanotic congenital heart disease complicated by the nephrotic syndrome, Ebstein's anomaly is one of the most common. Perhaps such a diagnosis cannot be supported on clinical grounds in this patient, but the kidneys are enlarged, somewhat granular and pale, with hypoplastic and hypertrophic glomeruli as found frequently in patients with polycythemia, clubbing, arterial oxygen unsaturation, and occasionally hepatic disease. The liver is atrophic. DR. NaDAS. I am inclined to discount any great functional significance for the anatomic lesions of the pulmonary valve. Surgical correction of Ebsteln's anomaly is not usually attempted unless the patient is severely cyanotic. Even catheterization is usually avoided because of the possibility of arrhythmia, but surgical correction was attempted because of this chiId's marked arterial unsaturation. We planned to put more blood into the lungs, bypass the vaIves and the outflow tract, and tie the superior vena cava directly into the pulmonary artery to increase pulmonary blood flow and decrease the arterial unsaturatlon. For some patients with Ebstein's malformation, this has been done successfuIly. T h e clinical diagnoses were: cyanotic congenital heart disease, with diminished arterial saturation; Ebstein's a n o m a l y of the tricuspid valve with tricuspid regurgitation and h y p e r t r o p h y of the right atrium; and right-to-left atrial shunt t h r o u g h dilated foramen ovale. T h e diagnoses at autopsy were:cyanotic
congenital heart disease; Ebstein's anomaly of the tricuspid valve with free tricuspid regurgitation and marked dilation of the right heart; right-to-left atrial shunt t h r o u g h dilated foramen ovale; diminished pulmonary arteries; supravalvular pulmonic stenosis with pulmonary valvular insufficiency; healed and subacute pericarditis; chronic passive congestion of the liver with atrophy; healed infarctions of the kidney and spleen; and nephromegaly with glomerular hypertrophy and hypoplasia.
PATHOLOGICAL
CONFERENCE
THE
CHILDREN'S
BOSTON,
HOSPITAL
MEDICAL
CENTER,
MASS.
Sidney Farber, M.D., Editor Gordon F. Vawter, M.D., Assistant Editor
T H I S 1 1 - Y E A R - O L D boy was admitted to The Children's Hospital Medical Center because of growth failure and restriction of activity. T h e child was first admitted at 3 days of age because of cyanosis noted on the first day of life. H e was born at term after the first pregnancy of a 28-year-old mother who had had fever and diarrhea in the third gestational month. T h e birth weight was 7 pounds, 7 ounces. T h e umbilical cord was around his neck at delivery, and he was generally cyanotic but improved greatly when in oxygen. T h e respiratory rate was 38 per minute and the pulse 120. T h e liver was palpable 1 cm. below the costal margin; the spleen was normal. The lungs were clear. A Grade 4 systolic cardiac m u r m u r obscured the first sound along the left sternal border with maximal intensity at the fifth intercostal space. O n roentgenographic examination, the heart appeared slightly large but had a narrow waist; the pulmonary artery was not visible and the pulmonary vasculature was descreased; the apex was slightly lifted and there was a prominent right-sided bulge. A barium contrast roentgenograph was normal. An electrocardiogram demonstrated a P-R interval of 0.12; rate 120 per minute; axis plus 30; the R wave in lead V~ was 19 mm. in height; P,, was 2 mm. T h e infant was discharged from the hospital to be followed in the Outpatient Department. At 7 months of age, frequent upper res-
piratory tract infections were noted. T h e patient had no cyanotic spells. Slight clubbing of the fingers and toes was evident. T h e weight was 20 pounds and height 28 inches, both at the ninetieth percentile. There was a history of squatting at 18 months which did not continue after this age. T h e patient had had no hypoxic spells. T h e heart rhythm was irregular and a third sound was present. Fluoroscopy demonstrated a large globular heart with a very large right atrium and definite right ventricular action. A n electrocardiogram showed a P-R interval of 0.15 (normal = 0.125); the P wave measured 4 mm. in lead I and 8 mm. in V1. At 2 8 9 years of age, the patient had a Grade 2 harsh systolic murmur, maximal at the fourich left intercostal space. The liver was palpable 3 cm. below the costal margin. An electrocardiogram demonstrated a P-R interval of 0.20; axis plus 155 degrees; tall, slurred P waves; and ventricular premature beats. At 3 years and 7 months of age, the boy was active but tired more easily than his peers. His weight was 39 pounds (at the ninetieth percentile) and height 39 inches (between the twenty-fifth and fiftieth percentiles). The blood pressure was 115 systolic, 65 diastolic. T h e systolic m u r m u r was Grade 4 at the left sternal border and apex and was poorly transmitted. T h e diastolic rumble was Grade 2. 817
8 18
Clinical pathological con[erence
W h e n the patient was 4 years and 2 months of age, a phonocardiogram demonstrated a late first sound; decreased second sound with no splitting; a third sound; a fourth sound after the P waves; variable medium-frequency systolic m u r m u r at the fourth left intercostal space; low-frequency presystolic m u r m u r at the second right intercostal space; and adventitial sounds. At 7 years of age, an anterior chest deformity was apparent. T h e patient's weight was 51~2 pounds (between the: fiftieth and seventy-fifth percentiles) and his height 46 inches (between the tenth and twenty-fifth percentiles). Clubbing of fingers and toes was 2 to 3 plus. T h e cardiac impulse was diffuse. G r o w t h failure became manifest between 7 and 9 years of age. He was given digitalis but tired easily and had shortness of breath on exertion. T h e systolic venous wave in the neck was 3 cm. at 30 degrees. T h e spleen and liver were both palpable 3 cm. below the costal margin. By ear oximetry, the oxygen saturation was 59 per cent of normal. Successively during the winter prior to his second admission, he had "flu" and required antibiotic therapy for streptococcal pharyngitis, measles, and several episodes of upper respiratory tract infection. T h e patient's second admission was at 11 years of age for cardiac catheterization and possible surgery. He was cyanotic and had severe clubbing of the fingers and toes and a bilateral precordial bulge. T h e heart rate was 118. T h e blood pressure was 120 systolic, 80 diastolic. T h e neck veins were distended at 30 degrees with the A wave. T h e liver was palpable 6 era. and the spleen 3 cm. below the costal margin. T h e lungs were clear. T h e cardiac apex was at the fourth left intercostal space at anterior axillary line (AAL) with a left ventricular impulse. Sj was normal and $2 single; Sa was audible at the apex and $4 at the lower left sternal border. A Grade 1 protodiastolic rumble was present at the left sternal border and apex; Grade 1 ejection systolic m u r m u r was heard at the left sternal border. Laboratory studies showed: hematocrit, 88 per cent; white blood cell count 6,650, with
May 1966
57 per cent polymorphonuclear cells, 39 per cent leukocytes, 2 per cent monocytes, and 2 per cent eosinophils. T h e platelet count was 98,000 per cubic millimeter. Urinary p H was 5.5, specific gravity 1.012, protein 175 mg. per cent, and there were 5 red blood cells per high-power field. A vectorcardiogram was obtained. Catheterization of the right side of the heart revealed a saturation of 57 per cent in the superior vena cava, right atrium, and right ventricle, except for one right atrial determination of 72 per cent. Brachial arterial saturation was 72 per cent. I n the superior vena cava, the pressures showed an "a" value of 7 and a mean value of 5. I n the right atrium, the "a" value was 7, "v" was 6, and the m e a n was 5. T h e right ventricular pressure was 20 and the brachial arterial pressure 92/66. T h e calculated pulmonary output was 1.2 1 per minute per square meter and systemic output 3.2 1 per minute per square meter, with respective stroke volumes of 12 and 35 c.c. T h e patient died with bradycardia and cardiac dilatation during cardiac surgery. DR. ALEXANDER NADAS."x" This child was admitted at 3 days of age because of cyanosis noted on the first day of life. This finding is not unusual and does not necessarily indicate the presence of a congenital cardiac malformation. The respiratory, cardiac, and central nervous systems are the three principal origins of pathologic cyanosis in the newborn. In addition, some newborn infants who later are perfectly all right, may be cyanotic, presumably from inadequate expansion of the lungs. Another curious syndrome of the newborn is profound cyanosis during the first 24 to 36 hours without obvious cardiac, pulmonary or central nervous system disease. In 48 to 72 hours, this cyanosis disappears completely and the infant becomes normal. This may possibly represent temporary persistence of the fetal circulation--a lack of expansion and relaxation of the pulmonary vascular bed which thus maintains the right-to-left shunt through the ductus arteriosus for a longer period than is physiologic. Differentiating among respiratory, cardiac, and *Cardiologist, The Children's Hospital Medical Center, Boston, Mass.
Volume 68
Number 5
central nervous system origins of cyanosis can tax the pediatrician's ingenuity. Sometimes this differentiation is impossible without waiting at least 24 hours to see the response to oxygen. Persistence of cyanosis in oxygen would not exclude conditions of central nervous system origin, but episodic cyanosis is more suggestive of central nervous system causes, while persistent cyanosis is more indicative of cardiac or respiratory origin. This boy was born at term to a 28-year-old mother who had had fever and diarrhea in the third gestational month. This maternal illness may have been viral and may have some bearing on any ensuing congenital malformation. Dr. Thomas Weller has been able to find high antibody titers against rubella in babies over 6 months of age who have congenital malformations similar to those associated with maternal rubella. No information of this sort is available for today's patient. The loud murmur at 3 days of age usually means stenosis of one of the semilunar valves, either aortic or pulmonic, because these are the orifices through which blood has to flow on the first day of life. In contrast, in a ventricular septal defect, no significant flow of blood occurs very early because the pressures within the two ventricles are equal. Hence, a patient who has a loud m u r m u r in the first 2 or 3 days of life is not likely to have a ventricular septal defect; those murmurs occur at 1 week or even at 1 or 2 months of age, when the pressure-volume characteristics of the right ventricle assume the pattern that allows a sizable left-to-right shunt. Atrial septal defects do not produce any murmurs within the first 2 days of life. Tricuspid or mitral regurgitation may cause a loud murmur this early in life because, from the very beginning of life, atrial pressures are significantly lower than ventricular systolic pressures. I am wary of taking very seriously the description of the murmur at 3 days of age with a heart rate of possibly 132. However, if the first sound really is obscured, atrioventricular valve regurgitation seems more likely than semilunar stenosis, because the ejection murmurs of the latter usually start an appreciable interval after the first sound. The roentgenogram shows that the heart was slightly large, with a narrow waist. This may not be significant; nor can I take very seriously the comments about no visible pulmonary artery and a decreased pulmonary vasculature. "'The apex
Clinical pathological con[erence
8 19
was slightly lifted" is also indefinite information, but the finding of a prominent right-sided bulge is tangible, usable information. One chooses from a protocol, as from a Thanksgiving fruit bowl, what one likes. The electrical axis of the electrocardiogram is given in the protocol as plus 30 degrees. Dr. Hugenholtz recalculated it for me as minus 90 degrees. T h e average axis in the newborn is about 116 degrees, but the range is from minus 5 to plus 190. This axis of minus 90 degrees is certainly abnormal but probably not highly significant for diagnostic purposes. The R wave in V 1 is 19 m m . : This is just below the maximal, but considerably above the average. The P2 of 2 mm. indicates atrial hypertrophy. The statement that the infant was discharged to be followed in the Outpatient Department is interesting, for this was 13 years ago. Today we would not send a baby of this sort home to come back in 6 months. Instead, we would attempt, by catheterization and angiography, to make an anatomic diagnosis. We are pursuing a much more aggressive policy, attempting an accurate diagnosis and instituting treatment on much younger infants than we did 13 years ago. At the end of this infant's first admission, one could not be sure that he had congenital heart disease, but the persistent cyanosis, the murmur, and abnormal cardiac silhouette with a large right atrium are strongly suggestive of cyanotic congenital heart disease. The likely diagnoses would be pulmonic stenosis alone or, more probably, within the syndrome of tetralogy of Fallot (pulmonic stenosis in association with ventricle septal defect). None of the other cyanotic lesions, such as transposition of the great arteries or more complex abnormalities, can be excluded on the basis of the first portion of this case record. The only strong clue is the description of the roentgenogram, which indicates a large right atrium; this is also suggested by the electrocardiogram, with large P waves in lead 2, and by the possible tricuspid regurgitation. The last is suggested by the early appearance of a loud, regurgitant murmur at the lower left sternal border. F r o m the information given about the patient at 7 months of age, the most catastrophic types of cyanotic congenital heart disease, such as hypoplastic left heart syndrome and complete transposition of the great arteries, can be excluded. Squatting at age 18 months, but not after" this time, is mentioned. Most babies barely get
820
Clinical pathological con[erence
up on their feet at this time, or in other words, all squat at this age. This may be an echo from the mother coming from a suggestion thrown out by the physician. The irregular cardiac rhythm, an indefinite finding in itself, might be related to the premature ventricular beats noted later. On fluoroscopy, the right atrium seemed impressively large. The lack of definite right ventricular action is also a fluoroscopic observation. This child had two fluoroscopic examinations within 18 months, which would probably not be done today. We are more cautious in using radiation and rely on plain films if possible. Dr Neuhauser suggested the policy of using plain films rather than fluoroscopy for follow-up. DR. SIDNEY FARBER. Dr. Neuhauser, what is the difference in radiation between fluoroscopy and plain roentgenography? DR. E. B. D. NEUHAUSER. Ten years ago the difference in amount of radiation was considerable. With the use of image amplifiers, the difference is less, but fluoroscopy still involves more radiation than plain roentgenography. For follow-up, the latter can give most of the required information, provided the data from the initial examination were adequate. Cardiac catheterization involves much more radiation than simple fluoroscopy. DR. NADAS. The difference between 0.I5 seconds and the normal of 0.125 seconds in the P-R interval on the electrocardiogram is not too impressive as a single observation, but makes sense in retrospect, for the P-R interval becomes longer and longer. An atrioventricular conduction distnrbance is developing, which at this early stage is slight and of only possible significance. The P wave in lead V 1 of 8 ram. is extremely high and unquestionably represents right atrial enlargement and hypertrophy. The progressive right atrial hypertrophy, both on roentgenograms and electrocardiograms and the appearance of a diastolic rumble at 2~/~ years of age exclude, for all practical purposes, one of the most likely diagnoses for a cyanotic baby--the tetralogy of Fallot. The phonocardiogram made when the patient was 2 years of age shows that the systolic murmur begins with the first sound, which, I believe, is both obscured by the murmur and diminished in amplitude. In addition, the murmur is a plateau" all through systole. The hug e P waves, third sound, diminished and single second sound, and perhaps a fourth sound indi-
May 1966
cating atrial activity are also noteworthy. In a new tracing with a newer machine, there is a jugular venous tracing with a big A wave corresponding to the fourth sound and to atrial activity. A large V wave tends to be superimposed on the A wave, which, with the fourth sound, means considerable tricuspid regurgitation, atrial activity, and right atrial hypertension. By age 11 years, the patient's growth disturbance is apparent. Why patients with congestive heart failure do not gain and grow normally remains to be investigated. A number of factors are involved: increased oxygen consumption, poor appetite, increased work in breathing, inefficient working of the heart, visceral congestion, and poor absorption. This patient must have been in congestive failure because he was digitalized, had exertional shortness of breath, and a systolic venous wave of 3 cm. at 30 degrees was visible in the neck when the second phonogram was made. The spleen and liver were both palpable beIow the costal margi n . Ear oximetry is not a very accurate way to determine arterial oxygen saturation, but it certainly indicates that this boy's blood was severely unsaturated. This may be an appropriate time to see the x-ray films. DR. NEUI-IAUS~R. The first examination was at age 7 days (Fig. 1). The cardiac silhouette is very large and grossly abnormal in contour with a high, prominent bulge on the right side, which, at that time, was interpreted as an enlarged right atrium. No right ventricle can be seen with any clarity and the lateral view has no shadow that could be interpreted as a large right ventricle. The left apex is elevated. The left cardiac waist is not especially narrow, and the border is fairly straight. The lungs are unduly clear with ahnost no visible vascular markings, and they are increased in volume. The liver may have been slightly increased in size even at this early age. Over the years, the heart becomes progressively larger but does not change in cortour, nor does the vascular pattern in the lungs alter noticeably. By 4 years of age, a few vessels in the lungs are apparent but are diminished out of proportion to the size of the heart (Fig. 2). The aorta is on t h e left and appears relatively small with possibly a slight engorgement of the right vena cava on the right side. DR. NADAS. The electrocardiograms show tall, abnormally shaped P waves, and no significant degree of right ventricular hypertrophy is present. A discrepancy exists between the hypertrophy in
Volume 68
Number 5
Fig. 1. At age 7 days, the cardiac silhouette is large and abnormal. The lungs are increased in volume and unduly clear.
Fig. 2. By age 4 years, the heart is larger but unchanged in contour. A few vessels in the lungs are apparent but diminished in size. the right atrium and the lack of it in the right ventricle. In the second part of this protocol, from the time the child is 7 months old, the situation is clarified considerably. First, this child has cyanotic congenital heart disease with diminished arterial oxygen saturation. Second, the condition is not one of the common kinds of cyanotic congenital heart disease. It is not pure pulmonic stenosis because evidence of ventricular hypertrophy is lacking. It certainly is not tetralogy of Fallot because the heart is too large, nor is it likely to be a hypoplastic left heart or pulmonary atresia because the patient lived to 11 years of age. Tricuspid atresia is unlikely because the electrical axis does not fit that diagnosis. Transposition of the great arteries is unlikely because of the decreased pulmonary vasculature and the long survival. Trans-
Clinical pathological con/erence
821
position of the pulmonary veins is unlikely because of the absence of right ventricular hypertrophy. One uncommon type of cyanotic congenital heart disease which would fit the whole picture is Ebstein's malformation of the tricuspid valve, a downward displacement of the valve that can give atrial trouble plus a right-to-left shunt at the atrial level. The second admission at 11 years of age for cardiac catheterization and possible surgery clearly resulted from his clinical deterioration as reflected in the history, physical findings, and laboratory data. DR. PAUL HUGENHOLTZ. The electrocardiogram showed a striking bundle branch block, and the electrical axis remained around minus 90 degrees. DR. NADAS. The axis remaining at minus 90 degrees is important in the embryologic aspects of this malformation. The right heart catheterization reveals a saturation of 57 per cent in the superior vena cava, the right atrium, and the right ventricle. One right atrial determination is 72 per cent as is the brachial arterial saturation; this sample probably represents left atrial saturation, since in the large atrial cavity it might be difficult to know exactly the placement of the catheter tip. On the assumption that the pulmonary veins are 98 per cent saturated, the brachial artery saturation shows a large right-to-left shunt at the atrial level, The pressures in the superior vena cava and in the right atrium are only modestly increased; more interesting, the right ventricular pressure is only 20, which is normal. The brachial artery pressure is normal with the narrow pulse pressure characteristic of congestive heart failure. Calculated cardiac output shows a small pulmonary flow and a normal systemic flOW. The patient died following bradycardia and cardiac dilatation during cardiac surgery. To my knowledge, he could have had only one anomaly --Ebstein's anomaly, with an atrial defect and a patent foramen ovale. In many instances in the past, patients with this rare anomaly have died during catheterization. Before the advent of the monitor and defibrillating systems, the cause of death at catheterization was primarily an arrhythmia. Although today the occurrence of arrhythmia may be as frequent and as severe, we have available the equipment and knowledge to counteract it. DR. GORDON VAWTER. The extraordinary dilatation of the heart which was apparent at autopsy made one wonder how the child had
8 2 2 Clinical pathological con[erence
survived as long as he did. The heart virtually filled the entire chest cavity. The dilatation is especially marked in the right atrium and ventricle, which chambers had approximately six times greater volume than the left atrium and ventricle. There is marked insufficiency of the tricuspid valve resulting both from cardiac dilation and from the so-called downward displacement of the posterior cusp, characteristic of Ebstein's anomaly of the tricuspid valve. The malattachment of the valve, as in this child, is frequently marked externally by a shallow groove. Cephalad to these landmarks, the right ventricular wall is continuous with that of the right atrium, the whole compound chamber having a thin and probably relatively ineffectual musculature. As is common in Ebstein's anomaly, there is a prominent Chiari network in the right atrium. The right-to-left shunt at the atrial level in this instance occurs through a patent foramen ovale, enlarged considerably by the massive atrial dilatation. Most examples of Ebstein's anomaly have been described as having a small, thick-walled pulmonary conus more suggestive of stenosis than dominant insufficiency, but, in this heart, the pulmonary conus is so hugely dilated and thin walled that there appears to be dilatation of the pulmonary valve ring, incompetence of the pulmonary valve, and an element of supravalvular pulmonary stenosis. While the pulmonic valve is said to be normal in most instances of Ebstein's anomaly and the abnormalities seen here may be secondary to tricuspid incompetence, they may have ultimately contributed to the circulatory aberration. It is of interest that pressure gradients are commonly reported at the pulmonic valve in published cardiac catheterization studies. The pulmonary arteries have a modest volume, walls of one-fifth normal thickness, and proximally show medial fibrosis and degeneration, perhaps related to histologically similar lesions found in the aortas of some cyanotic patients: The bundle branch block may be in part related to the stretching and thinning of the moderator band as well as to mild myocardial fibrosis found here. Syndromes associated with Ebstein's anomaly, in addition to those already mentioned (cardiac arrhythmias, conduction defects, and shdden death) include a high incidence of perlcarditis, often hemorrhagic, for which we have evidence here; encephalomalacia, not found in this patient
May 1966
who did, however, have healed renal and splenic infarcts; and systemic hypertension, not clearly established in this instance. Of those forms of cyanotic congenital heart disease complicated by the nephrotic syndrome, Ebstein's anomaly is one of the most common. Perhaps such a diagnosis cannot be supported on clinical grounds in this patient, but the kidneys are enlarged, somewhat granular and pale, with hypoplastic and hypertrophic glomeruli as found frequently in patients with polycythemia, clubbing, arterial oxygen unsaturation, and occasionally hepatic disease. The liver is atrophic. DR. NaDAS. I am inclined to discount any great functional significance for the anatomic lesions of the pulmonary valve. Surgical correction of Ebsteln's anomaly is not usually attempted unless the patient is severely cyanotic. Even catheterization is usually avoided because of the possibility of arrhythmia, but surgical correction was attempted because of this chiId's marked arterial unsaturation. We planned to put more blood into the lungs, bypass the vaIves and the outflow tract, and tie the superior vena cava directly into the pulmonary artery to increase pulmonary blood flow and decrease the arterial unsaturatlon. For some patients with Ebstein's malformation, this has been done successfuIly. T h e clinical diagnoses were: cyanotic congenital heart disease, with diminished arterial saturation; Ebstein's a n o m a l y of the tricuspid valve with tricuspid regurgitation and h y p e r t r o p h y of the right atrium; and right-to-left atrial shunt t h r o u g h dilated foramen ovale. T h e diagnoses at autopsy were:cyanotic
congenital heart disease; Ebstein's anomaly of the tricuspid valve with free tricuspid regurgitation and marked dilation of the right heart; right-to-left atrial shunt t h r o u g h dilated foramen ovale; diminished pulmonary arteries; supravalvular pulmonic stenosis with pulmonary valvular insufficiency; healed and subacute pericarditis; chronic passive congestion of the liver with atrophy; healed infarctions of the kidney and spleen; and nephromegaly with glomerular hypertrophy and hypoplasia.