- Email: [email protected]
Infective endocarditis
Infective endocarditis Guillermo Martinez MD Kamen Valchanov FRCA
Key points
Clinical findings, echocardiography, and blood cultures are the cornerstone of IE diagnostics, and serological tests and polymerase chain reaction may be useful in culture-negative patients. Transoesophageal echocardiography is recommended in all patients with suspected or confirmed IE. When heart failure or large vegetations (.10 mm) are present, early surgery is recommended and associated with improved long-term clinical outcomes. Antibiotic prophylaxis solely to prevent IE is no longer recommended for persons at risk of IE.
Guillermo Martinez MD Consultant in Anaesthesia and Intensive Care Department of Anaesthesia and Intensive Care Papworth Hospital, UK Kamen Valchanov FRCA Consultant in Anaesthesia and Intensive Care Department of Anaesthesia and Intensive Care Papworth Hospital NHS Foundation Trust Cambridge CB23 3RE, UK Tel: þ44 1480 830541/364406 Fax: þ44 1480 364936 E-mail: [email protected]. uk (for correspondence)
134
‘No one can measure his own days, one must resign oneself, it will be as providence wills, and so I finish my death-song; I must not leave it incomplete.’ Mozart (The Mozart Myths, William Stafford, Stanford University Press, 1991) There are many theories behind Mozart’s mysterious final illness and no reliably confirmed remains have been found. One of the theories of his demise is that it was endocarditis that killed him.1
Introduction Infective endocarditis (IE) is a microbial infection of a heart valve (native or prosthetic) or the mural endocardium, leading to tissue destruction and formation of vegetations. It is primarily a disease of the heart, but by virtue of its haematogenic spread, it is also a multisystem disorder. The aim of this article is to review the epidemiological and microbiological profile of IE, as well as pathophysiology, clinical presentation, and management of complications.
Aetiology and epidemiology The incidence of IE is 1.7–7.2 cases per 100 000 person-years. The female to male ratio has remained stable over the years at 1:2.2 However, the median age of endocarditis patients has increased from 30–40 to 47 –69 yr and rheumatic heart disease is no longer the main risk factor for IE in Western countries. Increasing longevity, degenerative valve disease, and medical treatment, including prosthetic heart valves and indwelling devices such as pacemakers and implanted defibrillators, are the main factors responsible for these substantial changes in the epidemiological profile over the last few decades.3 The majority of cases of IE are caused by gram-positive bacteria. Staphylococcus aureus is now more common than oral Streptococci (formerly Streptococcus viridans) and it has
become the most frequent microorganism causing IE (31–54%). The clinical profiles of methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are different. MSSA is more frequently isolated in community-acquired IE, affects mainly native valves, and it is associated with bacteraemia of unknown origin. On the other hand, MRSA IE is predominantly related to nosocomial infection, wound infection, permanent i.v. catheters, or surgical intervention in the previous 6 months. Viridans group IE is now less common (17– 26%) than in the past, but these strains can be challenging to treat due to difficulties in isolation and partial resistance to antibiotics (‘penicillin tolerance’). Coagulase-negative Staphylococci were the main cause of prosthetic valve endocarditis in the past, particularly within the first 6–12 months after valve surgery. However, current data show that coagulase-negative Staphylococci are isolated in only 17% of prosthetic valve endocarditis, whereas MRSA is isolated in 23–31% of cases.4 Some gram-positive organism such as Streptococcus bovis (5– 8%) can be associated with bowel malignancy or other mucosal lesions. Gram-negative microorganisms can also cause IE. The slow-growing HACEK (Haemophilus parainfluenzae, Aggregatibacter aphrophilus, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) group is a well recognized but unusual cause of IE, responsible for 1.8– 3% of cases. The HACEK group affects mainly native valves, although up to one-third of the cases involve prosthetic valves. Candida and Aspergillus species cause the majority of fungal IE (1–3% of IE). I.V. drug abusers, prosthetic-valve recipients, and patients with long-term central venous catheters are at highest risk of fungal IE, which should be suspected in the presence of bulky vegetations, metastatic infection, perivalvular invasion, or embolization to large blood vessels, despite negative blood cultures.
doi:10.1093/bjaceaccp/mks005 Advance Access publication 29 February, 2012 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 12 Number 3 2012 & The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
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Infective endocarditis (IE) is a systemic life-threatening disease mainly affecting patients with heart valve disease, prosthetic valve, intracardiac devices, and i.v. drug abusers.
Matrix reference 3G00, 2A12
Infective endocarditis
criteria have a low sensitivity and cannot reasonably be applied when blood cultures are negative, when infection affects a prosthetic valve or a pacing system, and when IE affects the right heart.
Pathophysiology
Clinical features
IE originates at sites where the endothelium is damaged by high blood velocity or mechanical damage and on foreign bodies in the circulation. Initially, a sterile thrombotic vegetation (non-bacterial thrombotic endocarditis) is formed, which facilitates bacterial adherence during transient bacteraemia. Platelets and fibrin deposits at the injury site provide an adherent surface for the formation of vegetations. Finally, the vegetations may produce the secondary effects of endocarditis such as tissue destruction, generalized and difficult to eradicate sepsis, and septic emboli and abscesses. Gram-positive bacteria are particularly resistant to the patient’s bactericidal activity (i.e. complement), which facilitates the adhesion and formation of vegetations. However, there is no evidence that bacteraemia associated with invasive or semi-invasive interventions is more significant than that after teeth brushing, for example, and other patient risk factors play a greater role in the physiopathology of IE.5
In 1885, William Osler presented the first comprehensive description of endocarditis. Thereafter, the descriptions of clinical features of IE were largely based on data obtained several decades ago. Nowadays, Oslerian peripheral stigmata of IE such as Osler’s nodes (3%) or Janeway lesions (5%) are uncommon, and physical examination is often unremarkable. A history of weight loss and night sweats is frequently described (up to 96% of cases); a new or a different heart murmur (48% and 20%, respectively) and elevated C-reactive protein are also common findings. When the left heart is affected, vegetations most often develop on the ventricular aspect of the aortic valve and atrial surface of the mitral valve, usually along the edges of valve leaflets (Fig. 1). This explains why peripheral embolism is common. Embolic events usually occur before clinical recognition of the disease, and up to 30% of the patients have renal or splenic infarction at the time of diagnosis. In addition, the heart, brain, intestine, and other large organs may also be affected by septic emboli. Rapid evolution of IE is common in S. aureus, with no time for development of immunological phenomena characteristic of subacute IE. This is also the case in i.v. drug users, where right-sided IE usually involves the tricuspid valve and occasionally the pulmonary valve. Therefore, instead of systemic vascular phenomena, septic pulmonary embolism is the most important complication, which can evolve to pulmonary infarction, pulmonary abscess, bilateral pneumothoraces, pleural effusion, and empyema. The severity of valvular destruction varies with the virulence of the infecting organism and the duration of the infection, and heart failure can be the initial presentation of IE.
Diagnosis: clinical features, microbiology, and echocardiography Clinical suspicion and prompt investigation of IE is imperative. A multidisciplinary team involving microbiologists, cardiologists, neurologists, anaesthetists, surgeons, and intensivists should be involved in caring for these patients. The modified Duke criteria (Table 1) are based on clinical, microbiological, and echocardiographic findings, and provide high sensitivity and specificity (around 80%) for the diagnosis of IE when applied to patients with native valve IE with positive blood cultures.6 The diagnosis of IE is confirmed in the presence of two major criteria, one major and two minor, or five minor criteria. The diagnosis of IE is considered possible in the presence of one major and one minor or three minor criteria. However, the modified Duke Table 1 Simplified Duke criteria for the diagnosis of IE Major criteria Positive blood cultures Positive echocardiogram for IE defined as Oscillating intracardiac mass Intracardiac abscess New partial dehiscence of prosthetic valve Minor criteria Predisposition such as heart condition or i.v. drug use Fever Vascular phenomena or immunological phenomena such as major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial haemorrhage, conjunctival haemorrhages, and Janeway lesions Other microbiological evidence such as PCR, serological tests, or positive blood culture but does not meet a major criterion
Fig 1 TOE, mid-oesophageal commissural view of mitral valve vegetation (arrow). LA, left atrium; LV, left ventricle. For associated video, please see Supplementary material online.
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Whenever blood-culture-negative IE is suspected, other organisms such as Coxiella burnetti, Legionella spp., Brucella spp., Bartonella spp., and Chlamydiae spp. must be considered.
Infective endocarditis
Microbiology
Echocardiography Echocardiography is important for the diagnosis and management of patients with IE. Whatever the level of suspicion, a transthoracic echocardiogram (TTE) should be performed promptly. It is a noninvasive technique, providing useful information for both the diagnosis and severity of IE. However, the sensitivity of TTE ranges from 45% to 60%, and the quality of the study is not always adequate ( particularly in obese patients, obstructive lung disease, or after thoracic surgery). Transoesophageal echocardiography (TOE) offers better image quality and the overall sensitivity for IE is 90–100%.7 TOE is mandatory whenever perivalvular complications or mitral valve involvement is suspected.8 Three echocardiographic findings are the major criteria for diagnosis of IE: (i) vegetation, a mobile echodense mass attached to valvular leaflets or mural endocardium (Figs 2 and 3); (ii) periannular abscess; and (iii) new dehiscence of a valvular prosthesis (Fig. 4). The vegetation is the hallmark lesion of IE. The sensitivity of TTE and TOE for vegetations is 75% and 90%, respectively. Around 10% of IE involves the right side of the heart—most commonly, the tricuspid valve alone (98%), although the pulmonary valve and Eustachian valve IE has been reported. Isolated rightsided vegetation is well detected by TTE and TOE is not mandatory, although 15% of IE in i.v. drug users affects left-side valves and TOE should be considered. An abscess typically affects the aortic root and presents as a perivalvular zone of reduced echo density without blood flow
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Fig 2 Three-dimensional TOE showing a vegetation (arrow) on the mitral valve. For associated video, please see Supplementary material online.
detected inside (Fig. 3). The sensitivity of TTE for perivalvular abscess is low (45–50%) compared with TOE (more than 90%). The diagnosis of an abscess is an indication for early surgery. Other echocardiographic findings, which are not the major criteria but may suggest the presence of IE, include aortic or mitral valve regurgitation, developing as a consequence of valvular necrosis, perforation, or prolapse. About 50 –60% of patients with IE develop heart failure due to valve destruction and early surgery becomes necessary. The mortality of IE patients in heart failure is 80% with non-surgical therapy. Vegetation size and mobility is important. Stroke complicates 20 –40% of left-sided IE and it is the second most common cause of death. A vegetation size of .10 mm or sessile vegetations are independent predictors of stroke and mortality, and early surgery (within 1 week of diagnosis) is associated with improved long-term outcomes through a reduction in systemic embolic events compared with non-surgical therapy. If the vegetations are small or have already embolized, echocardiography can produce false-negative results in about 15% of cases. When clinical suspicion is high, TOE can be repeated after 7 –10 days. Echocardiographic diagnosis can be difficult in the early stage of the disease or in patients with intracardiac devices. TOE allows the identification of high-risk patients and may identify patients who need surgery.
Prophylaxis of IE The role of anaesthetists and intensivists is crucial in the treatment of IE. They are involved in preventing infective complications associated with indwelling devices, antibiotic prophylaxis, and antibiotic treatment when required. Anaesthetists are also involved in echocardiographic and general assessment for patients for surgery and perioperative care. In 2008, the National Institute of Clinical Excellence (NICE) published guidance for antimicrobial prophylaxis of IE in adults
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A positive blood culture is still the best method for the identification of the microorganisms causing IE and it is considered to be a major diagnostic criteria. Blood cultures are positive in about 80% of cases, but may be negative in cases of intracellular or fastidious pathogens or after previous antibiotic treatment. Therefore, whenever IE is suspected (i.e. temperature . 388C, new regurgitant murmur, and history of valvular disease), it is mandatory to perform blood cultures before starting antibiotic treatment. When the antimicrobial agents have been administered before blood cultures are obtained, the recovery rate of bacteria is reduced by 35–40%. Three sets (including at least one aerobic and one anaerobic), obtained from a sterile site, are normally sufficient to identify the usual microorganisms, but some patients may need repetitive sampling. Culture-negative IE often delays diagnosis and the initiation of treatment, with a profound impact on clinical outcome. Specific serological data can also be used to identify the organisms of culture-negative IE. Polymerase chain reaction positivity has been proposed as a major diagnostic criterion for IE, but the technique seems unlikely to supersede blood cultures as a prime diagnostic tool. A polymerase chain reaction of excised valve tissue or embolic material should be performed in patients with negative blood cultures who undergo valve surgery or embolectomy.
Infective endocarditis
valve replacement, or structural congenital heart disease, excluding repaired atrial or ventricular septal defect or patent ductus arteriosus). Suggested antibiotic prophylaxis is listed in Table 2.
Treatment Antibiotics
Fig 4 TOE, mid-oesophageal short-axis view showing the prosthetic valve in the aortic position (dotted arrow) and peri-prosthetic aortic root abscess (continuous arrow).
and children undergoing interventional procedures.9 The NICE guidance suggests that there is weak evidence to support routine preoperative antibiotic prophylaxis for persons at risk of IE. It also states that there is a risk of allergic reactions related to antibiotics and there are financial and resistance implications from liberal overuse of antibiotics. Antibiotic prophylaxis to prevent IE is therefore no longer routinely recommended. However, in the case of actual infection at the operative site, antibiotic prophylaxis is still recommended in high-risk patients (such as acquired valvular heart disease, previous
Microbiology advice should be sought in all cases. Early antimicrobial therapy is paramount; empirical treatment (flucloxacillin and gentamicin) is started in most cases and antibiotics are later adjusted according to the sensitivity of the microorganism. The addition of an aminoglycoside is associated with side-effects including nephrotoxicity and levels should therefore be measured. Once-daily aminoglycoside regimens are now widely used for other infections, but data regarding their efficacy in endocarditis are limited. For patients with intracardiac prosthetic material or suspected MRSA vancomycin is recommended (adjusted to renal function), and its levels should be also monitored. Benzylpenicillin is the first choice when Streptococcus or Enterococcus penicillin-susceptible strains are isolated, but sometimes it can be started empirically when the presentation of the IE is indolent. For vancomycin-resistant MRSA, the use of teicoplanin, lipopeptide daptomycin, or oxazilidones (linezolid) is recommended. The treatment of fungal endocarditis is currently unsatisfactory and usually requires surgical intervention. Amphotericin B does not penetrate well into vegetations, although it has been
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Fig 3 Mitral and aortic valve endocarditis. TOE, long-axis mid-oesophageal view. LA, left atrium; LV, left ventricle; RV, right ventricle; Ao, ascending aorta. The arrows point to vegetations on the mitral and aortic valve. The arrows in the colour section point to mitral regurgitation and a perforated anterior mitral leaflet. For associated video, please see Supplementary material online.
Infective endocarditis
Table 2 Antibiotic prophylaxis and treatment for the more frequent causes of IE Clinical situation
Agent
Dosage and route
Duration
A B C
Prophylaxis Prophylaxis (allergic to penicillin) Empirical treatment or isolated MSSA
D
Empirical treatment when risk of MRSA infection, confirmed MRSA or penicillin allergy Streptococci and Group D streptococci (in beta-lactam allergic patients start treatment D without aminoglycoside)
Amoxicillin Clindamycin Flucloxacillin Gentamicin Vancomycin Gentamicin
2 g p.o. or i.v. 600 mg p.o. or i.v. 12 g daily divided into 4 –6 doses 3 mg kg21 divided into 3 doses. I.V. or i.m 30 mg kg21 24 h21 divided into 2 doses 3 mg kg21 divided into 3 doses. I.V. or i.m.
Single dose Single dose 4–6 weeks or .6 weeks if prosthetic valve 3–5 days or 2 weeks if prosthetic valve 4–6 weeks or .6 weeks if prosthetic valve 3–5 days or 2 weeks if prosthetic valve
Benzylpenicillin
12 – 18 million U day21 i.v., divided into 6 doses
4 weeks
E
Surgery Antimicrobial therapy can offer a curative treatment in only 50% of patients. The other half requires surgery, and the threshold for early surgical treatment has been lowered in the last few years. Whenever possible, the surgical aim is valve repair, but most patients require valve replacement. Patients with IE and large vegetations, intracardiac abscess (9–14%), or persisting infection (9–11%) almost always need surgery.10 Anaesthetic management may be difficult, and patients with mitral or aortic regurgitation are particularly challenging. Hypotension despite hyperdynamic left ventricular function and hypoxaemia due to severe pulmonary oedema can complicate the anaesthetic induction. Some patients may also develop acute right ventricular dysfunction and severe tricuspid regurgitation. Invasive monitoring including arterial pressure and central venous pressure is necessary. Inotropes and vasopressors should be used to maintain haemodynamics. The use of intraoperative TOE is mandatory in order to confirm the structural defect, examine the morphology and functionality of all cardiac structures, provide haemodynamic assessment and guidance for fluid and inotropic support, and assess the results of surgical intervention. Patients with a peri-annular abscess have a higher risk of para-valvular regurgitation and valve dehiscence after operation. The maintenance of adequate antibiotic plasma levels during and after cardiopulmonary bypass is essential in order to reduce the risk of prosthetic valve endocarditis. The current IE perioperative mortality is 5–15%. If sepsis is under control, however, the surgical mortality is similar to
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non-infected valve replacement. The most frequent postoperative complications are persistent septic shock, coagulopathy, acute renal failure, stroke, refractory heart failure, and conduction abnormalities.
Recurrent IE The rate of recurrent IE at 5 yr follow-up is around 1.5% per patient-year. Recurrent IE can be separated into two types: reinfection and relapse. The term reinfection is primarily used when a different microorganism produces a new episode of IE in patients at risk of IE such as previous valve disease or i.v. drug use. Relapse refers to a repeat episode of IE caused by the same microorganism as the previous episode and it is normally associated with insufficient duration of original treatment, suboptimal choice of initial antibiotics, and a persistent focus of infection (i.e. periprosthetic abscess).
Conclusion IE is an infrequent and dynamic disease. Recent changes in the epidemiology of IE make the diagnosis a challenge, and traditional diagnostic criteria are insufficient. Despite modern medical and surgical therapy, IE is still associated with a high rate of complications and increased mortality. Early surgery is becoming more common and TOE should be used for all patients. IE is resourceconsuming, and a multidisciplinary approach is essential to provide efficient and cost-effective treatment.
Supplementary material Supplementary material is available at Continuing Education in Anaesthesia, Critical Care & Pain online. Please note: the supplementary videos are quite short, so readers should play them continuously to facilitate the understanding of the images.
Declaration of interest None declared.
References 1. Lee SJK. Infective endocarditis and phlebotomies may have killed Mozart. Korean Circ J 2010; 40: 611–3
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successfully used in Candida endocarditis. Fluconazole is fungistatic and is only active against some Candida spp. Caspofungin is usually fungicidal for Candida spp.; however, the penetration of caspofungin and other echinocandins into the vegetation is unknown. I.V. antibiotic medication is normally continued for 4–6 weeks, with the aim of sterilizing endocarditic vegetations. Patients with blood-culture-negative IE should be treated in consultation with an infectious disease specialist. (Standard antibiotic treatment is listed in Table 2.)
Infective endocarditis
2. Beynon RP, Bahl VK, Prendergast BD. Infective endocarditis. Br Med J 2006; 12: 334–9 3. Prendergast BD. The changing face of infective endocarditis. Heart 2006; 92: 879– 85 4. Fowler VG, Jr, Miro JM, Hoen B et al. Staphylococcus aureus endocarditis: a consequence of medical progress. J Am Med Assoc 2005; 293: 3012–21 5. Morellion P, Que Ya. Infective endocarditis. Lancet 2004; 10: 139 –49 6. Li JS, Sexton DJ, Mick N et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30: 633–8
9. National Institute for Health and Clinical Excellence. Antimicrobial prophylaxis against infective endocarditis. Available from http://guidance. nice.org.uk/CG64 (accessed 2 February 2011) 10. Remadi JP, Habib G, Nadji G et al. Predictors of death and impact of surgery in Staphylococcus aureus infective endocarditis. Ann Thorac Surg 2007; 83: 1295– 302
Please see multiple choice questions 21 –24.
Continuing Education in Anaesthesia, Critical Care & Pain j Volume 12 Number 3 2012
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7. Evangelista A, Gonzalez-Alujas MT. Echocardiography in infective endocarditis. Heart 2004; 90: 614– 7
8. The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Guidelines on the prevention, diagnosis, and treatment of infective endocarditis. Eur Heart J 2009; 30: 2369–413
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Key points
Clinical findings, echocardiography, and blood cultures are the cornerstone of IE diagnostics, and serological tests and polymerase chain reaction may be useful in culture-negative patients. Transoesophageal echocardiography is recommended in all patients with suspected or confirmed IE. When heart failure or large vegetations (.10 mm) are present, early surgery is recommended and associated with improved long-term clinical outcomes. Antibiotic prophylaxis solely to prevent IE is no longer recommended for persons at risk of IE.
Guillermo Martinez MD Consultant in Anaesthesia and Intensive Care Department of Anaesthesia and Intensive Care Papworth Hospital, UK Kamen Valchanov FRCA Consultant in Anaesthesia and Intensive Care Department of Anaesthesia and Intensive Care Papworth Hospital NHS Foundation Trust Cambridge CB23 3RE, UK Tel: þ44 1480 830541/364406 Fax: þ44 1480 364936 E-mail: [email protected]. uk (for correspondence)
134
‘No one can measure his own days, one must resign oneself, it will be as providence wills, and so I finish my death-song; I must not leave it incomplete.’ Mozart (The Mozart Myths, William Stafford, Stanford University Press, 1991) There are many theories behind Mozart’s mysterious final illness and no reliably confirmed remains have been found. One of the theories of his demise is that it was endocarditis that killed him.1
Introduction Infective endocarditis (IE) is a microbial infection of a heart valve (native or prosthetic) or the mural endocardium, leading to tissue destruction and formation of vegetations. It is primarily a disease of the heart, but by virtue of its haematogenic spread, it is also a multisystem disorder. The aim of this article is to review the epidemiological and microbiological profile of IE, as well as pathophysiology, clinical presentation, and management of complications.
Aetiology and epidemiology The incidence of IE is 1.7–7.2 cases per 100 000 person-years. The female to male ratio has remained stable over the years at 1:2.2 However, the median age of endocarditis patients has increased from 30–40 to 47 –69 yr and rheumatic heart disease is no longer the main risk factor for IE in Western countries. Increasing longevity, degenerative valve disease, and medical treatment, including prosthetic heart valves and indwelling devices such as pacemakers and implanted defibrillators, are the main factors responsible for these substantial changes in the epidemiological profile over the last few decades.3 The majority of cases of IE are caused by gram-positive bacteria. Staphylococcus aureus is now more common than oral Streptococci (formerly Streptococcus viridans) and it has
become the most frequent microorganism causing IE (31–54%). The clinical profiles of methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are different. MSSA is more frequently isolated in community-acquired IE, affects mainly native valves, and it is associated with bacteraemia of unknown origin. On the other hand, MRSA IE is predominantly related to nosocomial infection, wound infection, permanent i.v. catheters, or surgical intervention in the previous 6 months. Viridans group IE is now less common (17– 26%) than in the past, but these strains can be challenging to treat due to difficulties in isolation and partial resistance to antibiotics (‘penicillin tolerance’). Coagulase-negative Staphylococci were the main cause of prosthetic valve endocarditis in the past, particularly within the first 6–12 months after valve surgery. However, current data show that coagulase-negative Staphylococci are isolated in only 17% of prosthetic valve endocarditis, whereas MRSA is isolated in 23–31% of cases.4 Some gram-positive organism such as Streptococcus bovis (5– 8%) can be associated with bowel malignancy or other mucosal lesions. Gram-negative microorganisms can also cause IE. The slow-growing HACEK (Haemophilus parainfluenzae, Aggregatibacter aphrophilus, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) group is a well recognized but unusual cause of IE, responsible for 1.8– 3% of cases. The HACEK group affects mainly native valves, although up to one-third of the cases involve prosthetic valves. Candida and Aspergillus species cause the majority of fungal IE (1–3% of IE). I.V. drug abusers, prosthetic-valve recipients, and patients with long-term central venous catheters are at highest risk of fungal IE, which should be suspected in the presence of bulky vegetations, metastatic infection, perivalvular invasion, or embolization to large blood vessels, despite negative blood cultures.
doi:10.1093/bjaceaccp/mks005 Advance Access publication 29 February, 2012 Continuing Education in Anaesthesia, Critical Care & Pain | Volume 12 Number 3 2012 & The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://ceaccp.oxfordjournals.org/ at Purdue University Libraries ADMN on July 11, 2015
Infective endocarditis (IE) is a systemic life-threatening disease mainly affecting patients with heart valve disease, prosthetic valve, intracardiac devices, and i.v. drug abusers.
Matrix reference 3G00, 2A12
Infective endocarditis
criteria have a low sensitivity and cannot reasonably be applied when blood cultures are negative, when infection affects a prosthetic valve or a pacing system, and when IE affects the right heart.
Pathophysiology
Clinical features
IE originates at sites where the endothelium is damaged by high blood velocity or mechanical damage and on foreign bodies in the circulation. Initially, a sterile thrombotic vegetation (non-bacterial thrombotic endocarditis) is formed, which facilitates bacterial adherence during transient bacteraemia. Platelets and fibrin deposits at the injury site provide an adherent surface for the formation of vegetations. Finally, the vegetations may produce the secondary effects of endocarditis such as tissue destruction, generalized and difficult to eradicate sepsis, and septic emboli and abscesses. Gram-positive bacteria are particularly resistant to the patient’s bactericidal activity (i.e. complement), which facilitates the adhesion and formation of vegetations. However, there is no evidence that bacteraemia associated with invasive or semi-invasive interventions is more significant than that after teeth brushing, for example, and other patient risk factors play a greater role in the physiopathology of IE.5
In 1885, William Osler presented the first comprehensive description of endocarditis. Thereafter, the descriptions of clinical features of IE were largely based on data obtained several decades ago. Nowadays, Oslerian peripheral stigmata of IE such as Osler’s nodes (3%) or Janeway lesions (5%) are uncommon, and physical examination is often unremarkable. A history of weight loss and night sweats is frequently described (up to 96% of cases); a new or a different heart murmur (48% and 20%, respectively) and elevated C-reactive protein are also common findings. When the left heart is affected, vegetations most often develop on the ventricular aspect of the aortic valve and atrial surface of the mitral valve, usually along the edges of valve leaflets (Fig. 1). This explains why peripheral embolism is common. Embolic events usually occur before clinical recognition of the disease, and up to 30% of the patients have renal or splenic infarction at the time of diagnosis. In addition, the heart, brain, intestine, and other large organs may also be affected by septic emboli. Rapid evolution of IE is common in S. aureus, with no time for development of immunological phenomena characteristic of subacute IE. This is also the case in i.v. drug users, where right-sided IE usually involves the tricuspid valve and occasionally the pulmonary valve. Therefore, instead of systemic vascular phenomena, septic pulmonary embolism is the most important complication, which can evolve to pulmonary infarction, pulmonary abscess, bilateral pneumothoraces, pleural effusion, and empyema. The severity of valvular destruction varies with the virulence of the infecting organism and the duration of the infection, and heart failure can be the initial presentation of IE.
Diagnosis: clinical features, microbiology, and echocardiography Clinical suspicion and prompt investigation of IE is imperative. A multidisciplinary team involving microbiologists, cardiologists, neurologists, anaesthetists, surgeons, and intensivists should be involved in caring for these patients. The modified Duke criteria (Table 1) are based on clinical, microbiological, and echocardiographic findings, and provide high sensitivity and specificity (around 80%) for the diagnosis of IE when applied to patients with native valve IE with positive blood cultures.6 The diagnosis of IE is confirmed in the presence of two major criteria, one major and two minor, or five minor criteria. The diagnosis of IE is considered possible in the presence of one major and one minor or three minor criteria. However, the modified Duke Table 1 Simplified Duke criteria for the diagnosis of IE Major criteria Positive blood cultures Positive echocardiogram for IE defined as Oscillating intracardiac mass Intracardiac abscess New partial dehiscence of prosthetic valve Minor criteria Predisposition such as heart condition or i.v. drug use Fever Vascular phenomena or immunological phenomena such as major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial haemorrhage, conjunctival haemorrhages, and Janeway lesions Other microbiological evidence such as PCR, serological tests, or positive blood culture but does not meet a major criterion
Fig 1 TOE, mid-oesophageal commissural view of mitral valve vegetation (arrow). LA, left atrium; LV, left ventricle. For associated video, please see Supplementary material online.
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Whenever blood-culture-negative IE is suspected, other organisms such as Coxiella burnetti, Legionella spp., Brucella spp., Bartonella spp., and Chlamydiae spp. must be considered.
Infective endocarditis
Microbiology
Echocardiography Echocardiography is important for the diagnosis and management of patients with IE. Whatever the level of suspicion, a transthoracic echocardiogram (TTE) should be performed promptly. It is a noninvasive technique, providing useful information for both the diagnosis and severity of IE. However, the sensitivity of TTE ranges from 45% to 60%, and the quality of the study is not always adequate ( particularly in obese patients, obstructive lung disease, or after thoracic surgery). Transoesophageal echocardiography (TOE) offers better image quality and the overall sensitivity for IE is 90–100%.7 TOE is mandatory whenever perivalvular complications or mitral valve involvement is suspected.8 Three echocardiographic findings are the major criteria for diagnosis of IE: (i) vegetation, a mobile echodense mass attached to valvular leaflets or mural endocardium (Figs 2 and 3); (ii) periannular abscess; and (iii) new dehiscence of a valvular prosthesis (Fig. 4). The vegetation is the hallmark lesion of IE. The sensitivity of TTE and TOE for vegetations is 75% and 90%, respectively. Around 10% of IE involves the right side of the heart—most commonly, the tricuspid valve alone (98%), although the pulmonary valve and Eustachian valve IE has been reported. Isolated rightsided vegetation is well detected by TTE and TOE is not mandatory, although 15% of IE in i.v. drug users affects left-side valves and TOE should be considered. An abscess typically affects the aortic root and presents as a perivalvular zone of reduced echo density without blood flow
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Fig 2 Three-dimensional TOE showing a vegetation (arrow) on the mitral valve. For associated video, please see Supplementary material online.
detected inside (Fig. 3). The sensitivity of TTE for perivalvular abscess is low (45–50%) compared with TOE (more than 90%). The diagnosis of an abscess is an indication for early surgery. Other echocardiographic findings, which are not the major criteria but may suggest the presence of IE, include aortic or mitral valve regurgitation, developing as a consequence of valvular necrosis, perforation, or prolapse. About 50 –60% of patients with IE develop heart failure due to valve destruction and early surgery becomes necessary. The mortality of IE patients in heart failure is 80% with non-surgical therapy. Vegetation size and mobility is important. Stroke complicates 20 –40% of left-sided IE and it is the second most common cause of death. A vegetation size of .10 mm or sessile vegetations are independent predictors of stroke and mortality, and early surgery (within 1 week of diagnosis) is associated with improved long-term outcomes through a reduction in systemic embolic events compared with non-surgical therapy. If the vegetations are small or have already embolized, echocardiography can produce false-negative results in about 15% of cases. When clinical suspicion is high, TOE can be repeated after 7 –10 days. Echocardiographic diagnosis can be difficult in the early stage of the disease or in patients with intracardiac devices. TOE allows the identification of high-risk patients and may identify patients who need surgery.
Prophylaxis of IE The role of anaesthetists and intensivists is crucial in the treatment of IE. They are involved in preventing infective complications associated with indwelling devices, antibiotic prophylaxis, and antibiotic treatment when required. Anaesthetists are also involved in echocardiographic and general assessment for patients for surgery and perioperative care. In 2008, the National Institute of Clinical Excellence (NICE) published guidance for antimicrobial prophylaxis of IE in adults
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A positive blood culture is still the best method for the identification of the microorganisms causing IE and it is considered to be a major diagnostic criteria. Blood cultures are positive in about 80% of cases, but may be negative in cases of intracellular or fastidious pathogens or after previous antibiotic treatment. Therefore, whenever IE is suspected (i.e. temperature . 388C, new regurgitant murmur, and history of valvular disease), it is mandatory to perform blood cultures before starting antibiotic treatment. When the antimicrobial agents have been administered before blood cultures are obtained, the recovery rate of bacteria is reduced by 35–40%. Three sets (including at least one aerobic and one anaerobic), obtained from a sterile site, are normally sufficient to identify the usual microorganisms, but some patients may need repetitive sampling. Culture-negative IE often delays diagnosis and the initiation of treatment, with a profound impact on clinical outcome. Specific serological data can also be used to identify the organisms of culture-negative IE. Polymerase chain reaction positivity has been proposed as a major diagnostic criterion for IE, but the technique seems unlikely to supersede blood cultures as a prime diagnostic tool. A polymerase chain reaction of excised valve tissue or embolic material should be performed in patients with negative blood cultures who undergo valve surgery or embolectomy.
Infective endocarditis
valve replacement, or structural congenital heart disease, excluding repaired atrial or ventricular septal defect or patent ductus arteriosus). Suggested antibiotic prophylaxis is listed in Table 2.
Treatment Antibiotics
Fig 4 TOE, mid-oesophageal short-axis view showing the prosthetic valve in the aortic position (dotted arrow) and peri-prosthetic aortic root abscess (continuous arrow).
and children undergoing interventional procedures.9 The NICE guidance suggests that there is weak evidence to support routine preoperative antibiotic prophylaxis for persons at risk of IE. It also states that there is a risk of allergic reactions related to antibiotics and there are financial and resistance implications from liberal overuse of antibiotics. Antibiotic prophylaxis to prevent IE is therefore no longer routinely recommended. However, in the case of actual infection at the operative site, antibiotic prophylaxis is still recommended in high-risk patients (such as acquired valvular heart disease, previous
Microbiology advice should be sought in all cases. Early antimicrobial therapy is paramount; empirical treatment (flucloxacillin and gentamicin) is started in most cases and antibiotics are later adjusted according to the sensitivity of the microorganism. The addition of an aminoglycoside is associated with side-effects including nephrotoxicity and levels should therefore be measured. Once-daily aminoglycoside regimens are now widely used for other infections, but data regarding their efficacy in endocarditis are limited. For patients with intracardiac prosthetic material or suspected MRSA vancomycin is recommended (adjusted to renal function), and its levels should be also monitored. Benzylpenicillin is the first choice when Streptococcus or Enterococcus penicillin-susceptible strains are isolated, but sometimes it can be started empirically when the presentation of the IE is indolent. For vancomycin-resistant MRSA, the use of teicoplanin, lipopeptide daptomycin, or oxazilidones (linezolid) is recommended. The treatment of fungal endocarditis is currently unsatisfactory and usually requires surgical intervention. Amphotericin B does not penetrate well into vegetations, although it has been
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Fig 3 Mitral and aortic valve endocarditis. TOE, long-axis mid-oesophageal view. LA, left atrium; LV, left ventricle; RV, right ventricle; Ao, ascending aorta. The arrows point to vegetations on the mitral and aortic valve. The arrows in the colour section point to mitral regurgitation and a perforated anterior mitral leaflet. For associated video, please see Supplementary material online.
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Table 2 Antibiotic prophylaxis and treatment for the more frequent causes of IE Clinical situation
Agent
Dosage and route
Duration
A B C
Prophylaxis Prophylaxis (allergic to penicillin) Empirical treatment or isolated MSSA
D
Empirical treatment when risk of MRSA infection, confirmed MRSA or penicillin allergy Streptococci and Group D streptococci (in beta-lactam allergic patients start treatment D without aminoglycoside)
Amoxicillin Clindamycin Flucloxacillin Gentamicin Vancomycin Gentamicin
2 g p.o. or i.v. 600 mg p.o. or i.v. 12 g daily divided into 4 –6 doses 3 mg kg21 divided into 3 doses. I.V. or i.m 30 mg kg21 24 h21 divided into 2 doses 3 mg kg21 divided into 3 doses. I.V. or i.m.
Single dose Single dose 4–6 weeks or .6 weeks if prosthetic valve 3–5 days or 2 weeks if prosthetic valve 4–6 weeks or .6 weeks if prosthetic valve 3–5 days or 2 weeks if prosthetic valve
Benzylpenicillin
12 – 18 million U day21 i.v., divided into 6 doses
4 weeks
E
Surgery Antimicrobial therapy can offer a curative treatment in only 50% of patients. The other half requires surgery, and the threshold for early surgical treatment has been lowered in the last few years. Whenever possible, the surgical aim is valve repair, but most patients require valve replacement. Patients with IE and large vegetations, intracardiac abscess (9–14%), or persisting infection (9–11%) almost always need surgery.10 Anaesthetic management may be difficult, and patients with mitral or aortic regurgitation are particularly challenging. Hypotension despite hyperdynamic left ventricular function and hypoxaemia due to severe pulmonary oedema can complicate the anaesthetic induction. Some patients may also develop acute right ventricular dysfunction and severe tricuspid regurgitation. Invasive monitoring including arterial pressure and central venous pressure is necessary. Inotropes and vasopressors should be used to maintain haemodynamics. The use of intraoperative TOE is mandatory in order to confirm the structural defect, examine the morphology and functionality of all cardiac structures, provide haemodynamic assessment and guidance for fluid and inotropic support, and assess the results of surgical intervention. Patients with a peri-annular abscess have a higher risk of para-valvular regurgitation and valve dehiscence after operation. The maintenance of adequate antibiotic plasma levels during and after cardiopulmonary bypass is essential in order to reduce the risk of prosthetic valve endocarditis. The current IE perioperative mortality is 5–15%. If sepsis is under control, however, the surgical mortality is similar to
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non-infected valve replacement. The most frequent postoperative complications are persistent septic shock, coagulopathy, acute renal failure, stroke, refractory heart failure, and conduction abnormalities.
Recurrent IE The rate of recurrent IE at 5 yr follow-up is around 1.5% per patient-year. Recurrent IE can be separated into two types: reinfection and relapse. The term reinfection is primarily used when a different microorganism produces a new episode of IE in patients at risk of IE such as previous valve disease or i.v. drug use. Relapse refers to a repeat episode of IE caused by the same microorganism as the previous episode and it is normally associated with insufficient duration of original treatment, suboptimal choice of initial antibiotics, and a persistent focus of infection (i.e. periprosthetic abscess).
Conclusion IE is an infrequent and dynamic disease. Recent changes in the epidemiology of IE make the diagnosis a challenge, and traditional diagnostic criteria are insufficient. Despite modern medical and surgical therapy, IE is still associated with a high rate of complications and increased mortality. Early surgery is becoming more common and TOE should be used for all patients. IE is resourceconsuming, and a multidisciplinary approach is essential to provide efficient and cost-effective treatment.
Supplementary material Supplementary material is available at Continuing Education in Anaesthesia, Critical Care & Pain online. Please note: the supplementary videos are quite short, so readers should play them continuously to facilitate the understanding of the images.
Declaration of interest None declared.
References 1. Lee SJK. Infective endocarditis and phlebotomies may have killed Mozart. Korean Circ J 2010; 40: 611–3
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successfully used in Candida endocarditis. Fluconazole is fungistatic and is only active against some Candida spp. Caspofungin is usually fungicidal for Candida spp.; however, the penetration of caspofungin and other echinocandins into the vegetation is unknown. I.V. antibiotic medication is normally continued for 4–6 weeks, with the aim of sterilizing endocarditic vegetations. Patients with blood-culture-negative IE should be treated in consultation with an infectious disease specialist. (Standard antibiotic treatment is listed in Table 2.)
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2. Beynon RP, Bahl VK, Prendergast BD. Infective endocarditis. Br Med J 2006; 12: 334–9 3. Prendergast BD. The changing face of infective endocarditis. Heart 2006; 92: 879– 85 4. Fowler VG, Jr, Miro JM, Hoen B et al. Staphylococcus aureus endocarditis: a consequence of medical progress. J Am Med Assoc 2005; 293: 3012–21 5. Morellion P, Que Ya. Infective endocarditis. Lancet 2004; 10: 139 –49 6. Li JS, Sexton DJ, Mick N et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000; 30: 633–8
9. National Institute for Health and Clinical Excellence. Antimicrobial prophylaxis against infective endocarditis. Available from http://guidance. nice.org.uk/CG64 (accessed 2 February 2011) 10. Remadi JP, Habib G, Nadji G et al. Predictors of death and impact of surgery in Staphylococcus aureus infective endocarditis. Ann Thorac Surg 2007; 83: 1295– 302
Please see multiple choice questions 21 –24.
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7. Evangelista A, Gonzalez-Alujas MT. Echocardiography in infective endocarditis. Heart 2004; 90: 614– 7
8. The Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Guidelines on the prevention, diagnosis, and treatment of infective endocarditis. Eur Heart J 2009; 30: 2369–413
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