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Ann Thorac Surg 2001;72:39-43
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Recurrent infective endocarditis: a multivariate analysis of 21 years of experience

Accepted for publication April 5, 2001.

Address reprint requests to Dr Renzulli, via Aquila 144, 80143, Naples, Italy
e-mail: arenzul{at}tin.it
e-mail: renzulliattilio{at}usa.net

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. To evaluate which variables predict recurrence of endocarditis after surgical treatment, we reviewed our 21-year experience.

Methods. Between January 1979 and May 2000, 308 consecutive valve replacement procedures for infective endocarditis were performed in 271 patients. Univariate and multivariate time-related analyses were performed to retrospectively evaluate the role of the following variables in the development of recurrent postoperative endocarditis: gender, site of endocarditis, previous valve disease, drug abuse, diabetes, positive valve/blood cultures, sepsis, perivalvular involvement, previous embolic events, type of replacement device, and persistent postoperative fever.

Results. Clinical and echocardiographic follow-up was 97.36% complete, mean follow-up time was 53.2 ± 3.4 months. Recurrent endocarditis developed in 58 cases (22.5%). Variables predicting recurrence were prosthetic endocarditis (p = 0.00001), positive valve culture (p = 0.0039), and persistence of fever at the seventh postoperative day (p = 0.000001).

Conclusions. Correct protocols of antibiotic therapy guided by microbiology may reduce the incidence of recurrent endocarditis to allow for surgery on sterile tissues and to prevent prosthetic infection.

Recurrence rate is not affected by the choice of valve substitute, but can be prevented by complete surgical debridement.

	Introduction

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The dramatic decrease in the incidence of rheumatic disease in the Western World has not led to a significant reduction of valve heart disease requiring valve replacement [1]. Progress in cardiac imaging techniques including echocardiography [2] and computed tomography scan has allowed a more accurate diagnosis in patients with heart failure and in elderly people [3]. Moreover, the incidence of infective endocarditis, in spite of antibiotic therapy and early diagnosis, has not significantly declined in recent years, ranging from 10 to 50 cases per million inhabitants per year [4].

Therefore, infective endocarditis seems to be among the most serious problems in valve heart disease. In spite of appropriate antibiotic treatment and improved surgical techniques, hospital mortality is higher than expected and the incidence of recurrence is still high [5, 6].

Many studies [5, 7] have assessed risk factors for hospital mortality in patients undergoing surgical treatment for valvular endocarditis: Erbel and associates [7] found a higher risk of death or serious postoperative complications in patients with one or more of the following risk factors: age above 60 years, delayed diagnosis, staphylococcal infection, aortic valve endocarditis, large valvular vegetations, congestive heart failure, cerebral or coronary embolism, prosthetic valve infection, recurrent events, and failed antibiotic therapy.

Although improvements in diagnosis, surgical techniques, and postoperative care have reduced hospital mortality, the recurrence rate is still high [6].

Recurrent endocarditis is a dreadful complication; the infection generally recurs on a prosthetic valve, and even with aggressive medical or surgical intervention, mortality rates for such a complication range between 25% and 60% [8–10]. Late follow-up is even more depressant, with a high number of re-recurrence having been reported. Many clinical studies and case reports have described patients with recurrent periprosthetic leak undergoing multiple consecutive valve replacements, ending with poor prognosis and quality of life [6].

The objective of this retrospective study was to establish which variables have been associated with a higher risk of recurrence of endocarditis over our 22-year surgical experience.

	Material and methods

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Between January 1979 and May 2000, 271 patients with infective endocarditis underwent 308 heart valve replacements at our institution. Ninety-six patients (31.2%) were female and 212 (68.8%) male, with age ranging between 8 and 79 years (mean 45.4 ± 1.01 years). The infection involved a native valve in 190 (61.7%) cases and a prosthetic valve in 118 (38.3%). Among them, 43 patients (14%) died during their hospital stay or within 30 days from the operation and were excluded from the study. The analysis involved 258 cases; follow-up was 97.36% complete. All cases of recurrence were recorded regardless of the type of treatment (medical or surgical) and the outcome. The following variables were analyzed for each case: site of infection, active infection at surgery, drug abuse, presence of type 2 diabetes, perivalvular involvement, prosthetic endocarditis, absence of fever on seventh postoperative day, positive blood cultures, positive valvular cultures, previous embolism, and type of prosthetic valve implanted.

Variable definitions are reported in the Appendix.

Definitions
Blood cultures were performed routinely in all patients admitted to our institution with valve disease and fever. Blood cultures performed in the referring hospital were recorded as well. Moreover, it has been our policy, since January 1980, to perform histology and microbiology examinations of all excised material at valvular surgery procedures, regardless of the aetiology of valve disease.

Cases of infective endocarditis as well as recurrences were defined according to Durack’s criteria [11]. Briefly, major criteria for diagnosis of infective native valve or prosthetic endocarditis were considered: positive histology; at least two positive blood cultures showing typical microorganisms of infective endocarditis; echocardiographic findings of abscesses or intracardiac mass on native valve or prosthesis in absence of alternative anatomic explanation; and new partial dehiscence of prosthetic valve. All data were recorded in dedicated software and reviewed by two infectivologists to determine whether cases should be classified as definite or rejected.

For the definitions of active, healed, native, prosthetic, and culture-negative endocarditis, modified Aranki’s criteria [12] were employed. Endocarditis was labeled "active" if the patient had fever or leukocytosis at the time of surgery or required surgical treatment before completion of a standard course of antibiotic treatment. Endocarditis was labeled "healed" if surgery was performed after completion of antibiotic treatment and no signs of active infection (fever, leukocytosis) were present. Prosthetic valve endocarditis was defined as infection occurring on any type of biological or mechanical valve device. "Early" prosthetic valve endocarditis was present if recurrent or residual endocarditis occurred within 180 days from surgery. Prosthetic valve endocarditis occurring after 180 days was labeled "late." Culture-negative endocarditis was present when no microorganism could be identified on serial blood cultures or on cultures from the explanted valvular tissue in patients presenting with the clinical picture of endocarditis, particularly in the presence of a new regurgitant murmur, congestive heart failure, or vegetations on echocardiogram. These were confirmed at operation by presence of leaflet perforation, vegetations, or valvular and perivalvular tissue destruction. The presence of acute or chronic inflammatory changes at microscopy confirmed the diagnosis of endocarditis.

Early mortality or morbidity was defined as death or complications occurring within 30 days or during postoperative hospital stay period. Late mortality and morbidity were classified according to Edmund’s criteria [13].

Operative procedures
Cardiopulmonary bypass, systemic hypothermia, and moderate hemodilution were used in all cases. Myocardial protection was achieved with systemic and local hypothermia and with antegrade crystalloid cardioplegic infusion in all cases.

Mechanical and bioprosthetic valves were implanted with interrupted sutures. Homografts were inserted with an interrupted proximal suture line and a continuous distal suture line. Extensive debridement of vegetations and annular abscesses was always performed.

Follow-up
Data regarding hospitalization were obtained from the hospital record charts. Data about the outcome after discharge and clinical status at follow-up were obtained from the Outpatient Clinic records or by telephone interviews either to the patients or to the general practitioner or to the referring physician. Follow-up was 97.36% complete. Follow-up time ranged from 1 to 234 months (mean 53.22 ± 3.42 months).

Statistical analysis
Data were recorded on dedicated software and processed with version SPSS 8.0 (SPSS Inc, Chicago, IL). All data were expressed as mean ± SE. Discrete variables were analyzed with Pearson’s exact test. For each variable, Kaplan-Meier actuarial curves were drawn; comparisons were obtained with the log-rank test. For the mutivariate analysis Cox regression (conditional forward stepwise) was employed. Values of p less than 0.05 were considered as significant.

	Results

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Microbiological results are shown in Table 1. A recurrent endocarditis was reported in 58 cases (22.5%). Surgical treatment was performed in 37 patients. In 21 cases with a moderate or mean periprosthetic regurgitation and no signs of active infection, or in cases of previous multiple redooperations, medical treatment was performed. Operative mortality in patients who underwent reoperation was 45.9% (17 of 37). Causes of death were low output syndrome in 8 cases, multiorgan failure in 4, renal failure in 3, and brain hemorrhage in 2. Meanwhile, 10 patients (47.5%, 10 of 21) died in the group of patients medically treated. Causes of death were progressive cardiac failure in 4, brain hemorrhage in 2, stroke in 2, and sudden death in 2.

Multivariate analysis showed at the final step that prosthetic endocarditis (p = 0.00001), positive valvular cultures (p = 0.0039), and persistence of postoperative fever (p = 0.000001) were independent risk factors for recurrence of endocarditis (Table 3).

	Comment

Top Abstract Introduction Material and methods Results Comment References

Reported mortality rates for surgical treatment of infective endocarditis range between 2% and 60%; determinants of outcome already have been investigated and have been reported by many authors [5, 7].

Better knowledge of variables predicting hospital mortality, improved antibiotic therapy, and surgical techniques have allowed a strong reduction of operative mortality in patients with infective endocarditis, but incidence of recurrence is still high. David and Associates [12] reported 6.1% of recurrence in a population of 122 patients with 46 prosthetic endocarditis, with a 10-year freedom from recurrence rate of 79 ± 9%. Studies investigating determinants of recurrent endocarditis have pointed out that many variables can affect the incidence of such a complication [6, 10].

There is a general consensus about the poor long-term prognosis of prosthetic endocarditis, and despite appropriate surgical techniques and 6-week postoperative antibiotic treatment, recurrence is still high, with a 5-year freedom from reoperation of 75% according to Lytle and associates [15]. Our study, including patients who did not require reoperation, revealed 31.6% 10-year freedom from recurrence.

The incidence of negative blood cultures ranges in the medical literature between 20% and 60% [9, 11] of patients who underwent surgical treatment. Lack of germ isolation and of sensibility test results precludes specific postoperative antibiotic therapy. Targeted postoperative antibiotic treatment for more than 4 weeks carries a better prognosis according to recent reports [9].

Incidence of positive cultures from vegetation and tissue retrieved at the operation is even lower than from the blood. In our series, we were able to identify the pathogens in 15.08% of the cases. Failure in isolating pathogens from vegetation and explanted materials may be caused by healed endocarditis, broad-range preoperative antibiotic treatment, attitude to prime the oxygenator with crystalloid solution and antibiotics, and use of crystalloid cardioplegia that may cause an osmotic shock to the bacteria still living in the vegetation.

Our previous study already reported a higher incidence of reoperation in patients with positive intraoperative cultures [16]. In the present study, positive valve tissue cultures proved to have a prognostic value for recurrence of infection.

Many authors [5] suggested that the prosthetic implant may reduce the incidence of recurrence. Others [17] reported a lower recurrence rate in patients with homograft or pulmonary autografts. In our series, the kind of valve substitute employed (mechanical valves, silver-coated mechanical valves, bioprostheses, and homografts) was not found to affect the incidence of recurrence. In particular, only 8 patients received a homograft, and in 4 of them (50%), recurrence was observed. None of those patients initially presented with sepsis, while all 4 showed persistent postoperative fever, suggesting incomplete resection of infective tissues at operation or inadequate peroperative antibiotic treatment.

Previous perivalvular involvement with abscess has been supposed to represent a risk factor for recurrency [5]. Danchin and associates [18], similar to our study, did not find any difference between patients with and without periannular involvement, reporting 58% 10-year freedom from reoperation in patients with periannular abscesses. In each case of periannular abscess in our series, the operative report described extensive debridement and closure of the abscess cavity. Conversely, inappropriate eradication of infection, resulting from poor intraoperative debridement [19] and unsuccessful antibiotic treatment (and manifesting with persistent postoperative fever at 7 days from operation) proved a significant risk factor for recurrency.

In conclusion, microbiology results guiding targeted perioperative antibiotic treatment can reduce recurrence of endocarditis. Infected tissue must be extensively removed, because inadequate resection with persistent postoperative fever always carries a high risk of recurrent endocarditis, regardless of the replacement device chosen.

	Appendix

 
Variables assessed in predictive models include the following:

• Gender
  
• Diabetes mellitus (fasting blood glucose > 140 mg/dL in at least two assays or use of antidiabetic medication)
  
• Drug abuse (present history of intravenous drug addiction)
  
• Site of lesions (aortic valve, mitral valve, tricuspid valve, or multiple)
  
• Previous valve disease
  
• Prosthetic endocarditis
  
• Sepsis (septic fever at the time of operation, despite antibiotic treatment)
  
• Embolism: clinical and instrumental evidence of previous embolism (limbs, cerebral, pulmonary, renal, splenic, coronary)
  
• Perivalvular tissue involvement (echocardiographic or intraoperative findings of intracardiac fistulae or perivalvular abscesses)
  
• Positive valve culture (positive cultures from tissue explanted at surgery)
  
• Positive blood cultures (typical microorganisms for infective endocarditis isolation from two separate blood cultures)
  
• Prosthetic model (kind of prosthetic device implanted: mechanical, silver-coated mechanical, biological, homograft)
  
• Delayed disappearance of fever: persistence of fever (body temperature > 37.5°C) after the seventh postoperative day.
  

	References

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