Symposium on Pediatric Cardiology
Infective Endocarditis and Diseases of the Pericardium
Welton M. Gersony, M. D}' and Allan J. Hordof, M. D.t
INFECTIVE ENDOCARDITIS Infective endocarditis is still a significant cause of morbidity and mortality among children and adolescents, despite advances in the management of the disease with antimicrobial agents and the widespread advocacy of prophylactic measures. Our inability to eradicate infective endocarditis by prevention or early treatment stems from several factors: the nature of the infecting organisms has changed over the years: physicians, dentists, and the public are not sufficiently aware of the threat of infective endocarditis and the preventive measures which are available; diagnosis may be difficult and thus delayed; and special risk groups have emerged which include an increasing number of narcotics abusers, survivors of cardiac surgery, and patients with low resistance to infection who require intravascular catheters. Infective endocarditis is common enough and serious enough so that pediatricians should be aware of its potentially severe effects on their patients. Unfortunately, the information which is available regarding the risks of contracting the disease remains rather scanty. Furthermore, recommendations for prevention are controversial, since they are based almost strictly on empiricism rather than the results of ':'Professor of Pediatrics, College of Physicians and Surgeons of Columbia University; Director, Division of Pediatric Cardiology, Babies Hospital, Columbia-Presbyterian Medical Center, New York, New York t Assistant Professor of Pediatrics, College of Physicians and Surgeons of Columbia University; Director, Pediatric Intensive Care Unit, Babies Hospital, Columbia-Presbyterian Medical Center, New York, New York
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controlled randomized studies. Despite these problems, there is no doubt that infective endocarditis either can be prevented; or if diagnosis and treatment are approached rationally and meticulously, the disease and many of its complications can be managed successfully.
Incidence The number of children admitted to large medical centers with infective endocarditis is reported to have increased in recent years, but it is difficult to be certain whether this represents a real increase in the prevalence of the disease in the overall population. The infection is seen most often as a complication of congenital or rheumatic heart disease, but can also occur in children with normal hearts (Table 1). G. K. 27. 28.;;2 The disease is extremely rare in infancy.27, 28 Recently reported increases in incidence appear to be mostly manifest in the congenital heart disease group, as might be expected since more patients who remain susceptible to the infection are surviving cardiac surgeryY' 28 A number of these individuals have intracardiac protheses. Although reflected primarily in adult incidence figures, infective endocarditis among narcotics users and patients with chronic illness is also being reported more frequently in the pediatric population. 29 The incidence of infective endocarditis related to specific heart defects has been relatively well defined. In general, patients who have a lesion which is associated with high velocity of blood ejected into a chamber or vessel are most susceptible to the infection. Vegetations usually form at the site of the endocardial or intimal erosion which results from the turbulent flow. Children with ventricular septal defect, leftsided valvular disease, and systemic-pulmonary arterial communications are at the highest risk for developing infective endocarditis, whereas, at the other extreme, a very low incidence is reported in secundum atrial septal defect, a lesion which is characterized by low velocity flow across the intra atrial communication. 27 The majority of studies regarding prevalence of endocarditis have provided only estimations since data are most often reported retrospectively on the basis of hospital admissions,27. 49 post mortem series,t7 or population studies,5, 40 rather than from controlled prospective observations. Furthermore, there has been little information available regarding the effect of cardiac surgery on the incidence of infective endocarditis in children with congenital heart disease. Recently, the cooperative study on the Natural History of Aortic Stenosis, Pulmonary Stenosis and Ventricular Septal Defect (NHS) has reported data from a controlled, strictly defined pediatric population which was collected over a period of 4 to 15 years. 18 From this study, an accurate assessment of the incidence of infective endocarditis among patients with these common defects was obtained, and the effects of surgery were systeII1atically evaluated. ~The incidence data from the NHS are summarized in Table 2. -Pulmonary stenosis was associated with an extremely low incidence of infective endocarditis at the six medical centers involved in the study, (0.211000 pt. yrs.) representing one case in 4648 patient years, whereas patients with aortic stenosis and ven-
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Table 1.
Underlying Heart Disease in Children with Infective Endocarditis
Congenital heart disease Tetralogy of Fallot Ventricular septal defect Aortic stenosis Patent ductus arteriosus Other Rheumatic heart disease No cardiac abnonnalities
78% 24% 16% 8% 7% 23% 14% 8%
tricular septal defect were more susceptible to the infection. Aortic valvotomy did not protect against endocarditis over the years following surgery; rather the incidence appeared to increase. This is most likely explained on the basis of residual deformities of the aortic valve. In contrast, successful repair of ventricular septal defect appeared to decrease significantly the long-term susceptibility to infective endocarditis. Only one patient in the series with a documented closed defect developed the disease during the observation period. A recent survey indicates that "late" infective endocarditis in adults with prosthetic valves is a major complication among these patients.30 The increasing use of valve replacements and valved conduit repairs in children with complex heart disease may lead to a larger number of cases of such infections. At the present time, palliative systemic to pulmonary shunts is the surgical procedure most associated with a high incidence of infective endocarditis in the pediatric age range. 2B
Predisposing Events In approximately 30 per cent of cases of infective endocarditis, a predisposing factor is recognized. lB. 2B A surgical or dental procedure can be implicated in approximately two-thirds of the cases in which a potential source of bacteremia is identified. Dental procedures are the major threat for infective endocarditis emerging from a more or less routine event in everyday life - a visit to the dentist. Although tranTable 2. Incidence of Infective Endocarditis among Children with Ventricular Septal Defect, Aortic Stenosis, and Pulmonary Stenosis (Natural History Study) DEFECT
RATE PER 1000 RISK BY AGE RISK BY AGE P PT.YEABS 30 YRS. (MEDICAL) 30 YRS. (POSTSURGICAL) VALUE
Ventricular septal defect Aortic stenosis Pulmonary stenosis
1.5 1.8 0.21:
9.7% 1.4% 0.9%
2.0%t 7.4%
'Medical vs. surgical risk. tIncludes patients with residual defects. !Pulmonary stenosis vs. aortic stenosis or ventricular septal defect (p < .01). ns = not Significant.
.05 ns ns
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sient bacteremia after dental manipulation is less likely in normal children than in adults, presumably due to the lesser degree of peridontal disease,42 the incidence is still striking. Furthermore, dental hygiene is poor in children with heart disease, especially in those with lesions resulting in cyanosis. 22 Other events which may lead to infective endocarditis include tonsillectomies and other upper respiratory surgery, bronchoscopy, urologic surgery, intravenous alimentation, burns, and ventriculovenous shunts for management of hydrocephalusY The occurrence of infective endocarditis directly following cardiac catheterization or heart surgery is relatively low. The Natural History Study provides prospective data in this regard. 18 Only one case of infective endocarditis was considered to have definitely occurred as the direct result of cardiac catheterization among the entire series of 2420 patients with ventricular septal defect, aortic stenosis, and pulmonary stenosis, most having been catheterized on two occasions. Two patients developed infective endocarditis within 4 months of cardiac surgery during 402 patient years of observation. However, despite this encouraging data, on the basis of the frequency of the performance of these procedures at a large number of hospitals, cardiac surgery, and to a lesser extent, cardiac catheterization, rank high on the list of significant antecedent events which have been reported prior to the onset of infecti ve endocarditis. 28
Etiology Streptococcus viridans remains the most common agent responsible for infective endocarditis (approximately 50 per cent of the cases) but its predominance has been decreasing in recent years (Table 3).6.8.27.28.52 Staphylococcal endocarditis has become more common over the past two decades, and is now estimated as being responsible for almost one-third of the cases. Other organisms, including fungal agents, cause endocarditis less frequently, and in approximately 10 per cent of cases, blood cultures are negative. No relationship exists between the infecting organism and the type of congenital defect, duration of the illness, or age of the child. However, staphylococcal endocarditis is more common in patients who do not have underlying heart disease. Diagnosis There is almost always some delay in the diagnosis of infective endocarditis, since the early symptoms and signs of the disease are usually mild and nondescript, especially when Streptococcus viridans is the infecting organism. Prolonged fever without other manifestations, persisting for as long as several months, may often be the only medical history which can be elicited. Depending on the virulence of the agent, the subsequent findings may include signs of embolization, changes in the cardiac examination, and splenomegaly. Laboratory data include evaluation of the sedimentation rate, leukocytosis, and microscopic hematuria. Echocardiography and/or sector scan have been utilized to document the presence and specific location of vegeta-
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Table 3. Causative Organisms of Infective Endocarditis in Children ORGANISM
PER CENT
Streptococcus viridans Staphylococci Streptococcus fecalis Beta streptococci Other organisms No agent isolated
46 32 4 3 4 11
tions,37 but these modalities cannot be expected to be helpful in the early phases of the disease. In most instances, a specific diagnosis will depend on positive blood cultures. Early diagnosis requires the physician to consider the presence of infective endocarditis in any child with heart disease who has unexplained fever for more than a few days. Blood cultures must be drawn even if the child feels well and has no other physical findings. Three separate blood collections should be obtained after careful preparation of the phlebotomy site. Contamination is extremely misleading since bacteria found on the skin may themselves cause infective endocarditis. The timing of collections is not especially important, because bacteremia can be expected to be relatively constant. In 90 per cent of cases of endocarditis, the etiologic agent is recovered from the first two blood cultures;51 therefore further blood drawing should be deferred for two or three days, until the results of the initial cultures are known.
Mortality and Complications In the pre-antibiotic era, infective endocarditis was a fatal disease. After a marked improvement in the 1950's, the percentage of survivals continues to increase, but at a slow rate. Mortality remains at 20 to 25 per cent in recent seri.es. Complications occur in 50 to 60 per cent of children with documented infective endocarditis, 18.27.28,37 the most common being cardiac failure due to vegetations involving the aortic or mitral valve. Myocardial abscesses and toxic myocarditis may also lead to congestive heart failure but without characteristic changes in auscultatory findings. Systemic emboli, often with central nervous system manifestations, are a major threat in patients with infective endocarditis, superimposed on left heart or aortic lesions. Pulmonary emboli are most often recognized in children with ventricular septal defect or tetralogy of Fallot, although massive life-threatening pulmonary embolization is extremely rare. Mycotic aneurysms, ruptured sinus of Valsalva, obstructive valve disease secondary to large vegetations, acquired ventricular septal defect, and heart block as a result of involvement of the specialized conduction system, all have been reported as a result of infective endocarditis. 37 Management Antibiotic therapy should be instituted immediately upon making
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the diagnosis of infective endocarditis. When virulent organisms are responsible, small delays may result in progressive endocardial damage and a greater likelihood of severe complications. The choice of antibiotics, method of administration, and length of treatment are outlined in Table 4. The principles of management are relatively simple; high serum bactericidal levels must be maintained for an adequate length of time in order to eradicate organisms that are growing in relatively inaccessible avascular vegetations. From 5 to 20 times the minimum in vitro inhibiting concentration must be produced at the site of infection in order to destroy bacteria growing at the core of these lesions. ' ° Several weeks are required for a vegetation to organize completely; thus therapy must be continued until this occurs, so that recrudescence can be avoided. A total of 4 to 6 weeks of treatment is recommended, with serumcidal levels by tube dilution of at least 1:8 prior to administration of a subsequent dose of antibiotic. 20 Depending on the clinical response and laboratory studies, antibiotic therapy may require modification, and in some instances more prolonged treatment is required. With highly sensitive Streptococcal viridans infections, shortened regimens including oral penicillin have been recommended by some authors. 35 Bed rest should be instituted and may be extended if congestive heart failure occurs. Similarly, digitalis, restriction of sodium, and diuretic therapy should be utilized if and when indicated. Surgical intervention during the course of infective endocarditis has become an integral part of management in cases in which severe aortic or mitral valve involvement leads to intractable heart failure. Rarely, mycotic aneurysms or rupture of aortic sinuses require emergency operation. Although antibiotic therapy should be administered for as long as possible prior to surgical intervention, active infection should not be a contraindication if the patient is critically ill as a result of critical hemodynamic deterioration from infective endocarditis. Removal of vegetations, and in some instances, valve replacement, may be life-saving, and sustained antibiotic administration will most often prevent re-infection. Successful late surgical intervention has been reported in children with infective endocarditis who have been unresponsive to treatment and in patients who have shown evidence of continued embolic phenomenon. 37 Replacement of infected prosthetic valves carries a higher risk, but is necessary in refractory cases.
Prophylaxis Antimicrobial prophylaxis prior to and after various procedures is considered to be essential in a prevention program designed to reduce the incidence of infective endocarditis in susceptible patients. 9 However, it is difficult to evaluate the results of preventive regimens when the risks are extremely low for any single procedure. For example, it is estimated that one case of endocarditis can be expected for every 533 tooth extractions,32 and a lesser frequency would be anticipated for other forms of dental manipulation. However, considering the number of such procedures, prophylaxis along with proper general dental care
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Table 4. Treatment of .Infective .Endocarditis DURATION ETIOLOGIC AGENT
Streptococcus viridans
DOSAGE
ROUTE
OF THERAPY
300,000 units/kg/day every 4 hours or up to 20 million units'
IV
4 to 6 wks.
Streptomycin t
30 mg/kg/day every 12 hours
1M
2 wks
Penicillin G
300,000 units/kg/day every 4 hours or up to 20 million units':'
IV
6 wks
200 mg/kg/day every 4 hours
IV
6 wks
Gentamicin
4 to 6 mg/kg/day every 8 to 12 hours
IV
6 wks
Penicillin G
300,000 units/kg/day every 4 hours or up to 20 million units'
IV
6 to 8 wks
Oxacillin or Nafcillin or Methicillin!
200 mg/kg/day every 4 to 6 hours
IV
6 to 8 wks
Gentamicint
4 to 6 mg/kg/day every 8 to 12 hours
IV
2 wks
Vancomycin
50 mg/kg/day every 6 hours
IV
6 to 8 wks
Penicillin G
300,000 units/kg/day every 4 hours or up to 20 million units'
IV
6 to 8 wks
200 mg/kg/day every 4 to 6 hours
IV
6 to 8 wks
4 to 6 mg/kg/day every 8 to 12 hours
IV
6 to 8 wks
DRUG
Penicillin G
+
Streptococcus fecalis
or Ampicillin
+
Staphylococcus aureus Penicillin sensitive
Penicillin resistant
+
Methicillin resistant
Unknown agent
+ Oxacillin
+ Gentamicin
"For relatively resistant organisms. t Addition of aminoglycoside advocated by some centers. tLeast preferred.
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and oral hygiene almost certainly will decrease the risk of infective endocarditis in susceptible individuals. Vigorous treatment of sepsis and local infections, and careful asepsis during cardiac surgery and catheterization will also contribute to a reduction in the incidence of infective endocarditis. Recommendations for specific antibiotic regimens for prevention of infective endocarditis under various circumstances have been published under the auspices of the American Heart Association and are readily available to physicians and dentists.!) However, some authorities question the effectiveness of current prophylactic regimens and suggest that modifications should be made, based on a better definition of the high-risk procedures and the susceptible patients. 31 It is generally agreed that prophylaxis is not necessary after ligation and division of patent ductus arteriosus, or closure of an uncomplicated secundum atrial septal defect. The low incidence of infective endocarditis with secundum atrial septal defect prior to surgery; pulmonary stenosis, either unoperated or after repair; and after successfully closed ventricular septal defect, suggests that recommendations concerning prophylaxis in these specific situations may require reappraisal. Children most prone to infective endocarditis and who require the most protection are those with cyanotic heart disease with or without palliative shunts, mitral valve deformities, aortic stenosis and/or insufficiency, and prosthetic valves or conduits. Antimicrobial prophylaxis is practical only for patients with known heart disease after a well defined potential predisposing event, and even then, protection against nonstreptococcal disease is marginal. An approximation of the percentage of episodes potentially preventable by prophylaxis in children can be calculated by the following equation (modified from Kaye)31 [.90 (underlying heart disease) x .20 (identifiable predisposing event) x .55 (potential streptococcal infection) = 12%]. Considering this relatively low estimate of protected patients, as well as an unknown but probably significant incidence of poor compliance, it is not surprising that the actual results of prophylaxis are difficult to assess. Because antimicrobial prophylaxis cannot be offered in the absence of a possible predisposing event, and since the disease may become established in susceptible patients despite prophylaxis, complete prevention of infective endocarditis is not possible. Thus, pediatricians must remain alert to the likelihood of the disease occurring in their patients with heart disease. Vigorous efforts must be undertaken to make a prompt diagnosis when clinical events indicate that a high degree of suspicion is warranted. It cannot be overemphasized that early diagnosis is extremely important in order to reduce mortality and serious complications from infective endocarditis.
DISEASES OF THE PERICARDIUM The spectrum of diseases of the pericardium can range from a mild inflammatory reaction resulting in little or no discomfort or dis-
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ability, to a rapidly progressive virulent process which, if not properly managed, can result in death. In many instances, the involvement of the pericardium is only one manifestation of a more generalized illness. The prominence of the pericardial component will vary, depending on the disease entity. In other patients, pericardial involvement occurs as an isolated process with no evidence of systemic disease. Major entities that involve the pericardium are: infectious: viral or acute benign, bacterial, tuberculous, fungal, parasitic; acute rheumatic fever; rheumatoid arthritis; lupus erythematosus; uremia; neoplastic disease; radiation; thalassemia; trauma; pericardial cyst; postpericardiotomy syndrome; and chronic constrictive.
Pathophysiology of Pericarditis Pericardial inflammation results in an accumulation of fluid in the pericardial space. The nature of the fluid varies, depending on the etiology of the pericarditis and may be serous, fibrinous, purulent, or hemorrhagic. The major concern in the management of a child with pericarditis is the occurrence of cardiac tamponade, since this can be a lifethreatening emergency. In a healthy child there is no more than 10 to 15 ml of fluid found in the pericardial space, whereas in an adolescent with pericarditis, in excess of 1000 ml of fluid may accumulate. The clinical course depends on a number of factors: the state of the myocardium, the nature of the fluid, the rate of the fluid accumulation, and the pressure-volume characteristics of the pericardial space. For every increment of fluid accumulation, there is an increase in intrapericardial pressure (Fig. 1). Once this reaches a critical level, there is a rapid rise in pressure culminating in severe cardiac compression. 25 The hemodynaInic consequences of cardiac tamponade is inhibition of ventricular filling during diastole, elevated systemic and pulmonary venous pressures, and, if untreated, eventual compromised cardiac output and shock. 39. 43 Diagnosis The first symptom of pericardial disease is often precordial pain. The major complaint is that of a sharp, stabbing sensation over the left chest, shoulder and back, exaggerated by lying and relieved by sitting, particularly when leaning forward. Since there is no sensory
... 0:
:> (/) (/)
Figure 1. Intrapericardial pressure - volume curve. For every increment of fluid accumulation there is an increase in intrapericardial pressure. When the intrapericardial volume increases from point A to point B there is a marked increase in intrapericardial pressure since this corresponds to a point on the steep portion of the curve.
... 0:
a.
'«0
°i ~ E uii: ...a. «
....0:
;!;
A INTRAPERICARDIAL VOLUME (mil
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innervation of the pericardium, the pain is most likely due to diaphragmatic and pleural irritation. Cough and fever may well accompany the chest discomfort. The presence of systemic symptoms or signs associated with other organ systems depend on the basic etiology of the pericarditis. On physical examination, many of the findings relate to the degree of fluid accumulation in the pericardial sac. The presence of a friction rub is helpful, but may be a late sign in acute pericarditis, becoming apparent only after the effusion is reduced. Narrow pulses, quiet precordium, distant heart sounds, neck vein distention, and paradoxical pulse suggest significant fluid accumulation. The documentation of greater than 20 mm Hg of paradoxical pulse in a child with pericarditis is a reliable indicator of the presence of cardiac tamponade, 10 to 20 mm Hg being equivocal. The method by which this important measurement is obtained deserves reiteration. There is normally a slight decrease in systolic arterial pressure during inspiration. With cardiac tamponade this normal phenomenon is exaggerated, probably due to decreased left heart filling with the inspiratory phase of respiration. 21 In order to determine the degree of pulsus paradoxus, one first measures the exact systolic blood pressure during normal expiration. The manometer is then slowly allowed to fall. The point when the systolic pressure is heard equally well during inspiration and expiration is then recorded. The difference between the two determinations represents the degree of paradox. Significant pulsus paradoxus is seen in conditions other than cardiac tamponade. It may be present with severe dyspnea of any origin and is not infrequent in patients who have emphysema or asthma, It; as well as children who are being ventilated with a positive pressure respirator. In these patients the paradoxical pulse is due to a marked increase in intrathoracic pressure. Determination of the etiology of paradoxical pulse in a child on a ventilator after cardiac surgery may be difficult to assess, since in this situation more than one potential mechanism is possible.
Laboratory Data The specific laboratory findings in pericarditis will depend on the underlying disease. However, electrocardiography, chest x-ray films, and echocardiography are important in the diagnosis of all types of pericarditis. ELECTROCARDIOGRAM. The effects of pericarditis on the electrocardiogram are multiple. Low voltage of the QRS complexes results from a damping effect of pericardial fluid. Pressure on the myocardium by fluid or exudate produces a current of injury that results in mild elevation of S-T segments. Generalized T wave inversion occurs as a consequence of associated myocardial inflammation. The S-T segment and T wave changes with pericarditis are more generalized than those seen with myocardial infarction, and the S-T segment elevations tend to precede the T wave changes. There may be an interval when the ECG is in a transitional phase and appears to be normal. This may
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occur during the acute phase of the illness, prior to diagnosis. In some instances, clear cut abnormalities are never identified. 45 CHEST X-RAY FILMS. A relatively large pericardial effusion must be present in order to cause an enlarged cardiac shadow with the usual "water-bottle" configuration (Fig. 2). In most instances the lung fields are clear. With constrictive disease, the heart appears to be relatively small, and calcification may be present (Fig. 3). II ECHOCARDIOGRAPHY. The echocardiogram has become one of the most sensitive techniques for evaluation of the size and progression of pericardial effusions. 14 Normally, the pericardium is closely adherent to the epicardium and the two layers can only be narrowly separated by the ultrasound beam. In patients with pericardial effusion a clear echo free space is recorded between the epicardium and pericardium (Fig. 4). The posterior effusion is recorded behind the left ventricular epicardium and ends at the junction of the left ventricle and left atrium. An anterior effusion will be recorded between the chest wall and the anterior right ventricular wall. The presence of both an anterior and posterior effusion generally indicates that a large collection of fluid is present. False positives are rare in the hands of experienced echocardiographers. 11,47 Viral and Acute Benign Pericarditis Viral and acute benign pericarditis are considered together since most episodes of what is called acute benign pericarditis appear to follow or coincide with a viral illness. 7 , 26 Viruses recognized to cause pericarditis include Coxsackie B, influenza, ECHO, and adenovirus. 15 Most cases are relatively mild and recovery occurs within several weeks. However, in rare instances the patient may be severely ill and cardiac tamponade may ensue. For most patients only symptomatic therapy is indicated and the disease is self-liIniting. However, there is an interesting group of paFig. 2
Fig. 3
Figure 2. Chest x-ray film from a patient with a large pericardial effusion. Note the markedly enlarged cardiac image with relatively clear lung field. Figure 3. Chest x-ray film from a patient with chronic constrictive pericarditis. The heart is not enlarged in the anteroposterior view (left), Prominent calcification of the pericardium is seen best on the lateral projection (right),
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.. 1!!!'I1lf!!Ir..1II
---
RVW
-
LVW
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Figure 4. Echocardiogram from a patient with a large anterior and posterior pericardial effusion. The anterior effusion [----+] is shown as an echo free space between the chest wall and the anterior right ventricular wall (RVW). The posterior effusion [--+1 is the echo free space behind the left ventricular posterior wall (LVW).
tients, most often adolescents, in which acute benign pericarditis becomes a chronic relapsing illness. The major differential diagnosis in this type of problem is that of a collagen vascular disease. These patients respond dramatically to anti-inflammatory therapy with corticosteroids. Milder forms may be controlled with aspirin. The clinical course may be months or even one or two years, during which time the patients are dependent on drug therapy for suppression of the pericarditis. Ultimately, the patients improve and the prognosis appears to be good. The etiology is unclear, but most likely is related to a hypersensitivity reaction to a viral illness, and pericardial inflammation is not the precursor of a generalized disease. 15 On occasion, the clinical differential diagnosis between acute pericarditis and myocarditis may be difficult. Indeed, in patients with pericarditis, there is usually a myocardial inflammatory component, and the reverse is also true. What becomes crucial is to decide which process is dominant, since management is quite different; the former stressing anti-inflammatory treatment and urgent response to cardiac tamponade, and the latter requiring therapy for congestive heart failure. The echocardiogram is helpful in this regard, as it will allow visualization of large pericardial effusions, and can also indicate the presence of myocardial dysfunction. 24
Purulent Pericarditis Purulent pericarditis is most often associated with a bacterial infection such as pneumonia, epiglotittis, meningitis, or osteomyelitis. Initially the diagnosis of pericardial involvement may be obscured by signs and symptoms of the primary infection. However, once the purulent process is established, the course is fulminant, terminated by acute cardiac tamponade and death. Open pericardial drainage is mandatory, along with appropriate intravenous antibiotics. Although closed pericardia! aspiration provides exudate for diagnostic purposes, and may be life-saving in the face of severe cardiac compression, it should not be considered to be final therapy. Without open drainage, tamponade will recur, since with large effusions only a small reaccumulation of pericardial fluid may markedly increase intrapericardial pressure (Fig. 1). Management with open pericardial drainage has significantly increased survival in patients with this disease. 19 The most common organisms to be implicated in purulent pericarditis are Staph-
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ylococcus aureus, Hemophilus influenza type B, and Neisseria meningitidis. 19, :34, 46 Tuberculous pericarditis rarely occurs in children outside of underdeveloped countries. Extensive treatment with antituberculous chemotherapy is required, and late constriction may occur.I5 Acute Rheumatic Fever Pericarditis occurs in acute rheumatic fever as a component of pancarditis. It should be emphasized that rheumatic pericarditis occurs with acute valvulitis, and a murmur of mitral and/or aortic regurgitation will be audible. If there is no evidence of acute valvulitis, another cause must be considered. Pericarditis appears to respond to therapy with steroids along with the other manifestation of acute rheumatic pancarditis. Cardiac tamponade is extremely rare. Rheumatoid Arthritis Pericarditis is not an uncommon manifestation of rheumatoid arthritis in children. Most often, pericardial inflammation is associated with the other signs of rheumatoid arthritis. However, rarely, pericarditis may be the only manifestation of rheumatoid arthritis and precede the onset of arthritis by months or even years. Differentiation of rheumatoid pericarditis from that seen with other collagen vascular disease, particularly lupus erythematosus, may be difficult. Treatment consists of steroids or salicylates, and may be needed on a long-term basis to suppress the disease process. 4 Uremia Uremic pericarditis occurs only in the presence of prolonged severe renal failure, and results from chemical irritation of the pericardium secondary to the metabolic abnormalities. Uremic pericarditis has been primarily a feature of end stage chronic renal disease and in most instances is an incidental part of the clinical picture. However, with the advent of chronic hemodialysis, uremic pericarditis has been recognized as a more chronic problem, culminating in cardiac tamponade. Pericardial effusion has also been implicated in the etiology of recurrent hypotension during hemodialysis. If adequate relief of uremic pericarditis does not occur with hemodialysis, pericardiectomy has been recommended. 1 Neoplastic Disease Neoplastic pericardial involvement is seen in patients with Hodgkin's disease, lymphosarcoma, and leukemia and results from direct neoplastic invasion of the pericardium. Cardiac tamponade or constriction may occur late in the course of the illness. Rarely, pericardial infiltration is the initial manifestation of neoplastic disease, and the basic diagnosis can be made by examination of the pericardial fluid for neoplastic cells. 2 ,:J In addition to showing signs of direct invasion of the pericardium, patients with malignancy may develop pericarditis as a result of radiation therapy to the mediastinum. This manifestation may be related to the radiation dose and to the technique utilized. 23
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Postpericardiotomy Syndrome
Postpericardiotomy syndrome is characterized by fever, chest pain, pleural and pericardial effusion, and fluid retention. This manifestation is seen 1 to 2 weeks following open heart surgery in approximately 15 per cent of postoperative patients. Recent evidence indicates that the syndrome is a nonspecific hypersensitivity reaction to trauma to the pericardium and epicardial surface of the heart. 12 High titers of anti-heart antibody have been reported to correlate with clinical signs of the syndrome. 13 In most patients, postpericardiotomy syndrome is a relatively short illness, and affected children will generally respond well to antiinflammatory therapy with aspirin or corticosteroids. Treatment is maintained for 1 to 3 months, but recurrences may be seen as long as one year postoperatively, requiring reinstitution of therapy. Constrictive Pericarditis Constrictive pericarditis represents a special problem both in terms of the clinical picture and the differential diagnosis. Predisposing pericardial disease include purulent pericarditis, tuberculous pericarditis, acute benign or viral pericarditis, mediastinal irradiation for intrathoracic malignancy, neoplastic invasion of the pericardium, and trauma. In most instances constriction occurs months or years after the initial insult, but occasionally may be an acute, rapidly progressive process. Despite the numerous known etiologies, constrictive pericarditis most often occurs without a preceding illness or generalized systemic disease. 44 The clinical manifestations of this disease occur as a result of impairment of diastolic ventricular filling, compromise of myocardial contractility, and resultant depression of cardiac function. 39 The prominent physical findings, hepatomegaly and ascites, may appear to be out of proportion to the other signs and symptoms, thus mimicking chronic liver disease. However, liver function studies are only mildly abnormal, and careful physical examination will reveal other sometimes subtle findings of constriction including neck vein distention, narrow pulses, quiet precordium, distant heart sounds, faint pericardial friction rub, and paradoxical pulse. Typical findings become apparent gradually, and thus may be easily overlooked. The auscultatory presence of an early pericardial knock and the appearance of calcification of the pericardium on chest x-ray films (Fig. 3) are the more obvious manifestations that are apparent when the disease is well established. Protein-losing enteropathy with hypoproteinemia and lymphopenia may be seen in association with constriction. 33 • 36 Constrictive pericarditis may be difficult to distinguish from chronic constrictive cardiomyopathy.38 Impairment of myocardial function occurs with both conditions. However, the myocardial disease of constrictive pericarditis is almost always reversible with pericardiectomy. At times, despite all efforts at differentiation, including echocardiography and cardiac catheterization, a definite diagnosis can only be made by exploratory thoractomy and direct examination of the pericardium.
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Surgical intervention is the only therapeutic modality in constrictive pericarditis. The surgical procedure of choice is radical pericardiectomy with decortication of the pericardium over a wide area of the heart to include the systemic and pulmonary veins. In most patients there is rapid response to surgical intervention, characterized by increased cardiac output and prompt diuresis. 41 • 48 Observing the dramatic improvement in the status of a chronically ill child with longstanding unsuspected constrictive pericarditis after proper diagnosis and treatment is a rewarding experience in medicine.
REFERENCES 1. Bailey, G. L., Hampers, C. L., Hager, E. B., et al.: Uremic pericarditis: Clinical features and management. Circulation, 38:582, 1968. 2. Battle, C. U., Bonfiglio, T. A., and Miller, D. R.: Pericarditis as the initial manifestation of acute leukemia: Report of a case. J. Pediat., 75:692, 1969. 3. Berg, M., Wilander, E., and Eriksson, A.: Mediastinal lymphosarcoma simulating pericarditis. Acta Paediat. Scand., 64:873, 1975. 4. Bernstein, B., Takghashi, M., and Hanson, V.: Cardiac involvement in juvenile rheumatoid arthritis. J. Pediat., 85:313, 1974. 5. Bloomfield, D. K.: The natural history of ventricular septal defects in patients surviving infancy. Circulation, 29:914, 1964. 6. Blumenthal, S., Griffiths, S. P., and Mortan, B. C.: Bacterial endocarditis in children with heart disease. A review based on the literature and experience with 58 cases. Pediatrics, 26,:993, 1960. 7. Bradley, E. C.: Acute benign pericarditis. Am. Heart. J., 67:121, 1964. 8. Caldwell, R. L.: Hurwitz, R. A., Girod, D. A.: Subacute bacterial endocarditis in children. Am. J. Dis. Child., 122:312, 1971. 9. Committee on Rheumatic Fever and Bacterial Endocarditis of the Council on Cardiovascular Disease in the Young of the American Heart Association: Prevention of bacterial endocarditis. Circulation, 56:139A, 1977. 10. Eagle, H., Fleischman, R., and Levy, M.: "Continuous" vs. "discontinuous" therapy with penicillin; Effect of interval between injection on therapeutic efficacy. New Engl. J. Med., 248:481, 1953. 11. Ellis, K., and King, D. L.: Pericarditis and pericardial effusion: Radiologic and echocardiographic diagnosis. Radiol. Clin. North Am., 11 :393, 1973. 12. Engle, M. A., Zabriskie, J. B., Senterfit, L. B., et al.: Postpericardiotomy syndrome: A new look at an old condition: Modern concepts. Cardiovasc. Dis., 44:59,1975. 13. Engle, M. A., Zabriskie, J. B., Senterfit, L. B., et al.: Immunologic and virologic studies in the postpericardiotomy syndrome. J. Pediat., 87: 1103, 1975. 14. Feigenbaum, H.: Echocardiographic diagnosis of pericardial effusion. Am. J. Cardiol., 26:475, 1970. 15. Fowler, N., and Manitsas, G.: Infectious pericarditis. Prog. Cardiovasc. Dis., 16:323, 1973. 16. Galant, S. P., Groncy, C. E., and Shaw, K. C.: The value of pulsus paradoxus in assessing the child with status asthmaticus. Pediatrics, 61 :46, 1978. 17. Gelfman, R., and Levine, S. A.: The incidence of acute and subacute bacterial endocarditis in congenital heart disease. Am. J. Med. Sci., 204:324, 1942. 18. Gersony, W. M., and Hayes, C. J.: Bacterial endocarditis in patients with pulmonary stenosis, aortic stenosis, or ventricular septal defect. Circulation, 56:84, 1977. 19. Gersony, W. M., and McCracken, G. H., Jr.: Purulent pericarditis in infancy. Pediatrics, 40:224, 1967. 20. Gersony, W. M., and Nadas, A. S.: Therapeutic principles for Streptococcus viridans infections: Recurrent bacterial endocarditis in a child with congenital heart disease. Pediatrics, 35: 704, 1965. 21. Golinko, R. J" Kaplan, N., and Rudolph, A. M.: The mechanism of pulsus paradoxus during acute pericardial tamponade. J. Clin. Invest., 42:249,1963. 22. Gould, M. S. H., and Picton, D. C. N.: The gingival condition of congenitally cyanotic individuals. Brit. Dent. J., 109:96, 1969. 23. Greenwood, R. D., Rosenthal, A., Cassady, R., et al.: Constrictive pericarditis in childhood due to mediastinal irradiation. Circulation, 50:1033,1974. 24. Hirschman, S., and Hammer, G.: Coxsackie virus myopericarditis: A microbiological and clinical review. Am. J. Cardiol., 34:224, 1974. 25. Holt, J. P.: The normal pericardium. Am. J. Cardiol., 26:455, 1970.
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26. Johnson, R. T., Portnoy, B., Rogers, N., et al.: Acute benign pericarditis. Arch. Intern. Med., 108:823, 1961. 27. Johnson, D. H., Rosenthal, A., and Nadas, A. S.: A forty year review of bacterial endocarditis in infancy and childhood. Circulation 51:581, 1975. 28. Kaplan, E. L.: Infective endocarditis in the pediatric age group. An overview. In Kaplan, E. L., Taranto, A. V. (eds.): Infective Endocarditis. An American Heart Association Symposium, Dallas, 1977, p. 5l. 29. Kaplan, E. L., Rich, H., Gersony, W. M., et al.: A.H.A. cooperative study of the occurrence of infective endocarditis. Circulation, 56 (Supp!.): (Part II) 1977, pp. III-39. 30. Karchmer, A. W., and Swartz, M. N.: Infective endocarditis in patients with prosthetic heart valves. In Kaplan, E. L., and Taranto, A. V. (eds.): Infective Endocarditis. An American Heart Association Symposium, Dallas, 1977, p. 58. 31. Kaye, D.: Prophylaxis against bacterial endocarditis: A dilemma. In Kaplan, E. L., and Taranto, A. V. (eds.): Infective Endocarditis. An American Heart Association Symposium, Dallas, 1977, p. 67. 32. Kelson, S. R., and White, P. D.: Notes on 250 cases of subacute bacterial (streptococcal) endocarditis studied and treated between 1927 and 1939. Ann. Intern. Med., 22:40, 1945. 33. Nelson, D. L., Blaese, R. M., Strober, W., et al.: Constrictive pericarditis, intestinal lymphangiectasia, and reversible immunologic deficiency. J. Pediat., 86:548, 1975. 34. Okoromo, E. 0., Perry, L. W., and Scott, L. P.: Acute bacterial pericarditis in children: Report of 25 cases. Am. Heart J., 90: 709, 1975. 35. Phair, J. P., and Tan, J. S.: Therapy of Streptococcus viridans endocarditis. In Kaplan, E. L., and Taranto, A. V. (eds.): Infective Endocarditis, An American Heart Association Symposium, Dallas, 1977, p. 55. 36. Plauth, W. H., Jr, Waldmann, T., Wochner, R. D., et al.: Protein-losing enteropathy secondary to constrictive pericarditis in childhood. Pediatrics, 34 :636, 1964. 37. Rosenthal, M., and Nadas, A.: Infective endocarditis in infancy and childhood. In Rahimtoola, F. H. (ed.): Infective Endocarditis. New York, Grune and Stratton, Inc., 1977, pp. 149-178. 38. Shabetgi, R., Fowler, W., and Fenton, J.: Restrictive cardiac disease: Pericarditis and the myocardiopathies. Am. Heart J., 69:271, 1965. 39. Shabetai, R., Fowler. N. 0., and Guntheroth, W. G.: The hemodynamics of cardiac tamponade and constrictive pericarditis. Am. J. Cardio!', 26:481, 1970. 40. Shah, P., Singh, W. S. A., Rose, V., et al.: Incidence of bacterial endocarditis in ventricular septal defects. Circulation, 34:127, 1966. 41. Somerville, W.: Constrictive pericarditis: With special reference to the change in natural history brought about by surgical intervention. Circulation, 37 and 38 (Supp!. V): V-102, 1968. 42. Speck, W. T., Hurwitz, G. A., and Keller, G. B.: Transient bacteremia in periatric patients following dental manipulation. Am. J. Dis. Child., 121 :286, 1971. 43. Spodick, D. H.: Acute cardiac tamponade: Pathology, physiology, diagnosis and management. Prog. Cardiovasc. Dis., 10:64, 1967. 44. Strauss, A. W., Santa-Maria, M., and Goldring, D.: Constrictive pericarditis in children. Am. J. Dis. Child., 129:822, 1975. 45. Surawicz, E., and Lasseter, K. C.: Electrocardiogram in pericarditis. Am. J. Cardiol., 26:271, 1970. 46. Van Reken, D., Strauss, A., Hernandez, A., and Feigin, R. D.: Infectious pericarditis in children. J. Pediat., 85: 165, 1974. 47. Vignola, P. A., Pohost, G. M., Curfman, G. D., et a!.: Correlation of echocardiographic and clinical findings in patients with pericardial effusion. Am. J. Cardio., 37: 701, 1976. 48. Viola, A. R.: The influence of pericardiectomy on the hemodynamics of chronic constrictive pericarditis. Circulation, 48: 1038, 1973. 49. Walker, W. J., Gonzalez, E. G., Hall, R. J., et al.: Interventricular septal defect. Analysis of 415 catheterized cases, ninety with serial hemodynamic studies. Circulation, 31 :54, 1965. 50. Washington, J. A., II: Blood culture techniques in the diagnosis of infective endocarditis. In Kaplan, E. L., and Taranto, A. V. (eds.): Infective Endocarditis. An American Heart Association Symposium, Dallas, 1977, pp. 44. 51. Werner, A. S., Cobbs, C. G., Kaye, D., et al.: Studies on the bacteremia of bacterial endocarditis. J. A. M. A., 202:199, 1967. 52. Zakrewski, T., and Keith, J. D.: Bacterial endocarditis in infants and children. J. Pediat., 67:1179, 1965. Division of Pediatric Cardiology Babies Hospital Columbia-Presbyterian Medical Center New York, New York 10032
Infective Endocarditis and Diseases of the Pericardium
Welton M. Gersony, M. D}' and Allan J. Hordof, M. D.t
INFECTIVE ENDOCARDITIS Infective endocarditis is still a significant cause of morbidity and mortality among children and adolescents, despite advances in the management of the disease with antimicrobial agents and the widespread advocacy of prophylactic measures. Our inability to eradicate infective endocarditis by prevention or early treatment stems from several factors: the nature of the infecting organisms has changed over the years: physicians, dentists, and the public are not sufficiently aware of the threat of infective endocarditis and the preventive measures which are available; diagnosis may be difficult and thus delayed; and special risk groups have emerged which include an increasing number of narcotics abusers, survivors of cardiac surgery, and patients with low resistance to infection who require intravascular catheters. Infective endocarditis is common enough and serious enough so that pediatricians should be aware of its potentially severe effects on their patients. Unfortunately, the information which is available regarding the risks of contracting the disease remains rather scanty. Furthermore, recommendations for prevention are controversial, since they are based almost strictly on empiricism rather than the results of ':'Professor of Pediatrics, College of Physicians and Surgeons of Columbia University; Director, Division of Pediatric Cardiology, Babies Hospital, Columbia-Presbyterian Medical Center, New York, New York t Assistant Professor of Pediatrics, College of Physicians and Surgeons of Columbia University; Director, Pediatric Intensive Care Unit, Babies Hospital, Columbia-Presbyterian Medical Center, New York, New York
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controlled randomized studies. Despite these problems, there is no doubt that infective endocarditis either can be prevented; or if diagnosis and treatment are approached rationally and meticulously, the disease and many of its complications can be managed successfully.
Incidence The number of children admitted to large medical centers with infective endocarditis is reported to have increased in recent years, but it is difficult to be certain whether this represents a real increase in the prevalence of the disease in the overall population. The infection is seen most often as a complication of congenital or rheumatic heart disease, but can also occur in children with normal hearts (Table 1). G. K. 27. 28.;;2 The disease is extremely rare in infancy.27, 28 Recently reported increases in incidence appear to be mostly manifest in the congenital heart disease group, as might be expected since more patients who remain susceptible to the infection are surviving cardiac surgeryY' 28 A number of these individuals have intracardiac protheses. Although reflected primarily in adult incidence figures, infective endocarditis among narcotics users and patients with chronic illness is also being reported more frequently in the pediatric population. 29 The incidence of infective endocarditis related to specific heart defects has been relatively well defined. In general, patients who have a lesion which is associated with high velocity of blood ejected into a chamber or vessel are most susceptible to the infection. Vegetations usually form at the site of the endocardial or intimal erosion which results from the turbulent flow. Children with ventricular septal defect, leftsided valvular disease, and systemic-pulmonary arterial communications are at the highest risk for developing infective endocarditis, whereas, at the other extreme, a very low incidence is reported in secundum atrial septal defect, a lesion which is characterized by low velocity flow across the intra atrial communication. 27 The majority of studies regarding prevalence of endocarditis have provided only estimations since data are most often reported retrospectively on the basis of hospital admissions,27. 49 post mortem series,t7 or population studies,5, 40 rather than from controlled prospective observations. Furthermore, there has been little information available regarding the effect of cardiac surgery on the incidence of infective endocarditis in children with congenital heart disease. Recently, the cooperative study on the Natural History of Aortic Stenosis, Pulmonary Stenosis and Ventricular Septal Defect (NHS) has reported data from a controlled, strictly defined pediatric population which was collected over a period of 4 to 15 years. 18 From this study, an accurate assessment of the incidence of infective endocarditis among patients with these common defects was obtained, and the effects of surgery were systeII1atically evaluated. ~The incidence data from the NHS are summarized in Table 2. -Pulmonary stenosis was associated with an extremely low incidence of infective endocarditis at the six medical centers involved in the study, (0.211000 pt. yrs.) representing one case in 4648 patient years, whereas patients with aortic stenosis and ven-
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Table 1.
Underlying Heart Disease in Children with Infective Endocarditis
Congenital heart disease Tetralogy of Fallot Ventricular septal defect Aortic stenosis Patent ductus arteriosus Other Rheumatic heart disease No cardiac abnonnalities
78% 24% 16% 8% 7% 23% 14% 8%
tricular septal defect were more susceptible to the infection. Aortic valvotomy did not protect against endocarditis over the years following surgery; rather the incidence appeared to increase. This is most likely explained on the basis of residual deformities of the aortic valve. In contrast, successful repair of ventricular septal defect appeared to decrease significantly the long-term susceptibility to infective endocarditis. Only one patient in the series with a documented closed defect developed the disease during the observation period. A recent survey indicates that "late" infective endocarditis in adults with prosthetic valves is a major complication among these patients.30 The increasing use of valve replacements and valved conduit repairs in children with complex heart disease may lead to a larger number of cases of such infections. At the present time, palliative systemic to pulmonary shunts is the surgical procedure most associated with a high incidence of infective endocarditis in the pediatric age range. 2B
Predisposing Events In approximately 30 per cent of cases of infective endocarditis, a predisposing factor is recognized. lB. 2B A surgical or dental procedure can be implicated in approximately two-thirds of the cases in which a potential source of bacteremia is identified. Dental procedures are the major threat for infective endocarditis emerging from a more or less routine event in everyday life - a visit to the dentist. Although tranTable 2. Incidence of Infective Endocarditis among Children with Ventricular Septal Defect, Aortic Stenosis, and Pulmonary Stenosis (Natural History Study) DEFECT
RATE PER 1000 RISK BY AGE RISK BY AGE P PT.YEABS 30 YRS. (MEDICAL) 30 YRS. (POSTSURGICAL) VALUE
Ventricular septal defect Aortic stenosis Pulmonary stenosis
1.5 1.8 0.21:
9.7% 1.4% 0.9%
2.0%t 7.4%
'Medical vs. surgical risk. tIncludes patients with residual defects. !Pulmonary stenosis vs. aortic stenosis or ventricular septal defect (p < .01). ns = not Significant.
.05 ns ns
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sient bacteremia after dental manipulation is less likely in normal children than in adults, presumably due to the lesser degree of peridontal disease,42 the incidence is still striking. Furthermore, dental hygiene is poor in children with heart disease, especially in those with lesions resulting in cyanosis. 22 Other events which may lead to infective endocarditis include tonsillectomies and other upper respiratory surgery, bronchoscopy, urologic surgery, intravenous alimentation, burns, and ventriculovenous shunts for management of hydrocephalusY The occurrence of infective endocarditis directly following cardiac catheterization or heart surgery is relatively low. The Natural History Study provides prospective data in this regard. 18 Only one case of infective endocarditis was considered to have definitely occurred as the direct result of cardiac catheterization among the entire series of 2420 patients with ventricular septal defect, aortic stenosis, and pulmonary stenosis, most having been catheterized on two occasions. Two patients developed infective endocarditis within 4 months of cardiac surgery during 402 patient years of observation. However, despite this encouraging data, on the basis of the frequency of the performance of these procedures at a large number of hospitals, cardiac surgery, and to a lesser extent, cardiac catheterization, rank high on the list of significant antecedent events which have been reported prior to the onset of infecti ve endocarditis. 28
Etiology Streptococcus viridans remains the most common agent responsible for infective endocarditis (approximately 50 per cent of the cases) but its predominance has been decreasing in recent years (Table 3).6.8.27.28.52 Staphylococcal endocarditis has become more common over the past two decades, and is now estimated as being responsible for almost one-third of the cases. Other organisms, including fungal agents, cause endocarditis less frequently, and in approximately 10 per cent of cases, blood cultures are negative. No relationship exists between the infecting organism and the type of congenital defect, duration of the illness, or age of the child. However, staphylococcal endocarditis is more common in patients who do not have underlying heart disease. Diagnosis There is almost always some delay in the diagnosis of infective endocarditis, since the early symptoms and signs of the disease are usually mild and nondescript, especially when Streptococcus viridans is the infecting organism. Prolonged fever without other manifestations, persisting for as long as several months, may often be the only medical history which can be elicited. Depending on the virulence of the agent, the subsequent findings may include signs of embolization, changes in the cardiac examination, and splenomegaly. Laboratory data include evaluation of the sedimentation rate, leukocytosis, and microscopic hematuria. Echocardiography and/or sector scan have been utilized to document the presence and specific location of vegeta-
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Table 3. Causative Organisms of Infective Endocarditis in Children ORGANISM
PER CENT
Streptococcus viridans Staphylococci Streptococcus fecalis Beta streptococci Other organisms No agent isolated
46 32 4 3 4 11
tions,37 but these modalities cannot be expected to be helpful in the early phases of the disease. In most instances, a specific diagnosis will depend on positive blood cultures. Early diagnosis requires the physician to consider the presence of infective endocarditis in any child with heart disease who has unexplained fever for more than a few days. Blood cultures must be drawn even if the child feels well and has no other physical findings. Three separate blood collections should be obtained after careful preparation of the phlebotomy site. Contamination is extremely misleading since bacteria found on the skin may themselves cause infective endocarditis. The timing of collections is not especially important, because bacteremia can be expected to be relatively constant. In 90 per cent of cases of endocarditis, the etiologic agent is recovered from the first two blood cultures;51 therefore further blood drawing should be deferred for two or three days, until the results of the initial cultures are known.
Mortality and Complications In the pre-antibiotic era, infective endocarditis was a fatal disease. After a marked improvement in the 1950's, the percentage of survivals continues to increase, but at a slow rate. Mortality remains at 20 to 25 per cent in recent seri.es. Complications occur in 50 to 60 per cent of children with documented infective endocarditis, 18.27.28,37 the most common being cardiac failure due to vegetations involving the aortic or mitral valve. Myocardial abscesses and toxic myocarditis may also lead to congestive heart failure but without characteristic changes in auscultatory findings. Systemic emboli, often with central nervous system manifestations, are a major threat in patients with infective endocarditis, superimposed on left heart or aortic lesions. Pulmonary emboli are most often recognized in children with ventricular septal defect or tetralogy of Fallot, although massive life-threatening pulmonary embolization is extremely rare. Mycotic aneurysms, ruptured sinus of Valsalva, obstructive valve disease secondary to large vegetations, acquired ventricular septal defect, and heart block as a result of involvement of the specialized conduction system, all have been reported as a result of infective endocarditis. 37 Management Antibiotic therapy should be instituted immediately upon making
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the diagnosis of infective endocarditis. When virulent organisms are responsible, small delays may result in progressive endocardial damage and a greater likelihood of severe complications. The choice of antibiotics, method of administration, and length of treatment are outlined in Table 4. The principles of management are relatively simple; high serum bactericidal levels must be maintained for an adequate length of time in order to eradicate organisms that are growing in relatively inaccessible avascular vegetations. From 5 to 20 times the minimum in vitro inhibiting concentration must be produced at the site of infection in order to destroy bacteria growing at the core of these lesions. ' ° Several weeks are required for a vegetation to organize completely; thus therapy must be continued until this occurs, so that recrudescence can be avoided. A total of 4 to 6 weeks of treatment is recommended, with serumcidal levels by tube dilution of at least 1:8 prior to administration of a subsequent dose of antibiotic. 20 Depending on the clinical response and laboratory studies, antibiotic therapy may require modification, and in some instances more prolonged treatment is required. With highly sensitive Streptococcal viridans infections, shortened regimens including oral penicillin have been recommended by some authors. 35 Bed rest should be instituted and may be extended if congestive heart failure occurs. Similarly, digitalis, restriction of sodium, and diuretic therapy should be utilized if and when indicated. Surgical intervention during the course of infective endocarditis has become an integral part of management in cases in which severe aortic or mitral valve involvement leads to intractable heart failure. Rarely, mycotic aneurysms or rupture of aortic sinuses require emergency operation. Although antibiotic therapy should be administered for as long as possible prior to surgical intervention, active infection should not be a contraindication if the patient is critically ill as a result of critical hemodynamic deterioration from infective endocarditis. Removal of vegetations, and in some instances, valve replacement, may be life-saving, and sustained antibiotic administration will most often prevent re-infection. Successful late surgical intervention has been reported in children with infective endocarditis who have been unresponsive to treatment and in patients who have shown evidence of continued embolic phenomenon. 37 Replacement of infected prosthetic valves carries a higher risk, but is necessary in refractory cases.
Prophylaxis Antimicrobial prophylaxis prior to and after various procedures is considered to be essential in a prevention program designed to reduce the incidence of infective endocarditis in susceptible patients. 9 However, it is difficult to evaluate the results of preventive regimens when the risks are extremely low for any single procedure. For example, it is estimated that one case of endocarditis can be expected for every 533 tooth extractions,32 and a lesser frequency would be anticipated for other forms of dental manipulation. However, considering the number of such procedures, prophylaxis along with proper general dental care
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Table 4. Treatment of .Infective .Endocarditis DURATION ETIOLOGIC AGENT
Streptococcus viridans
DOSAGE
ROUTE
OF THERAPY
300,000 units/kg/day every 4 hours or up to 20 million units'
IV
4 to 6 wks.
Streptomycin t
30 mg/kg/day every 12 hours
1M
2 wks
Penicillin G
300,000 units/kg/day every 4 hours or up to 20 million units':'
IV
6 wks
200 mg/kg/day every 4 hours
IV
6 wks
Gentamicin
4 to 6 mg/kg/day every 8 to 12 hours
IV
6 wks
Penicillin G
300,000 units/kg/day every 4 hours or up to 20 million units'
IV
6 to 8 wks
Oxacillin or Nafcillin or Methicillin!
200 mg/kg/day every 4 to 6 hours
IV
6 to 8 wks
Gentamicint
4 to 6 mg/kg/day every 8 to 12 hours
IV
2 wks
Vancomycin
50 mg/kg/day every 6 hours
IV
6 to 8 wks
Penicillin G
300,000 units/kg/day every 4 hours or up to 20 million units'
IV
6 to 8 wks
200 mg/kg/day every 4 to 6 hours
IV
6 to 8 wks
4 to 6 mg/kg/day every 8 to 12 hours
IV
6 to 8 wks
DRUG
Penicillin G
+
Streptococcus fecalis
or Ampicillin
+
Staphylococcus aureus Penicillin sensitive
Penicillin resistant
+
Methicillin resistant
Unknown agent
+ Oxacillin
+ Gentamicin
"For relatively resistant organisms. t Addition of aminoglycoside advocated by some centers. tLeast preferred.
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and oral hygiene almost certainly will decrease the risk of infective endocarditis in susceptible individuals. Vigorous treatment of sepsis and local infections, and careful asepsis during cardiac surgery and catheterization will also contribute to a reduction in the incidence of infective endocarditis. Recommendations for specific antibiotic regimens for prevention of infective endocarditis under various circumstances have been published under the auspices of the American Heart Association and are readily available to physicians and dentists.!) However, some authorities question the effectiveness of current prophylactic regimens and suggest that modifications should be made, based on a better definition of the high-risk procedures and the susceptible patients. 31 It is generally agreed that prophylaxis is not necessary after ligation and division of patent ductus arteriosus, or closure of an uncomplicated secundum atrial septal defect. The low incidence of infective endocarditis with secundum atrial septal defect prior to surgery; pulmonary stenosis, either unoperated or after repair; and after successfully closed ventricular septal defect, suggests that recommendations concerning prophylaxis in these specific situations may require reappraisal. Children most prone to infective endocarditis and who require the most protection are those with cyanotic heart disease with or without palliative shunts, mitral valve deformities, aortic stenosis and/or insufficiency, and prosthetic valves or conduits. Antimicrobial prophylaxis is practical only for patients with known heart disease after a well defined potential predisposing event, and even then, protection against nonstreptococcal disease is marginal. An approximation of the percentage of episodes potentially preventable by prophylaxis in children can be calculated by the following equation (modified from Kaye)31 [.90 (underlying heart disease) x .20 (identifiable predisposing event) x .55 (potential streptococcal infection) = 12%]. Considering this relatively low estimate of protected patients, as well as an unknown but probably significant incidence of poor compliance, it is not surprising that the actual results of prophylaxis are difficult to assess. Because antimicrobial prophylaxis cannot be offered in the absence of a possible predisposing event, and since the disease may become established in susceptible patients despite prophylaxis, complete prevention of infective endocarditis is not possible. Thus, pediatricians must remain alert to the likelihood of the disease occurring in their patients with heart disease. Vigorous efforts must be undertaken to make a prompt diagnosis when clinical events indicate that a high degree of suspicion is warranted. It cannot be overemphasized that early diagnosis is extremely important in order to reduce mortality and serious complications from infective endocarditis.
DISEASES OF THE PERICARDIUM The spectrum of diseases of the pericardium can range from a mild inflammatory reaction resulting in little or no discomfort or dis-
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ability, to a rapidly progressive virulent process which, if not properly managed, can result in death. In many instances, the involvement of the pericardium is only one manifestation of a more generalized illness. The prominence of the pericardial component will vary, depending on the disease entity. In other patients, pericardial involvement occurs as an isolated process with no evidence of systemic disease. Major entities that involve the pericardium are: infectious: viral or acute benign, bacterial, tuberculous, fungal, parasitic; acute rheumatic fever; rheumatoid arthritis; lupus erythematosus; uremia; neoplastic disease; radiation; thalassemia; trauma; pericardial cyst; postpericardiotomy syndrome; and chronic constrictive.
Pathophysiology of Pericarditis Pericardial inflammation results in an accumulation of fluid in the pericardial space. The nature of the fluid varies, depending on the etiology of the pericarditis and may be serous, fibrinous, purulent, or hemorrhagic. The major concern in the management of a child with pericarditis is the occurrence of cardiac tamponade, since this can be a lifethreatening emergency. In a healthy child there is no more than 10 to 15 ml of fluid found in the pericardial space, whereas in an adolescent with pericarditis, in excess of 1000 ml of fluid may accumulate. The clinical course depends on a number of factors: the state of the myocardium, the nature of the fluid, the rate of the fluid accumulation, and the pressure-volume characteristics of the pericardial space. For every increment of fluid accumulation, there is an increase in intrapericardial pressure (Fig. 1). Once this reaches a critical level, there is a rapid rise in pressure culminating in severe cardiac compression. 25 The hemodynaInic consequences of cardiac tamponade is inhibition of ventricular filling during diastole, elevated systemic and pulmonary venous pressures, and, if untreated, eventual compromised cardiac output and shock. 39. 43 Diagnosis The first symptom of pericardial disease is often precordial pain. The major complaint is that of a sharp, stabbing sensation over the left chest, shoulder and back, exaggerated by lying and relieved by sitting, particularly when leaning forward. Since there is no sensory
... 0:
:> (/) (/)
Figure 1. Intrapericardial pressure - volume curve. For every increment of fluid accumulation there is an increase in intrapericardial pressure. When the intrapericardial volume increases from point A to point B there is a marked increase in intrapericardial pressure since this corresponds to a point on the steep portion of the curve.
... 0:
a.
'«0
°i ~ E uii: ...a. «
....0:
;!;
A INTRAPERICARDIAL VOLUME (mil
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innervation of the pericardium, the pain is most likely due to diaphragmatic and pleural irritation. Cough and fever may well accompany the chest discomfort. The presence of systemic symptoms or signs associated with other organ systems depend on the basic etiology of the pericarditis. On physical examination, many of the findings relate to the degree of fluid accumulation in the pericardial sac. The presence of a friction rub is helpful, but may be a late sign in acute pericarditis, becoming apparent only after the effusion is reduced. Narrow pulses, quiet precordium, distant heart sounds, neck vein distention, and paradoxical pulse suggest significant fluid accumulation. The documentation of greater than 20 mm Hg of paradoxical pulse in a child with pericarditis is a reliable indicator of the presence of cardiac tamponade, 10 to 20 mm Hg being equivocal. The method by which this important measurement is obtained deserves reiteration. There is normally a slight decrease in systolic arterial pressure during inspiration. With cardiac tamponade this normal phenomenon is exaggerated, probably due to decreased left heart filling with the inspiratory phase of respiration. 21 In order to determine the degree of pulsus paradoxus, one first measures the exact systolic blood pressure during normal expiration. The manometer is then slowly allowed to fall. The point when the systolic pressure is heard equally well during inspiration and expiration is then recorded. The difference between the two determinations represents the degree of paradox. Significant pulsus paradoxus is seen in conditions other than cardiac tamponade. It may be present with severe dyspnea of any origin and is not infrequent in patients who have emphysema or asthma, It; as well as children who are being ventilated with a positive pressure respirator. In these patients the paradoxical pulse is due to a marked increase in intrathoracic pressure. Determination of the etiology of paradoxical pulse in a child on a ventilator after cardiac surgery may be difficult to assess, since in this situation more than one potential mechanism is possible.
Laboratory Data The specific laboratory findings in pericarditis will depend on the underlying disease. However, electrocardiography, chest x-ray films, and echocardiography are important in the diagnosis of all types of pericarditis. ELECTROCARDIOGRAM. The effects of pericarditis on the electrocardiogram are multiple. Low voltage of the QRS complexes results from a damping effect of pericardial fluid. Pressure on the myocardium by fluid or exudate produces a current of injury that results in mild elevation of S-T segments. Generalized T wave inversion occurs as a consequence of associated myocardial inflammation. The S-T segment and T wave changes with pericarditis are more generalized than those seen with myocardial infarction, and the S-T segment elevations tend to precede the T wave changes. There may be an interval when the ECG is in a transitional phase and appears to be normal. This may
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occur during the acute phase of the illness, prior to diagnosis. In some instances, clear cut abnormalities are never identified. 45 CHEST X-RAY FILMS. A relatively large pericardial effusion must be present in order to cause an enlarged cardiac shadow with the usual "water-bottle" configuration (Fig. 2). In most instances the lung fields are clear. With constrictive disease, the heart appears to be relatively small, and calcification may be present (Fig. 3). II ECHOCARDIOGRAPHY. The echocardiogram has become one of the most sensitive techniques for evaluation of the size and progression of pericardial effusions. 14 Normally, the pericardium is closely adherent to the epicardium and the two layers can only be narrowly separated by the ultrasound beam. In patients with pericardial effusion a clear echo free space is recorded between the epicardium and pericardium (Fig. 4). The posterior effusion is recorded behind the left ventricular epicardium and ends at the junction of the left ventricle and left atrium. An anterior effusion will be recorded between the chest wall and the anterior right ventricular wall. The presence of both an anterior and posterior effusion generally indicates that a large collection of fluid is present. False positives are rare in the hands of experienced echocardiographers. 11,47 Viral and Acute Benign Pericarditis Viral and acute benign pericarditis are considered together since most episodes of what is called acute benign pericarditis appear to follow or coincide with a viral illness. 7 , 26 Viruses recognized to cause pericarditis include Coxsackie B, influenza, ECHO, and adenovirus. 15 Most cases are relatively mild and recovery occurs within several weeks. However, in rare instances the patient may be severely ill and cardiac tamponade may ensue. For most patients only symptomatic therapy is indicated and the disease is self-liIniting. However, there is an interesting group of paFig. 2
Fig. 3
Figure 2. Chest x-ray film from a patient with a large pericardial effusion. Note the markedly enlarged cardiac image with relatively clear lung field. Figure 3. Chest x-ray film from a patient with chronic constrictive pericarditis. The heart is not enlarged in the anteroposterior view (left), Prominent calcification of the pericardium is seen best on the lateral projection (right),
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Figure 4. Echocardiogram from a patient with a large anterior and posterior pericardial effusion. The anterior effusion [----+] is shown as an echo free space between the chest wall and the anterior right ventricular wall (RVW). The posterior effusion [--+1 is the echo free space behind the left ventricular posterior wall (LVW).
tients, most often adolescents, in which acute benign pericarditis becomes a chronic relapsing illness. The major differential diagnosis in this type of problem is that of a collagen vascular disease. These patients respond dramatically to anti-inflammatory therapy with corticosteroids. Milder forms may be controlled with aspirin. The clinical course may be months or even one or two years, during which time the patients are dependent on drug therapy for suppression of the pericarditis. Ultimately, the patients improve and the prognosis appears to be good. The etiology is unclear, but most likely is related to a hypersensitivity reaction to a viral illness, and pericardial inflammation is not the precursor of a generalized disease. 15 On occasion, the clinical differential diagnosis between acute pericarditis and myocarditis may be difficult. Indeed, in patients with pericarditis, there is usually a myocardial inflammatory component, and the reverse is also true. What becomes crucial is to decide which process is dominant, since management is quite different; the former stressing anti-inflammatory treatment and urgent response to cardiac tamponade, and the latter requiring therapy for congestive heart failure. The echocardiogram is helpful in this regard, as it will allow visualization of large pericardial effusions, and can also indicate the presence of myocardial dysfunction. 24
Purulent Pericarditis Purulent pericarditis is most often associated with a bacterial infection such as pneumonia, epiglotittis, meningitis, or osteomyelitis. Initially the diagnosis of pericardial involvement may be obscured by signs and symptoms of the primary infection. However, once the purulent process is established, the course is fulminant, terminated by acute cardiac tamponade and death. Open pericardial drainage is mandatory, along with appropriate intravenous antibiotics. Although closed pericardia! aspiration provides exudate for diagnostic purposes, and may be life-saving in the face of severe cardiac compression, it should not be considered to be final therapy. Without open drainage, tamponade will recur, since with large effusions only a small reaccumulation of pericardial fluid may markedly increase intrapericardial pressure (Fig. 1). Management with open pericardial drainage has significantly increased survival in patients with this disease. 19 The most common organisms to be implicated in purulent pericarditis are Staph-
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ylococcus aureus, Hemophilus influenza type B, and Neisseria meningitidis. 19, :34, 46 Tuberculous pericarditis rarely occurs in children outside of underdeveloped countries. Extensive treatment with antituberculous chemotherapy is required, and late constriction may occur.I5 Acute Rheumatic Fever Pericarditis occurs in acute rheumatic fever as a component of pancarditis. It should be emphasized that rheumatic pericarditis occurs with acute valvulitis, and a murmur of mitral and/or aortic regurgitation will be audible. If there is no evidence of acute valvulitis, another cause must be considered. Pericarditis appears to respond to therapy with steroids along with the other manifestation of acute rheumatic pancarditis. Cardiac tamponade is extremely rare. Rheumatoid Arthritis Pericarditis is not an uncommon manifestation of rheumatoid arthritis in children. Most often, pericardial inflammation is associated with the other signs of rheumatoid arthritis. However, rarely, pericarditis may be the only manifestation of rheumatoid arthritis and precede the onset of arthritis by months or even years. Differentiation of rheumatoid pericarditis from that seen with other collagen vascular disease, particularly lupus erythematosus, may be difficult. Treatment consists of steroids or salicylates, and may be needed on a long-term basis to suppress the disease process. 4 Uremia Uremic pericarditis occurs only in the presence of prolonged severe renal failure, and results from chemical irritation of the pericardium secondary to the metabolic abnormalities. Uremic pericarditis has been primarily a feature of end stage chronic renal disease and in most instances is an incidental part of the clinical picture. However, with the advent of chronic hemodialysis, uremic pericarditis has been recognized as a more chronic problem, culminating in cardiac tamponade. Pericardial effusion has also been implicated in the etiology of recurrent hypotension during hemodialysis. If adequate relief of uremic pericarditis does not occur with hemodialysis, pericardiectomy has been recommended. 1 Neoplastic Disease Neoplastic pericardial involvement is seen in patients with Hodgkin's disease, lymphosarcoma, and leukemia and results from direct neoplastic invasion of the pericardium. Cardiac tamponade or constriction may occur late in the course of the illness. Rarely, pericardial infiltration is the initial manifestation of neoplastic disease, and the basic diagnosis can be made by examination of the pericardial fluid for neoplastic cells. 2 ,:J In addition to showing signs of direct invasion of the pericardium, patients with malignancy may develop pericarditis as a result of radiation therapy to the mediastinum. This manifestation may be related to the radiation dose and to the technique utilized. 23
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Postpericardiotomy Syndrome
Postpericardiotomy syndrome is characterized by fever, chest pain, pleural and pericardial effusion, and fluid retention. This manifestation is seen 1 to 2 weeks following open heart surgery in approximately 15 per cent of postoperative patients. Recent evidence indicates that the syndrome is a nonspecific hypersensitivity reaction to trauma to the pericardium and epicardial surface of the heart. 12 High titers of anti-heart antibody have been reported to correlate with clinical signs of the syndrome. 13 In most patients, postpericardiotomy syndrome is a relatively short illness, and affected children will generally respond well to antiinflammatory therapy with aspirin or corticosteroids. Treatment is maintained for 1 to 3 months, but recurrences may be seen as long as one year postoperatively, requiring reinstitution of therapy. Constrictive Pericarditis Constrictive pericarditis represents a special problem both in terms of the clinical picture and the differential diagnosis. Predisposing pericardial disease include purulent pericarditis, tuberculous pericarditis, acute benign or viral pericarditis, mediastinal irradiation for intrathoracic malignancy, neoplastic invasion of the pericardium, and trauma. In most instances constriction occurs months or years after the initial insult, but occasionally may be an acute, rapidly progressive process. Despite the numerous known etiologies, constrictive pericarditis most often occurs without a preceding illness or generalized systemic disease. 44 The clinical manifestations of this disease occur as a result of impairment of diastolic ventricular filling, compromise of myocardial contractility, and resultant depression of cardiac function. 39 The prominent physical findings, hepatomegaly and ascites, may appear to be out of proportion to the other signs and symptoms, thus mimicking chronic liver disease. However, liver function studies are only mildly abnormal, and careful physical examination will reveal other sometimes subtle findings of constriction including neck vein distention, narrow pulses, quiet precordium, distant heart sounds, faint pericardial friction rub, and paradoxical pulse. Typical findings become apparent gradually, and thus may be easily overlooked. The auscultatory presence of an early pericardial knock and the appearance of calcification of the pericardium on chest x-ray films (Fig. 3) are the more obvious manifestations that are apparent when the disease is well established. Protein-losing enteropathy with hypoproteinemia and lymphopenia may be seen in association with constriction. 33 • 36 Constrictive pericarditis may be difficult to distinguish from chronic constrictive cardiomyopathy.38 Impairment of myocardial function occurs with both conditions. However, the myocardial disease of constrictive pericarditis is almost always reversible with pericardiectomy. At times, despite all efforts at differentiation, including echocardiography and cardiac catheterization, a definite diagnosis can only be made by exploratory thoractomy and direct examination of the pericardium.
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Surgical intervention is the only therapeutic modality in constrictive pericarditis. The surgical procedure of choice is radical pericardiectomy with decortication of the pericardium over a wide area of the heart to include the systemic and pulmonary veins. In most patients there is rapid response to surgical intervention, characterized by increased cardiac output and prompt diuresis. 41 • 48 Observing the dramatic improvement in the status of a chronically ill child with longstanding unsuspected constrictive pericarditis after proper diagnosis and treatment is a rewarding experience in medicine.
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26. Johnson, R. T., Portnoy, B., Rogers, N., et al.: Acute benign pericarditis. Arch. Intern. Med., 108:823, 1961. 27. Johnson, D. H., Rosenthal, A., and Nadas, A. S.: A forty year review of bacterial endocarditis in infancy and childhood. Circulation 51:581, 1975. 28. Kaplan, E. L.: Infective endocarditis in the pediatric age group. An overview. In Kaplan, E. L., Taranto, A. V. (eds.): Infective Endocarditis. An American Heart Association Symposium, Dallas, 1977, p. 5l. 29. Kaplan, E. L., Rich, H., Gersony, W. M., et al.: A.H.A. cooperative study of the occurrence of infective endocarditis. Circulation, 56 (Supp!.): (Part II) 1977, pp. III-39. 30. Karchmer, A. W., and Swartz, M. N.: Infective endocarditis in patients with prosthetic heart valves. In Kaplan, E. L., and Taranto, A. V. (eds.): Infective Endocarditis. An American Heart Association Symposium, Dallas, 1977, p. 58. 31. Kaye, D.: Prophylaxis against bacterial endocarditis: A dilemma. In Kaplan, E. L., and Taranto, A. V. (eds.): Infective Endocarditis. An American Heart Association Symposium, Dallas, 1977, p. 67. 32. Kelson, S. R., and White, P. D.: Notes on 250 cases of subacute bacterial (streptococcal) endocarditis studied and treated between 1927 and 1939. Ann. Intern. Med., 22:40, 1945. 33. Nelson, D. L., Blaese, R. M., Strober, W., et al.: Constrictive pericarditis, intestinal lymphangiectasia, and reversible immunologic deficiency. J. Pediat., 86:548, 1975. 34. Okoromo, E. 0., Perry, L. W., and Scott, L. P.: Acute bacterial pericarditis in children: Report of 25 cases. Am. Heart J., 90: 709, 1975. 35. Phair, J. P., and Tan, J. S.: Therapy of Streptococcus viridans endocarditis. In Kaplan, E. L., and Taranto, A. V. (eds.): Infective Endocarditis, An American Heart Association Symposium, Dallas, 1977, p. 55. 36. Plauth, W. H., Jr, Waldmann, T., Wochner, R. D., et al.: Protein-losing enteropathy secondary to constrictive pericarditis in childhood. Pediatrics, 34 :636, 1964. 37. Rosenthal, M., and Nadas, A.: Infective endocarditis in infancy and childhood. In Rahimtoola, F. H. (ed.): Infective Endocarditis. New York, Grune and Stratton, Inc., 1977, pp. 149-178. 38. Shabetgi, R., Fowler, W., and Fenton, J.: Restrictive cardiac disease: Pericarditis and the myocardiopathies. Am. Heart J., 69:271, 1965. 39. Shabetai, R., Fowler. N. 0., and Guntheroth, W. G.: The hemodynamics of cardiac tamponade and constrictive pericarditis. Am. J. Cardio!', 26:481, 1970. 40. Shah, P., Singh, W. S. A., Rose, V., et al.: Incidence of bacterial endocarditis in ventricular septal defects. Circulation, 34:127, 1966. 41. Somerville, W.: Constrictive pericarditis: With special reference to the change in natural history brought about by surgical intervention. Circulation, 37 and 38 (Supp!. V): V-102, 1968. 42. Speck, W. T., Hurwitz, G. A., and Keller, G. B.: Transient bacteremia in periatric patients following dental manipulation. Am. J. Dis. Child., 121 :286, 1971. 43. Spodick, D. H.: Acute cardiac tamponade: Pathology, physiology, diagnosis and management. Prog. Cardiovasc. Dis., 10:64, 1967. 44. Strauss, A. W., Santa-Maria, M., and Goldring, D.: Constrictive pericarditis in children. Am. J. Dis. Child., 129:822, 1975. 45. Surawicz, E., and Lasseter, K. C.: Electrocardiogram in pericarditis. Am. J. Cardiol., 26:271, 1970. 46. Van Reken, D., Strauss, A., Hernandez, A., and Feigin, R. D.: Infectious pericarditis in children. J. Pediat., 85: 165, 1974. 47. Vignola, P. A., Pohost, G. M., Curfman, G. D., et a!.: Correlation of echocardiographic and clinical findings in patients with pericardial effusion. Am. J. Cardio., 37: 701, 1976. 48. Viola, A. R.: The influence of pericardiectomy on the hemodynamics of chronic constrictive pericarditis. Circulation, 48: 1038, 1973. 49. Walker, W. J., Gonzalez, E. G., Hall, R. J., et al.: Interventricular septal defect. Analysis of 415 catheterized cases, ninety with serial hemodynamic studies. Circulation, 31 :54, 1965. 50. Washington, J. A., II: Blood culture techniques in the diagnosis of infective endocarditis. In Kaplan, E. L., and Taranto, A. V. (eds.): Infective Endocarditis. An American Heart Association Symposium, Dallas, 1977, pp. 44. 51. Werner, A. S., Cobbs, C. G., Kaye, D., et al.: Studies on the bacteremia of bacterial endocarditis. J. A. M. A., 202:199, 1967. 52. Zakrewski, T., and Keith, J. D.: Bacterial endocarditis in infants and children. J. Pediat., 67:1179, 1965. Division of Pediatric Cardiology Babies Hospital Columbia-Presbyterian Medical Center New York, New York 10032
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