Clinical Research Artical
 

Predictors of Embolic Events in Pediatric Infective Endocarditis
Rubina A Karatela, Gurmukh S. Sainani

Anita Saxena Neeraj Aggarwal Pankaj Gupta Rajnish Juneja Shyam S Kothari Ravi Math

Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Abstract

Background: Infective endocarditis is an uncommon disease in children, but is often associated with significant morbidity and mortality. Embolization of vegetation to systemic or pulmonary circulation is a major contributor to morbidity and mortality of infective endocarditis, its incidence in adults varies from 22% to 40%. Very little data exists on the incidence and predictors of embolisation in children. We analysed the clinical and echocardiographic data of 50 consecutive children admitted to our centre with infective endocarditis over a five year period to determine the predictors of embolization.
Methods: This was a retrospective study of children below 12 years of age, who were admitted in the ward with a diagnosis of infective endocarditis. Their demographic, clinical, hematological and echocardiographic data were analysed to look for predictors of embolic events. The details of treatment and course in the hospital were also recorded.
Results: The mean age was 6+/-3.6 years with a range from 4 months to 12 years. Congenital heart disease was the underlying diagnosis in 44 cases. Twenty three cases had undergone cardiac surgery earlier. Blood cultures were positive in only 19 cases (38%). Seven children grew fungus in their blood culture. Echocardiography revealed vegetation in all; the size of vegetation was > 10 mm in 18 cases and < 3 mm in 11. Clinically obvious embolisation occurred in 23 cases (46%), the size of vegetation was >10 mm in 13. Embolic events were more common when vegetation was present in the right sided valves or chambers (16/24, 66%). Embolic events were acutely fatal in 7 cases, 6 of these had vegetations which were >10 mm. Repeat echocardiography failed to show regression of vegetation size in 19 /23 cases with embolic events, as against 15/27 without embolic events. A total of 11 patients died. Thirteen patients underwent surgery, 9 within two weeks of treatment.
Conclusions: In our study, large vegetations (>10mm) at presentation and failure to diminish in size on treatment are predictors of embolisation. Vegetations on right side of the heart are more likely to embolise.

Introduction

Infective endocarditis is defined as an “endovascular microbial infection of intracardiac structures facing the blood including infections of the large intrathoracic vessels and of intracardiac foreign bodies”1 It is an uncommon disease in children, but its importance lies in the significant morbidity and mortality associated with the disease, need for prolonged parenteral antibiotic treatment and the potential complications including embolic events. Congenital heart disease is the most frequent underlying condition in pediatric population. Infective endocarditis in cases with rheumatic heart disease continues to be a significant problem, especially in developing countries with a high prevalence of rheumatic fever and rheumatic heart disease.

Despite advances in diagnosis and therapeutic strategies, the in-hospital mortality remains high at 16% -25% in various series on adult patients2-4. Recent data in children has reported a lower mortality with aggressive combination of antibiotic therapy and surgical intervention5-7. Embolic events, occurring in 20%-40%, contribute significantly to increased morbidity and mortality of infective endocarditis. Embolism occurs due to migration of cardiac vegetations into the major arterial beds including brain, spleen, lungs, peripheral limbs, kidneys and coronary arteries. In about 20% of cases, the embolism may be asymptomatic8. Embolic events have been related to the size of the vegetation, site of vegetation, underlying organisms and other factors.9-12. Data from adult series has demonstrated that risk of new embolism after initiation of therapy is much

Correspondence:Dr Anita Saxena, Professor of Cardiology, All India Institute of Medical Sciences, New Delhi 110029, India, Telephone: 91 11 2659486,1 Fax: 91 11 26588641
E-mail: [email protected]

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lower, varying from 6%-21%, with maximum risk in first 2 weeks of therapy9,11,13,14. There is very little data on risk and predictors of embolic events in children5,7,15. Despite the key role played by echocardiography in diagnosing infective endocarditis, its value for predicting embolic events has been questioned due to conflicting results by various authors. The objective of the present study was to study various factors, including echocardiographic parameters that may be predictive of embolic events in children with infective endocarditis.

Material and Methods

This was a retrospective study. Records of all consecutive children ≤ 12 years diagnosed to have infective endocarditis and admitted to our tertiary referral centre over a five year period were reviewed and analysed. Fifty children were diagnosed to have infective endocarditis, on the basis of Duke Criteria; these formed the study group. Total number of admissions during this period was 3150 giving a prevalence of infective endocarditis as 1.6% (1 in 63 of all admissions).

Data Collection
The following data were collected:

Demographic details: age, gender, underlying cardiac diagnosis, history and date of previous cardiac surgery if any, nature of treatment received before presentation to our centre, if any.
Clinical details: History and duration of fever, symptoms such as cough, breathlessness, hemoptysis, and pain in joints, chest or abdomen were noted. Record was also made of abnormal findings on examination like clubbing petechie, splenomegaly, neurological deficit, congestive heart failure.
Hematological investigations including hemoglobin, complete and differential blood counts, erythrocyte sedimentation rate, microscopic hematuria, C-reactive protein, blood cultures.
Other investigations such as ECG, X-ray chest, ultrasound abdomen, computerized tomography (if done).
Echocardiography: Number, size, and site of vegetations, myocardial abscess, aortic root abscess and torn valve leaflets. The maximum size of vegetation was used for analysis. If multiple vegetations were present, the size of largest vegetation was considered. Same details were noted for repeat echocardiographic examination done during hospital stay.
The nature of treatment taken, course in the hospital including complications like heart failure, arrhythmias, embolic events, need for emergency surgery, mortality.

RESULTS

A total of 50 children, age ≤ 12 years were seen during the five year period. The age ranged from 4 months to 12 years, with a mean of 6+3.6 years. There were 29 male patients (male to female ratio 1.3:1). Three patients were under one year of age. Congenital heart disease was the underlying diagnosis in 44 cases and rheumatic heart disease in three. In rest of three patients, no structural heart disease could be identified; all three were on prolonged intravenous antibiotic therapy for various reasons before developing infective endocarditis. Twenty three patients had undergone cardiac surgery earlier; in 21, surgery was performed more than six months ago.

Blood cultures were positive in only 19 of 50 cases (38%). Staphylococcus aureus was grown in six, streptococcus viridans in four, candida species in six, aspergillus, klebsiella (ESBL positive) and acinobacter in one case each. Of seven patients with fungal endocarditis, six were on previous long term antibiotic therapy. One culture negative child grew candida in urine and was successfully treated with amphotericin. Another four month child with negative blood culture and continuous fever after closure of ventricular septal defect was empirically treated with amphotericin successfully.

Echocardiography: Vegetations were present in all children on transthoracic echocardiography. Multiple vegetations at more than one site were seen in four cases. The size of vegetation was >10mm in 18, 3-10 mm in 21 and <3 mm in 11 patients. The various sites of vegetation are shown in the table. There were two instances of aortic root abscesses in association with bicuspid aortic valve.

Embolic Events
Clinically obvious embolic events occurred in 23 of 50 cases (46%). The sites of embolic events were cerebral in eight, lungs in eleven, limbs in two, and intestines in two patients. One case each had splenic and renal embolisation. More than one embolic event occurred in 2 cases.

Timing of embolic events: Embolic event was the presenting feature in seven of 23 patients. Embolic events on antibiotic therapy after admission were seen in 16. In 7 of these 16, embolic events occurred with in the first two weeks of therapy. Nine cases had embolic events beyond two weeks of therapy, only in two of these fever was continuing at the time of embolisation. Embolic events occurred in two stable patients after four weeks of apparent effective antibiotic therapy.

Size of vegetation on echocardiography: In cases with embolic events, the size of vegetation was >10 mm in 13 cases and 3-10 mm in 10 cases (table).


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Site of vegetation: Embolic events were more frequent in patients with right sided endocarditis as compared to left. Of the total 24 right sided endocarditis (vegetation over pulmonary or tricuspid valve or right ventricular outflow tract), 16 cases had embolic events (66%). On the other hand, only 6 cases had embolic events out of a total of 22 left sided endocarditis (27%). Three patients had endocarditis over the Dacron patch used for closing ventricular septal defect, none of these embolised. One child with uncorrected tetralogy of Fallot, had vegetations over aortic valve as well as pulmonary valve and developed cerebral embolism (table1).

Table

Embolic Events in Relation to Site and Size of Vegetations

Size of vegetation
          Number of cases

<3 mm
11

3-10 mm
21

> 10 mm
18

Total
50

Vegetations in left heart
          Embolic events

3
0

9
0

10
6

22
6

Vegetations in right heart
          Embolic events

4
0

12
9

8
7

24
16

Vegetation on both sides
         Embolic events

-
-

1
1

-
-

1
1

Vegetations on VSD patch
          Embolic events

           -
-

3
0

-
-

3
0

Total embolic events
  

0

10

13

23

Relation to type of microorganism: Embolic events occurred in 6 of 7 patients who grew fungus (candida or aspergillus) in their blood cultures, all these also had large vegetations (>10mm). Embolic event also occurred in the child who had candida growth in the urine and sterile blood cultures. The size of the vegetation was 4 mm in this child.

Course in the hospital: Embolic events were acutely fatal in 7 cases, in 6 of these the vegetation was >10mm. On repeat echocardiography during hospital stay, regression of vegetation size was seen in 16 of 50 patients. These included four cases with vegetations larger than 10 mm. Regression was seen in only 4 of 23 cases with embolic events as against in 12 of 27 who did not have an embolic event.

Surgical Intervention
Surgery was performed in 13 patients. Indications for surgery were hemodynamic instability and congestive heart failure (4), persistently large vegetation (3), aortic root abscess (3), aorta to right ventricular communication (1), ruptured mycotic aneurysm (1) and acute severe mitral regurgitation (1).  Nine of these 13 cases had to be operated early; with in 2 weeks of antibiotic treatment, either due to continuing fever with large vegetation or aortic root abscesses. Twelve of 13 patients survived, one died secondary to low cardiac output syndrome with multiorgan failure.

 

Mortality
A total of 11 patients died in the hospital (mortality 22%). Embolic events were responsible for mortality in 7 cases (cerebral in 3, pulmonary in 4). Other causes of death were severe congestive heart failure (1), ongoing sepsis with shock (1), cerebral hemorrhage (1). One patient died in the postoperative period as mentioned above.

Discussion

Embolic events are a frequent and life threatening complication of infective endocarditis, its incidence has varied from 18% to 31% in patients with congenital heart disease.5,7,16 In our series of 50 children, embolic event occurred in 46% (23/50). Since embolic events are associated with higher mortality and morbidity, there is need to identify patients who are at a higher risk for embolic complications and thereby a higher morbidity and mortality. In this study, we have analyzed factors which may predict the risk of embolisation.

Vegetation size
There is conflicting data on the relation of vegetation size, as determined by echocardiography, to the risk of embolic events. Some authors have reported an increased risk of embolic events in patients with large or mobile vegetations9,11,13,14,17. Others did not find such a correlation18-21. All these studies have been reported in adult population. There is no data in children on the relationship of size of vegetation by echocardiography with embolic events. Our study showed that larger vegetations (length >10mm) are more likely to be associated with embolic events. We also found that failure of regression of vegetation size on therapy was predictive of embolic events. Hence serial echocardiography during antibiotic treatment is useful and is recommended to decide for possible surgical intervention in an otherwise stable patient. According to the guidelines by ACC/AHA and ESC, there is no general consensus on this issue1,22 Surgery for vegetations in excess of 10mm with or without an embolic event is a class II b indication with level of evidence as C.

Vegetation site
In adult patients, there is data to suggest that location of the vegetation may also be a factor for predicting embolic events. Mitral vegetations have been associated with higher rates of embolisation than aortic vegetations (25% vs 10%, respectively)24. Others have also reported higher incidence of embolic events in mitral valve endocarditis10,11. However in the study by Thuny et al9 no such correlation could be found. In our study, which is in pediatric age group, where underlying cardiac conditions are different from those in adults, embolic events were more common with right sided vegetations than with left sided vegetations (16/24 vs 6/22 respectively).

 

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Type of Microorganism
Positive blood cultures were seen in only 38% in our study. There are reports that staphylococcus aureus and bovis, and fungal infections carry a higher risk of embolism regardless of vegetation size or its location8,25. In our study also 6 of 7 fungal vegetations embolised and 4 of these patients died. Two more cases with sterile blood cultures, but presumably fungal also had embolic events. We recommend repeated cultures of blood and urine for fungus, especially in those with ongoing fever despite antibiotic therapy. Typically fungal endocarditis has high mortality rates. We cannot comment on association of embolic events with other micro organisms due to the small numbers of positive blood cultures.

Surgical Intervention for Large Vegetation
Recent reports suggest that the mortality in infective endocarditis can be brought down by early surgical intervention27, however the type and optional timing of surgery are still debated and the practice varies from centre to centre. Surgery is usually indicated in cases of recurrent emboli. In one study, size of the vegetation was one of the reasons for surgery in 54% of cases of native valve infective endocarditis and in 25% of prosthetic valve endocarditis28. In children, these guidelines may not be valid as for the same size of vegetation, embolic events could result in far more catastrophic outcome than in adults. In our series also, first episode of clinical embolic event resulted in death in seven cases, not allowing time for surgery. Indications for surgery in children should be more liberal than in adults. Surgery was performed in 13 of 50 cases (26%) and 12 of these cases survived. In a previous study, from India, 43.2% of children died due to worsening cardiovascular status, septicemia or inability to offer emergency surgery29. Surgical option must be considered when large vegetations are detected. Failure of vegetation to diminish in size during clinically adequate therapy may also be an indication for early surgery.

Conclusion
In our study of 50 children with infective endocarditis, large vegetations (size >10mm), failure of vegetation to diminish in size on antibiotic therapy, vegetation on right side of the heart and fungal vegetations were more likely to embolise. An early and more aggressive surgical approach is recommended for such high risk cases. Our study confirms that good outcome with early surgery is possible even in developing countries if the child is referred early to a centre where facilities for surgery are available.

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