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Evaluating Treatment Options for Patients With Infective Endocarditis

When Is It the Right Time for Surgery?
Aneil Malhotra, Bernard D Prendergast Future Cardiol. 2012;8(6):847-861.

Abstract
Infective endocarditis remains a life-threatening condition with an unchanging incidence and mortality of nearly 30% at 1 year. Surgery is required in 2550% of acute infections and 2040% of patients during convalescence. Operative procedures are often technically challenging and high-risk, often due to coexistent multisystem disease. However, international guidelines provide clear indications for surgical intervention, which are applicable for the majority of patients. These are not, however, supported by particularly robust clinical evidence and decision-making often needs to be tailored to the advancing age of the overall patient cohort, the presence of multisystem disease, comorbidities, prior antibiotic therapy of varying duration and the availability of surgical expertise. Native valve endocarditis will be the initial focus of this article, along with subgroups including prosthetic valve endocarditis. We present the treatment options for patients with infective endocarditis, evaluate the evidence-base that supports current clinical practice and attempt to provide an insight and subsequent recommendations for the timing of surgery.

Search Strategy
We systematically searched Medline (19952011) and Embase (19952011) for both English and non-English language articles by entering 'infective endocarditis', 'native valve endocarditis', 'prosthetic valve endocarditis', 'surgery endocarditis' and 'endocarditis complications' as both medical subject heading (MeSH) terms and text words. We then retrieved all relevant articles as determined by consensus among the authors and searched the reference lists of retrieved articles to find other potentially relevant articles. Further studies were identified by consultation with experts.

The Role of Surgery in Infective Endocarditis

Infective endocarditis (IE) is a serious condition with a mortality rate of nearly 30% at 1 year. [1,2] Surgery is required in up to half of acute infections and a significant proportion of those in convalescence. [3,4] Guidelines provide clear indications for when surgical intervention is indicated but these need to be adjusted to an advancing cohort of patient age with an increasing number of comorbidites.[5,6] Contemporary data in Europe suggest that surgery is now undertaken in half of IE patients, the most frequent indications being congestive cardiac failure (60%), vegetation size (48%), refractory sepsis (40%) and embolic complications (18%). However, many patients have more than one of these factors.[7] During the last three decades, valve replacement and repair have become commonplace in the management of selected complications of IE, and a reduction in the mortality of IE has been ascribed to the combination of improved antibiotic therapy and timely surgical intervention. Patient outcome is improved[8] by the involvement of a specialized IE team but expeditious surgery in carefully selected patients is also an important factor. In active IE, long-term survival rates are approximately 70% in most series.[3,4,927] Assessment of surgical outcome however, is made more difficult to ascertain, since patients who are referred are frequently those with severe complications related to more virulent organisms. Conversely, those who are most seriously affected often include elderly patients with multiple comorbidities who are often deemed unfit for surgery. In general terms, prognosis is better if surgery is performed prior to progression of cardiac tissue destruction as the subsequent deterioration in the patient's preoperative condition increases the hazards of intervention. Contrary to previous belief, final outcomes are not related to the duration and intensity of prior antibiotic therapy; when surgery is clearly indicated, it should not be delayed in the vain hope that a sterile field can be achieved.

Numerous series have attempted to identify variables predictive of early and late mortality[3,4,6,1022,28,29] and these are summarized in . However, the outcome measures used along with the variety of patient cohorts hamper interpretation. In particular, most studies have been retrospective, single-center series of patients with both native and prosthetic valve IE rather than randomized studies. Furthermore, analysis is inherently biased given the selection of patients for surgery who have an anticipated poor outcome but acceptable operative risk. Although surgery may be recommended and commonly performed for indications such as embolic complications or persistent infection, it should be recognized that there is no definitive proof of improved outcome in these situations (in contrast to congestive heart failure secondary to valvular regurgitation see below). It has been shown that there is a significant decrease in mortality associated with early surgery in the subgroup of patients with most indications for surgery.[30] More recent analyses using sophisticated propensity scoring models have yielded conflicting results concerning the benefits of surgery, [13,2022,28,29] with one study showing that surgery is preferably coded as a time-dependent variable; although the postoperative mortality is initially increased within 14 days, it is improved after a period of time estimated around 6 months. [29] These papers emphasize the need for further high-quality prospective studies. One such example is a recent singlecenter randomized controlled trial that emphasises the benefits of timely surgical intervention in patients with large vegetations and severe valvular dysfunction, even without heart failure, outweighing the risks of surgery in patients with active infection.[31] The argument for early surgery is strongly supported by this study, which provides a stimulus for designing randomized trials that will further refine the indications for and timing of surgery. Hence, clinical decision-making is difficult with overall management requiring input not only from an experienced surgical team but also from cardiologists and microbiologists.
Table 1. Key papers assessing surgical outcome in infective endocarditis. InPatient hospit Mean Statistical Count Subjec characterist al follow methods ry ts (n) ics mortali -up ty Longterm surviv al rate

Author (Year)

Study design

Summary of findings

Re f.

Retrospect ive singleJault et center al. surgical (1997) cohort study

Multivariat e logistic Franc regressio e n analysis

247

Native valve 7.6% IE alone (surgic 6 al years Surgery: series) 100%

71%

Predictors of operative mortality: age, insidious illness, CHF. Long-term survival good except for neurological complications and mitral valve IE

[3]

Prospectiv Castillo e singleet al. center (2000) cohort study

Simple group Spain compariso ns

Native valve: IE 69% 138 PVE: 31% Surgery: 51%

Overall : 21% Surgic al: 21% Medica l: 20% p = NS

10 years

71%

Early surgery associated with good long-term results and no increase in mortality. Not a comparative study

[4]

Lalani et al. (2010)

Prospectiv e Propensit multination USA y analysis al cohort study

Surgic Native valve al: IE alone 12.1% 1152 Surgery: 46%

Not report Medica ed l: 20.7%

Early surgery for NVE associated Not with reduction of [28 reporte in-hospital ] d mortality compared with medial therapy

alone, especially in subgroup analysis of paravalvular complications, systemic embolization, Staphylococcus aureus NVE and stroke but not with valve perforation or CHF Conflicting results from previous studies related to Adjust different ed statistical hazard methods. When [29 ratio: appropriate ] 0.55 (p models used, = 0.01) valve surgery associated with significantly reduced longterm mortality Predictors of operative mortality: CHF, impaired LV function Predictors of recurrence: PVE Native valve Retrospect ive singleAlexiou center et al. surgical (2000) cohort study Multivariat e logistic UK regressio n analysis IE: 70% 118 PVE: 30% Surgery: 100% 7.6% (surgic 10 al years series) Predictors of late mortality: myocardial [10 invasion, ] reoperation Predictors of poor long-term survival: coagulasenegative Staphylococcus, annular abscess, long ICU stay Duration of illness, age, gender, site of infection, organism and LV function did

Prospectiv Bannay e Cox et al. population- model (2011) based analysis study

Franc e

Left-sided IE alone 449 Surgery: 53%

Adjust ed hazard ratio: 5 3.69 (p years < 0.0001 )

73%

Wallac e et al. (2002)

Retrospect ive singlecenter cohort study

Multivariat e logistic UK regressio n analysis

208

Native valve Overall : 18% 6 IE: 68% month 73% Impact s PVE: 32% of surger

[11 ]

Surgery: 52%

y not reporte d

not predict outcome. Abnormal white cell count, raised creatinine, 2+ Duke criteria, visible vegetation conferred poor prognosis Mortality associated with comorbidity, abnormal mental status, CHF, [12 nonstreptococca ] l IE, medical therapy. Prognostic classification proposed Valve surgery associated with reduced mortality after adjustment for baseline variables and propensity scores. Benefits of surgery greatest in patients with CHF Predictors of in hospital mortality: CHF, S. aureus. Predictors of long-term mortality: early PVE, comorbidity, CHF, staphylococcal infection, new prosthetic dehiscence. Mortality reduced by surgery in high risk subgroups with staphylococcal infection and

Retrospect Hasbun ive et al. multicenter (2003) cohort study

Multivariat e logistic USA regressio n analysis

513

Native valve IE alone Not 6 reporte month 74% Surgery: d s 45%

Retrospect Vikram ive Propensit et al. multicenter USA y analysis (2003) cohort study

Native valve 513 IE alone Surgery: 45% Not 6 reporte month 74% d s

[13 ]

Overall : 21% Retrospect ive multicenter cohort study Multivariat e logistic Franc regressio e n analysis PVE alone 104 Surgery: 49% Surgic al: 17% Medica l: 25% (p = NS)

Habib et al. (2005)

32 month 62% s

[14 ]

complicated PVE Overall : 17% Surgic al: 14% Medica l: 19% (p = NS) Overall : 36% Prospectiv e multicenter cohort study Native valve Native IE: 66% valve: 32% PVE: 34% Surgery: 100% PVE: 45% (surgic al series) Poor clinical outcome after urgent surgery. Not Persistent reporte infection and d renal failure associated with higher mortality Predictors of mortality: CHF, immunosuppres sion, insulinNot dependent DM, reporte left-sided IE, d septic shock, coma, cerebral hemorrhage, high CRP

Native valve Prospectiv e Delaha multicenter ye et al. population(2007) based survey Multivariat e logistic Franc regressio e n analysis IE: 85% 559 PVE: 15% Surgery: 47%

Not report ed

[15 ]

Revilla (2007)

Multivariat e logistic Spain regressio n analysis

508

Not report ed

[17 ]

Hill et al. (2007)

Prospectiv e single center cohort study

Multivariat e logistic Belgiu 193 regressio m n analysis

Native valve IE: 66% PVE 34% Surgery 63% S. aureus IE alone

78% overall Not 6 (26% if reporte month CI to d s surger y) Overall : 26%

Predictors of mortality: age, Staphylococcus [18 aureus, CI to ] surgery (present in 50% of deaths) Predictors of mortality: comorbidity, CHF, severe sepsis, PVE, major neurological events. Early surgery associated with improved outcome

Prospectiv Remadi e et al. multicenter (2007) cohort study

Multivariat e logistic Franc regressio e n analysis

116

Surgic Native valve al: IE: 83% 16% PVE: 17% Surgery: 47% Medica l: 34% (p < 0.05)

3 years

57%

[19 ]

Overall Native valve : 17% Prospectiv e single center cohort study Propensit y score matching: USA logistic regressio n analysis IE: 69% 426 PVE 19% Other: 12% Surgery: 29% Left sided: IE Surgic al: 12% Medica

Aksoy et al. (2007)

5 years

Factors associated with surgical Surgic treatment: age, al interhospital ~48% transfer, staphylococcal Medic infection, CHF, al intracardiac ~28% abscess, hemodialysis with iv. catheter.

[20 ]

l: 18%

Surgery associated with long-term benefit. Factors associated with mortality: DM, paravalvular infection, indwelling iv. catheter

Retrospect Matched Tleyjeh ive single propensity et al. center USA (2007) cohort Analysis study

546

No survival benefits associated with Native valve Surgic surgery despite Not 6 al 73% correction for IE alone reporte month timing and early d s Medic operative Surgery: al 76% deaths. 24% Prospective study recommended

[21 ]

Retrospect Tleyjeh ive single Propensit et al. center USA y analysis (2008) cohort study

546

Strong correlation Native valve between Surgic propensity score Not 6 al 73% IE alone and timing of [22 reporte month surgery. ] d s Medic Surgery: Individual effect al 76% 24% of each variable difficult to measure

CHF: Congestive heart failure; CI: Contraindication; DM: Diabetes mellitus; ICU: Intensive care unit; IE: Infective endocarditis; iv.: Intravenous; LV: Left ventricle; NS: Not significant; PVE: Prosthetic valve endocarditis. Adapted with permission from [32].

Indications for Surgery

The indications for surgery in IE have increased over time. It is important to consider early surgical intervention in active IE to avoid progression to heart failure, irreversible structural damage and systemic embolism. The European Society of Cardiology published guidelines on the prevention and treatment of IE in 2009, [5] including helpful recommendations concerning the timing of surgery the indications for surgery in these guidelines closely resemble those recommended by The American College of Cardiology/American Heart Association.[6] The general consensus is that surgery is warranted for patients with active native IE who have one or more of the following:

Congestive cardiac failure (CCF) directly related to valvular dysfunction; Uncontrolled infection secondary to persistent sepsis, perivalvular infection with abscess, fistula or pseudoaneursym formation or resistant pathogens; Systemic embolism.

Figure 1 & summarize the indications for surgery and its timing in native valve endocarditis as recommended by the European Society of Cardiology.[5,32]
Table 2. European Society of Cardiology surgical indications.

Indications for surgery

Timing

Class Level

Heart failure Aortic or mitral IE with severe acute regurgitation or valve obstruction causing refractory pulmonary edema or cardiogenic shock Aortic or mitral IE with fistula into a cardiac chamber or pericardium causing refractory pulmonary edema or shock Aortic or mitral IE with severe acute regurgitation or valve obstruction and persisting heart failure or echocardiographic signs of poor hemodynamic tolerance (early mitral closure or pulmonary hypertension) Aortic or mitral IE with severe regurgitation and no heart failure Uncontrolled infection Locally uncontrolled infection (abscess, false aneurysm, enlarging vegetation) Persisting fever and positive blood cultures >710 days Infection caused by fungi or multiresistant organisms Prevention of embolism Aortic or mitral IE with large vegetations (>10 mm) following one or more embolic episodes despite appropriate antibiotic therapy Aortic or mitral IE with large vegetations (>10 mm) and other predictors of complicated course (heart failure, persistent infection abscess) Isolated very large vegetations (>15 mm)

Emergency Emergency

I I

B B

Urgent Elective

I IIa

B B

Urgent Urgent

I I

B B B

Urgent/elective I

Urgent Urgent Urgent

I I IIb

B C C

Emergency: surgery within 24 h, urgent: surgery within a few days, elective: after at least 1 or 2 weeks of antibiotic therapy.

Class of recommendation. Level of evidence. Surgery maybe preferred if procedure preserving valve is feasible.

Data taken with permission from [5].

Figure 1.

Surgical indications in native valve infective endocarditis.

Surgery is considered if previous embolism and persistent vegetations. Surgery can also be considered if isolated very large vegetations (>15 mm) are present, especially if conservative surgery is feasible. Adapted with permission from [32].

Congestive Cardiac Failure

CCF is the most frequent complication and indication for surgery in IE.[8] The condition is observed in more than half of all cases and occurs more often when the aortic rather than mitral valve is affected (29 vs 20% respectively).[7] CCF also has the greatest impact on prognosis.[11,12] Studies from the 1970s and 1980s compared medical and surgical treatment of CCF complicating IE and demonstrated a consistent reduction in mortality after surgery from 5686% to 1135%.[33,34] Although no correction was made for underlying comorbidity, similar results were reported in two more recent Scandinavian studies[23,35] in which best results were obtained with early intervention within 1 week of presentation. Prompt intervention is important before severe or refractory hemodynamic deterioration occurs and valve surgery in CCF patients is associated with reduced mortality when compared with medical therapy alone.[4,13,19,20,36] This scenario is now the most common and clearest indication for surgery, being present in 72% of patients who underwent early intervention in a recent European series.[17] There is a significant decrease in mortality associated with early surgery in those patients with the strongest and most numerous indications for surgery.[30]

CCF is usually caused by severe aortic or mitral regurgitation which may develop acutely as a result of leaflet perforation or chordal rupture, or as a consequence of coaptation disruption. Rarer causes include intracardiac shunts from fistulating tracts, prosthetic dehiscence or valve obstruction by large vegetations. Patients with CCF may present clinically with acute dyspnea, pulmonary edema and cardiogenic shock. Transthoracic echocardiography (TTE) will help evaluate flow velocities and deceleration times which are usually low and short, respectively, in the left atrium in mitral regurgitation and left ventricle in aortic regurgitation. TTE also helps quantification of the degree of valvular dysfunction and its hemodynamic impact.[37] Transesophageal echocardiography (TOE) is particularly useful in cases of valve leaflet perforation, secondary mitral lesions and aneurysm assessment and is nowadays indicated in virtually all cases of IE. [37] Although surgery is indicated in those with clinical evidence of CCF complicating IE, there are other issues that ought to be considered. Patients with less dramatic presentations of CCF may respond to appropriate medical management with diuretics and after load reduction with vasodilators. There is no clear evidence to guide management of these patients and both cardiologists and surgeons are reluctant to subject patients to early surgery; intervention can therefore often be postponed to allow a brief period of antibiotic therapy under close clinical and echocardiographic observation. However, even mild CCF can insidiously progress despite appropriate medical therapy. Delayed surgery in these circumstances is associated with a substantial operative mortality[38] as a consequence of progressive cardiac decompensation and increasing secondary risks of IE. In rarer groups of patients with well-tolerated valvular insufficiency and no other surgical indication, medical management under close surveillance can be recommended. This is a particularly suitable option for the elderly, frail patient with multiple comorbidities for whom surgery would be hazardous, or in the young female of childbearing age for whom valve replacement may pose a lifelong problem.

Uncontrolled Infection
This is the second most common indication for surgery[8] and encompasses persistent bacteremia, extension of perivalvular infection and resistant organisms.
Persistent Bacteremia

Persistent sepsis from an ongoing bacteremia after 57 days, or lack of clinical improvement after 1 week of appropriate antibiotic therapy is generally an indication for surgery. An extracardiac abscess (e.g., renal or splenic) should also be sought and if excluded early surgery should be undertaken. Persistent sepsis is more common with larger vegetations that are more difficult for antibiotics to penetrate and in IE secondary to more aggressive organisms, including Staphylococcus aureus.[19] Current guidelines indicate that surgery should be considered if fever or positive blood cultures persist after 7 days of appropriate therapy.[5,6] An important distinction is the patient who develops recurrent fever after initially favorable progress. In this setting, antibiotic sensitivity or an alternative source of infection (including the possibility of central line colonization) are likely and surgery should only be considered once these have been excluded with confidence. Relapse following initially successful treatment is more common in patients with either nonstreptococcal endocarditis or prosthetic valve endocarditis. Surgery should also be considered in these patients.
Perivalvular Extension

Extension of IE beyond the valve leaflets, apparatus and annulus is associated with increased mortality, development of congestive heart failure and a higher likelihood of surgery.[3942] Perivalvular extension in IE is the most common cause of uncontrolled infection, affecting 1040% of patients with native valve IE, and is most frequent in IE affecting the aortic valve, when abscess expansion near the membranous septum and atrioventricular node may result in heart block. Periannular infection is of even greater concern in prosthetic valve endocarditis, occurring in 56100% of patients, and accounting for high mortality in this group.[43] Clinical clues include persistent fever, new atrioventricular conduction defects and pericardial effusion. Hence, serial ECGs should be performed in these patients although diagnosis is best confirmed by TOE. Fistula and aneurysm formation due to extension of IE are associated with frequent surgery (87%) and high mortality (41%).[44] Other complications include ventricular septal defects, acute coronary syndromes and third degree atrioventricular block.[4547] Factors associated with mortality included moderate-to-severe CCF,

prosthetic valve involvement and need for an urgent operative procedure. Despite such high-risk surgery, there is no other real alternative, even when the patient remains hemodynamically stable. Only in patients with small abscesses (<1 cm) in whom fever is controlled with no evidence of the aforementioned complications can a strategy of medical therapy with close clinical and echocardiographic monitoring be implemented.[5]
Resistant Pathogens

Several organisms are resistant to medical therapy and therefore a surgical approach is advocated. S. aureus native valve endocarditis, for example, causes severe valvular damage, large vegetations, embolic complications and poor overall prognosis.[16,19,48] Early surgery should be considered in most cases of native valve endocarditis and all cases of prosthetic valve endocarditis if there is no immediate response to appropriate antibiotic therapy.[19,49] Coagulase-negative cocci such as Staphylococcus lugdunensis are associated with a high rate of cardiac tissue destruction and requirement for early valve surgery.[50] Fungal IE, secondary to infection with Candida or Aspergillus, is often complicated by bulky vegetations, perivalvular spread and embolic events. Penetrance of antifungal agents, such as amphotericin B, into these large vegetations is poor and early surgery is almost always necessary, particularly when complications are present.[51] In those who are deemed unfit for surgery, long-term antibiotic suppressive therapy can be considered.[52] Pseudomonas aeruginosa is associated with nosocomial infections. While medical therapy may suffice in rightsided endocarditis, this is rarely effective in left-sided disease. Therefore surgery offers the best prospect of complete cure.[53] Brucella IE is characterized by an aggressive course with frequent valve destruction, congestive heart failure and abscess formation. Antimicrobial therapy alone is rarely effective and early surgery is recommended. [54] Coxiella burnetii, the agent responsible for Q fever, is resistant to medical cure and recolonization after successful valve surgery is a frequent event. Surgery is recommended in patients with congestive heart failure, prosthetic valve endocarditis and uncontrolled infection[55] and prolonged postoperative antimicrobial therapy (up to 2 years) is recommended to prevent recurrence.[56] Surgery provides the only means of eradication of infection when IE is caused by multiresistant organisms, including methicillin-resistant S. aureus and vancomycin-resistant enterococci. Early involvement of microbiology teams is essential to determine the selection and duration of appropriate antibiotic therapy. In summary, patients with uncontrolled infection from persistent sepsis, perivalvular extension and resistant pathogens should undergo early surgery unless severe comorbidites exist.

Systemic Embolism
Systemic embolism occurs in 2250% of patients with IE and is a life-threatening complication.[57,58] The brain is most frequently affected, accounting for 65% of embolic events from left-sided vegetations, 90% of these arising in the distribution of the middle cerebral artery.[59] However, other organs with large vascular supplies are also often affected, including the lungs, coronary arteries, spleen, liver, bowel and peripheral vasculature. Embolic complications can also be clinically silent in up to one-quarter of cases and detected only after systematic imaging.[59,60] Although embolic complications may arise at any stage in the natural history of IE, most events occur before diagnosis or subsequently within 2 weeks. Importantly, and specifically in relation to the timing of surgery, several independent studies have confirmed that embolic risk falls dramatically during the first 2 weeks of successful antibiotic therapy (and most steeply within the first three days).[57,61,62] The highest rate of embolic complications is seen in left-sided IE, especially when infection is related to S. aureus, Candida, HACEK and Abiotrophia organisms. Identifying predictive factors for embolic complications and, in turn, those patients who will benefit most from early surgery is difficult and has been the subject of detailed investigation, at present echocardiography plays a key role.[35,57,61,6366] Increased vegetation size, mobility[57,59,61,6368] and location[61,6265,67] are associated with an increased risk of embolism, as is the dynamic variation of vegetation size under antibiotic therapy. [61,67] Patients

with vegetations measuring more than 1 cm in length are at higher embolic risk [57,59,65] and this risk increases even higher with vegetations longer than 1.5 cm.[61] Clinical predictors of embolism include particular microorganisms (staphylococci[61] , Streptococcus bovis [69] , Candida), previous embolism,[70] multiple valve IE[71] and biological markers.[72] The benefits of surgery to prevent embolism are therefore greatest at an early stage, deferral of surgery for 23 weeks for this indication alone is of little value. A low threshold for early surgery is most appropriate for patients in whom a conservative procedure (isolated vegetectomy and/or valve repair) is likely or when other factors predict adverse outcome (e.g., severe valvular regurgitation or infection with a resistant microorganism).
Neurological Complications

Neurological events are common in 2040% of patients with IE, mainly as a consequence of cerebral embolism[58,60,73] and are most common in those with S. aureus infection.[58,60] The clinical spectrum of complications includes ischemic or hemorrhagic stroke, transient ischemic attack, silent cerebral embolism, symptomatic or asymptomatic mycotic aneurysm, cerebral abscess, meningitis, toxic encephalopathy and seizure. All manifestations are associated with excess mortality.[60,70] Figure 2 & summarizes the European Society of Cardiology recommendations for the management of neurological complications of IE. [5]
Table 3. Management of neurological complications. Class Level

After a silent cerebral embolism or transient ischemic attack, surgery is recommended without delay if an indication remains Following intracranial hemorrhage, surgery must be postponed for at least 1 month Neurosurgery or endovascular therapy are indicated for very large, enlarging or ruptured intracranial aneurysm After a stroke, surgery indicated for heart failure, uncontrolled infection, abscess or persistent high embolic risk should not be delayed. Surgery should be considered as long as coma is absent and cerebral hemorrhage has been excluded by cranial CT Intracranial aneurysm should be looked for in any patient with IE and neurological symptoms CT or MR angiography should be considered for diagnosis

I I I

B C C

IIa

IIa

B B

Conventional angiography should be considered when noninvasive techniques are negative and IIa suspicion of intracranial aneurysms remains

Class of recommendation. Level of evidence.

CT: Computed tomography; MR: Magnetic resonance. Data taken with permission from [5].

Figure 2.

A schematic flow diagram assessing patients with neurological complications for consideration of valve surgery. Adapted with permission from [5]. Rapid diagnosis and initiation of appropriate antibiotic therapy are fundamental in the prevention of a first or recurrent neurological event. Most patients with a neurological complication have at least one other indication for cardiac surgery. Although there are concerns regarding the role of surgery in these situations (neurological deterioration or perioperative cerebral bleeding), surgery can be performed without delay provided that cerebral hemorrhage has been excluded by computed tomography and neurological damage is not severe. Pre- and peri-operative risks are low after a silent cerebral embolism, transient ischemic attack or ischemic stroke,[60] although evidence regarding optimal timing is conflicting.[60,7477] In the presence of cerebral hemorrhage, cardiac surgery should be postponed for at least 1 month[61,63] unless an isolated mycotic aneurysm suitable for endovascular therapy is the source of the cerebral bleed.[78] A bioprosthesis (or valve repair when applicable) is preferred to avoid the need for long-term anticoagulation.

Surgical Considerations
Preoperative Management

TTE and TOE are the first-line diagnostic tools in IE and also allow assessment of the extent of IE and anatomical characterization before surgery. TOE has superior sensitivity and specificity and is recommended in virtually all patients in whom surgery is considered.[32,79] Coronary angiography is unnecessary for the diagnosis of IE but should be considered in men >40 years of age, postmenopausal women and those with a history of ischemic heart disease or an adverse risk factor profile. Alternative noninvasive techniques such as multislice computed tomography may be used if available. Although the duration of appropriate preoperative antimicrobial therapy is associated with the likelihood of positive valve culture at the time of surgery, there has been no association demonstrated between the duration of prior antibiotic therapy and clinical outcome.[80] Surgery, when indicated, should not be delayed to allow prolonged antibiotic therapy. There is an increased risk of adverse outcomes in patients with IE taking oral anticoagulants, particularly during the first 2 weeks when embolic risk is highest and surgical decisions are usually necessary. [81] Anticoagulants should be discontinued in this phase if possible; in patients for who anticoagulation is essential (e.g., metallic valves), transfer to intravenous unfractionated heparin is recommended.
Intraoperative Management

Perioperative TOE is a useful tool to determine the location and extent of infection,[18] assist the choice of reconstruction procedure, validate the surgical result and guide hemodynamic management. The excised native or prosthetic valve should be sent for immediate culture. Molecular examination of excised valve tissue may play a role, particularly in culture-negative patients.[82]
Surgical Technique

The two primary objectives of surgery are control of infection and reconstruction of cardiac morphology. [83,8486] The mode of surgery (replacement vs repair) or type of prosthesis used (mechanical vs biological) has no influence on operative mortality,[87] although repair techniques reduce the risk of late complications (notably recurrent IE) and avoid the need for lifelong anticoagulation.[88,89]

Postoperative Management
A detailed discussion of postoperative management and follow-up is beyond the scope of this article and is covered in published European guidelines.[90] In the vast majority of patients, antibiotic therapy for 46 weeks is recommended, regardless of the timing of surgery. Positive cultures of excised valve tissue usually reflect intended early valve surgery and do not indicate the need for a fresh 6 week course of postoperative antibiotic therapy. If surgery is performed late and valve cultures remain positive, the duration of postoperative treatment should be discussed with the microbiological team and tailored to the individual patient. A postoperative TTE following completion of antibiotic therapy is helpful to confirm cure and provide a baseline measure for longterm follow-up. Survivors of surgery are a high-risk group for recurrent IE and patients should be made aware of the need to seek early medical advice for fever or other concerning symptoms. Similarly, primary care physicians should be made aware of the need for blood cultures before use of empiric antibiotic therapy. Prosthetic valve IE is potentially avoidable and patient education regarding the importance of dental and skin hygiene, avoidance of unnecessary medical instrumentation (e.g., intravenous cannulae, urinary catheterization) and use of antibiotic prophylaxis at the time of invasive procedures is essential in this group.

Subgroups That Require Further Consideration

Prosthetic Valve Endocarditis

Prosthetic valve endocarditis (PVE) accounts for 1020% of most series with an overall incidence of 0.12.3% per patient-year.[8,91] Cases may be classified as early or late depending on whether infection arises within 1 year of surgery or later. Early surgery is required in approximately 50% of patients and in-hospital mortality

approaches 30%.[8,13,87] Furthermore, long-term follow-up is frequently complicated by recurrent infection, hemodynamic complications, need for repeat surgery and death. The incidence of early-onset PVE has fallen dramatically as a result of improvements in surgical technique, perioperative antibiotic management and operating room sterility. Early infection peaks 2 months following surgery and is most often due to coagulase-negative staphylococci or S. aureus.[8] Surgical treatment results in improved survival at both immediate and long-term follow-up[92] and is best performed early, especially when infection is caused by S. aureus.[93,94] Operations are frequently technically demanding and these procedures are best undertaken by an experienced surgical team (not necessarily the original surgeon). Rates of recurrent PVE are high at 615% and further surgery for this indication or dysfunction of the newly implanted prosthesis is required in up to 25% of patients.[9597] The microbial spectrum of late PVE mirrors that of native valve disease. Aggressive tissue destruction is less frequent and early antibiotic therapy is able to effect cure in many patients, especially those in whom infection is caused by a sensitive organism when surgery is often unnecessary.[83]
The Elderly

Valvular heart disease is becoming increasingly frequent in the aging population and this group undergo an increasing variety of invasive medical interventions. Patients aged >65 years have a ninefold increased risk of IE[98] and diagnosis may be particularly difficult owing to delayed presentation, subtle clinical signs and frequent use of pragmatic and empirical antibiotic therapy before hospital admission. Overall outcome is poor[99,100] and although comorbidity may complicate decision-making, age alone is not a preclusion to surgery.[101]
Intravenous Drug Users

Intravenous drug users predominate in series of young people and overall incidence of IE in this group is 1 5%/year.[102] The tricuspid valve is infected in over 70% of cases and the majority have no known pre-existing cardiac disease.[103,104] Staphyloccus aureus species predominate, although unusual infections including Pseudomonas aeruginosa, fungi, Bartonella, Salmonella and Listeria may also be encountered, particularly in those who are HIV-positive.[104] This group of patients present particular management difficulties due to their drug-seeking behavior and poor compliance with treatment. Medical therapy is usually recommended and short-course therapy and oral regimes may be considered in view of difficulties with compliance. The threshold for intervention and choice of surgical approach may vary in individual patients, where recurrence of infection due to continued drug abuse or compliance with anticoagulant therapy present a dilemma[105] (use of a homograft may be considered in these situations). HIV infection is not a contraindication to cardiac surgery and postoperative complications, including mortality, are not increased in this group.[106]
Right-sided Endocarditis

A conservative approach is recommended for the majority of patients with IE affecting the tricuspid and/or pulmonary valve.[107] Recurrent pulmonary emboli are not an indication for surgery, which is only needed if fever persists despite 3 weeks of appropriate antibiotic treatment in the absence of a pulmonary abscess. [25] Surgical options include debridement of the infected area, vegetectomy with either valve preservation or valve repair, or excision of the tricuspid valve with prosthetic valve replacement.[107,108]
Device-related Endocarditis

The incidence of IE related to permanent pacemakers, implantable defibrillators and other intracardiac devices is rising as a consequence of their widespread use.[109] Management is difficult and entire system removal necessary, although advances in percutaneous techniques mean that a cardiac surgeon is usually not required. Eradication of infection is essential before implantation of a new system.

Conclusion & Future Perspective

Referral for surgery in IE involves a complex decision analysis that balances the risks of medical treatment with those of surgical intervention, including operative mortality and morbidity, the risks of long-term cardiac dysfunction and recurrent embolism, comorbidities and the complications of prosthetic valves and anticoagulation. The established role of surgery seems set to increase as the complexity of patients with IE rises and the benefits of early surgery become clearer. The future will hopefully see a more robust evidence

base to guide management strategy. Nevertheless, decision-making in individual patients will remain challenging: expert input and multidisciplinary collaboration between cardiology, microbiology and cardiac surgery teams will always be required to achieve optimum outcome.

Sidebar
Executive Summary

Indications

Congestive heart failure:

o o o

Congestive heart failure caused by severe aortic or mitral regurgitation or, more rarely, by valve obstruction caused by vegetations. Severe acute aortic or mitral regurgitation with echocardiographic signs of elevated left ventricular end diastolic pressure or significant pulmonary hypertension. Congestive heart failure as a result of prosthetic dehiscence or obstruction.

Systemic embolism:

o o o o o o

Recurrent emboli despite appropriate antibiotic therapy. Large vegetations (>10 mm) following one or more clinical or silent embolic events after initiation of antibiotic therapy. Large vegetations and other predictors of a complicated course. Very large vegetations (>15 mm) without embolic complications, especially if valve sparing surgery is likely (remains controversial). In all cases, surgery for the prevention of embolism must be performed very early since embolic risk is highest during the first days of therapy. Cerebrovascular complications:

Silent neurological complication or transient ischemic attack and other surgical indications. Ischemic stroke and other surgical indications, provided that cerebral hemorrhage has been excluded and neurological complications are not severe (e.g., coma). Surgery is contraindicated for at least 1 month after intracranial hemorrhage unless neurosurgical or endovascular intervention can be performed to reduce bleeding risk.

Uncontrolled infection:

Persistent sepsis, fever or positive blood cultures persisting for >57 days despite an appropriate antibiotic regime, assuming that vegetations or other lesions requiring surgery persist and that extracardiac sources of sepsis have been excluded. Relapsing infective endocarditis (IE), especially when caused by organisms other than sensitive streptococci or in patients with prosthetic valves. Most patients with abscess, fistulous tract or pseudoaneurysm formation.

o o

Resistant pathogens:

o o

Staphylococcus aureus IE involving a prosthetic valve and most cases involving a left sided native valve. IE caused by other aggressive organisms ( Brucella, Staphyloccus lugdunensis).

IE caused by multiresistant organisms (e.g., methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci) and rare infections caused by Gram-negative bacteria or fungal infections. Pseudomonas aeruginosa IE.

Prosthetic valve endocarditis:

o o o

Most cases of early prosthetic valve endocarditis. Most cases of prosthetic valve endocarditis caused by S. aureus . Late prosthetic valve endocarditis with heart failure caused by prosthetic dehiscence or obstruction, or other indications for surgery.

Surgery should be performed immediately, irrespective of antibiotic therapy, in patients with persistent pulmonary edema or cardiogenic shock. If congestive heart failure disappears with medical therapy and there are no other surgical indications, intervention can be postponed to allow a period of days or weeks antibiotic treatment under careful clinical and echocardiographic observation. In patients with well-tolerated severe valvular insufficiency or prosthetic dehiscence and no other reasons for surgery, conservative therapy under careful clinical and echocardiographic observation is recommended with consideration of deferred surgery after resolution of the infection, depending upon tolerance of the valve lesion.

The Timing of Surgery

Emergency surgery (within 24 h):

Native (aortic or mitral) or prosthetic valve endocarditis and severe congestive heart failure or cardiogenic shock caused by:

Acute valvular regurgitation. Severe prosthetic dysfunction (dehiscence or obstruction). Fistula into a cardiac chamber or the pericardial space.

Urgent surgery (within days):

o o o o o o o

Native valve endocarditis with persisting congestive heart failure, signs of poor hemodynamic tolerance or abscess. Prosthetic valve endocarditis with persisting congestive heart failure, signs of poor hemodynamic tolerance or abscess. Prosthetic valve endocarditis caused by staphylococci or Gram-negative organisms Large vegetation (>10 mm) with an embolic event. Large vegetation (>10 mm) with other predictors of a complicated course. Very large vegetation (>15 mm) especially if conservative surgery is feasible. Large abscess and/or periannular involvement with uncontrolled infection.

Early elective surgery (during the in-hospital stay usually after 1 or 2 weeks of antibiotics):

o o

Severe aortic or mitral regurgitation with congestive heart failure and good response to medical therapy. Prosthetic valve endocarditis with valvular dehiscence or congestive heart failure and good response to medical therapy.

o o o
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Presence of abscess or periannular extension. Persisting infection when extracardiac focus has been excluded. Fungal or other infections resistant to medical cure.

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Acknowledgements The authors are very grateful to S Harris and R Khosla for their assistance with the preparation and formatting of this review. Future Cardiol. 2012;8(6):847-861. 2012 Future Medicine Ltd.