European Heart Journal (2013) 34, 1186–1197 REVIEW

doi:10.1093/eurheartj/ehs372

Clinical update

Management of pericardial effusion

Massimo Imazio 1* and Yehuda Adler 2
1
Department Cardiology, Maria Vittoria Hospital, Via Luigi Cibrario 72, Torino 10141, Italy; and 2Chaim Sheba Medical Center, Tel Hashomer, and Sackler University, Tel Aviv, Israel

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Received 26 June 2012; revised 10 August 2012; accepted 9 October 2012; online publish-ahead-of-print 2 November 2012

Pericardial effusion is a common finding in clinical practice either as incidental finding or manifestation of a systemic or cardiac disease. The
spectrum of pericardial effusions ranges from mild asymptomatic effusions to cardiac tamponade. The aetiology is varied (infectious, neo-
plastic, autoimmune, metabolic, and drug-related), being tuberculosis the leading cause of pericardial effusions in developing countries
and all over the world, while concurrent HIV infection may have an important promoting role in this setting. Management is guided by
the haemodynamic impact, size, presence of inflammation (i.e. pericarditis), associated medical conditions, and the aetiology whenever pos-
sible. Pericardiocentesis is mandatory for cardiac tamponade and when a bacterial or neoplastic aetiology is suspected. Pericardial biopsy is
generally reserved for cases with recurrent cardiac tamponade or persistence without a defined aetiology, especially when a bacterial or
neoplastic aetiology is suspected and cannot be assessed by other conventional and less invasive means. A true isolated effusion may not
require a specific treatment if the patient is asymptomatic, but large ones are at risk of progression to cardiac tamponade (up to one
third). Pericardiocentesis alone may be curative for large effusions, but recurrences are also common and pericardiectomy or less invasive
options (i.e. pericardial window) should be considered with recurrent cardiac tamponade or symptomatic pericardial effusion (either circum-
ferential or loculated). The aim of this paper was to summarize and critically evaluate current knowledge on the management of pericardial
effusion.
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Keywords Pericardial effusion † Aetiology † Diagnosis † Management † Pericarditis

Introduction cause of pericardial disease and concurrent HIV infection may

Probably no serious disease is so frequently overlooked by the prac-
titioner. Postmortem experience shows how often pericarditis is not
recognized or goes to resolution and adhesion without attracting
notice (Osler, The Principles and Practice of Modern Medicine, 1892).
Pericardial effusion is a common finding in clinical practice either as
incidental finding or manifestation of a systemic or cardiac disease.
The spectrum of pericardial effusions ranges from mild asymptom-
atic effusions to cardiac tamponade. Moreover, pericardial effusion
may accumulate slowly or suddenly.1 – 3 Unfortunately, there are
few epidemiological data on the incidence and prevalence of
such effusions in the clinical setting. In Maria Vittoria hospital, an
urban general hospital in Torino and an Italian referral centre for
pericardial diseases, the mean annual incidence and prevalence of
pericardial effusion have been, respectively, 3 and 9% in a 6
years experience of the echo laboratory (2000–05).4 Such data
mainly depend on the epidemiological background (especially
developed vs. developing country, where tuberculosis is a leading
have an important promoting role),5 the institutional setting
(tertiary referral centre vs. secondary and general hospitals), and
the availability of specific subspecialties (especially nephrology,
rheumatology, and oncology).
No specific guidelines and management recommendations have
been issued by medical societies beyond the 2000 national Spanish
guidelines6 and the 2004 European Society of Cardiology guide-
lines on the management of pericardial diseases,7 and some narra-
tive reviews on the topic,4,8,9 whereas no specific guidelines have
been issued from the American Heart Association (AHA) and
American College of Cardiology (ACC).
It is the aim of this review to critically evaluate current knowl-
edge on the management of pericardial effusion. A thorough litera-
ture review has been performed without language restriction with
the MeSH term ‘pericardial effusion’ or ‘pericardial’[All Fields] and
‘effusion’[All Fields]) or ‘pericardial effusion’[All Fields]. After the
initial identification of 1520 papers, 139 papers were selected for
detailed review based on novelty or important data leading to
the final inclusion of 50 papers in the final reference list.

* Corresponding author. Tel: +39 011 4393391, Fax: +39 011 4393334, Email: massimo_imazio@yahoo.it
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com
Management of pericardial effusion
Initial evaluation and
pathophysiological issues
When a pericardial effusion is detected, the first step is to evaluate
its size and haemodynamic importance, as well as the possible as-
sociation with concomitant diseases. Echocardiography is the first
diagnostic tool for this assessment as also acknowledged by the
AHA/ACC guidelines on the use of echocardiography, that gave
a class I indication for the use of echocardiography in any case
of suspected pericardial disease.10
Pericardial effusion may be classified based on its onset (acute,
subacute vs. chronic when dating .3 months), distribution (cir-
cumferential or loculated), haemodynamic impact (none, cardiac
tamponade, effusive-constrictive), composition (exudates, transu-
date, blood, rarely air, or gas from bacterial infections), and espe-
cially by its size as mild, moderate, and large (Table 1) based on a
simple semiquantitative echocardiographic assessment (Figure 1)
that has been demonstrated useful also to estimate the risk of
specific aetiology and complications during follow-up.4,7,9,11,12
The normal pericardial sac contains 10 –50 mL of pericardial
fluid acting as a lubrificant between the pericardial layers. Surpris-
ingly, little is known about the formation and removal of pericardial
fluid, because of the paucity of comprehensive studies, especially
in human subjects, and methodological difficulties to distinguish
between the dynamics of normal pericardial fluid and those of a
pathological effusion (Supplementary material online, Reference
A). Nevertheless, normal pericardial fluid is generally considered
an ultrafiltrate of plasma (Supplementary material online, Refer-
ence B). The arrangement of lymphatic vessels is complex and
has been described in human cadavers (Supplementary material
online, References C and D). The lymphatic vessels include differ-
ent pathways according to ventral, lateral, and posterior surfaces,
Table 1 Classification of pericardial effusion
Onset Acute (,1 week)
Subacute (.1 week but ,3 months)
Chronic (.3 months)
Size Mild (,10 mm)
Moderate (10– 20 mm)
Large (.20 mm)
Distribution Circumferential
Loculated
Haemodynamic Without cardiac tamponade
effect With cardiac tamponade
Effusive-constrictive
Composition/type Transudate
Exudate
Hydropericardium (transudate, plasma
ultrafiltrate)
Haemopericardium (blood in pericardial
space)
Chylopericardium (chylous pericardial fluid)
Pyopericardium (purulent pericardial effusion)
Pneumopericardium (air in the pericardium)
No precise definition is available for acute and subacute pericardial effusion,
while the definition of chronic as .3 months is more clearly defined.
1187
but, in any case, terminate to mediastinal, tracheobronchial, or iux-
taesophageal lymph nodes. On the ventral surface, the lymphatics
of the parietal pericardium connect to lymphatics in the pericardial
fat and areolar tissue. On the lateral and posterior surfaces, the
lymphatics of the parietal pericardium anastomose with lymphatics
of the reflected mediastinal pleura (Supplementary material online,
Reference C). Lymphatic drainage of the pericardium to the medi-
astinal and tracheobronchial lymph nodes and interactions with
pleural lymphatics (Supplementary material online, Reference D)
provide the anatomical basis for pathological involvement of the
pericardium in specific diseases (i.e. pleuro-pulmonary diseases
such as pulmonary tuberculosis and lung cancer).
Any pathological process usually causes an inflammatory
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process with the possible increased production of pericardial
fluid (exudate). An alternative mechanism of the formation of peri-
cardial fluid may be the decreased reabsorption due to increased
systemic venous pressure generally as a result of congestive
heart failure or pulmonary hypertension (transudate). If pericardial
fluid is free to move within the pericardial sac following the gravity
forces, it usually starts accumulating posteriorly to the left ventricle
when the patient is laying on his/her left side for echocardiographic
evaluation (mild effusion detected initially as posterior), then cir-
cumferentially in the case of moderate to large pericardial effu-
sions. A mild pericardial effusion may also be detected close to
the right atrium because this is the cardiac chamber with the
lowest pressures within the cardiac cycle and thus pericardial
fluid accumulation is easier in this position (Figure 2). An isolated
mild anterior pericardial fluid is unusual on echocardiography
without previous pericardial scarring as following surgery or
chronic pericarditis, and should be regarded as fat rather than peri-
cardial fluid.13 Computed tomography (CT) or cardiac magnetic
resonance (CMR) may confirm the finding in specific cases14
(Figure 3). On the contrary after pericardial scarring (i.e. after
cardiac surgery or chronic pericarditis, or bacterial infections),
pericardial fluid may not have a uniform distribution within the
pericardial space and may give rise to loculated effusions that
should be evaluated with multiple cardiac views.14,15
The pressure– volume curve of the normal pericardium is a
J-shaped curve: after an initial short shallow portion that allows
the pericardium to stretch slightly in response to physiological
events, such as changes in posture or volume status, with
minimal pressure increase, then the pericardium does not allow
further sudden increases of the volume without a marked increase
in the intrapericardial pressure. Thus a sudden increase of pericar-
dial volume of 100–200 mL, as in haemopericardium, may elevate
pericardial pressure till 20 –30 mmHg with acute cardiac tampon-
ade (acute or surgical cardiac tamponade). On the contrary a
slowly accumulating pericardial fluid may allow pericardial disten-
tion till the accumulation of 1–2 L of pericardial fluid without
the development of cardiac tamponade (Figure 4) till advanced
stages often because of intercurrent events (chronic cardiac tam-
ponade or medical cardiac tamponade).1,3,16
Aetiology
A wide variety of aetiologic agents may be responsible of pericar-
dial effusions, since all known causes of pericardial disease may
1188 M. Imazio and Y. Adler

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Figure 1 (A) The semiquantitative assessment of the pericardial effusion size in a case of idiopathic chronic pericardial effusion. A large peri-
cardial effusion of .30 mm in diastole is shown in parasternal long-axis view. (B) Acute pleuropericarditis with ST segment elevation and sinus
tachycardia on ECG strip. A large pericardial effusion .20 mm with concomitant pleural effusion is also evident posteriorly to the aorta. Pe,
pericardial effusion; pl, pleural effusion; Ao, aorta.

Figure 2 Presentation of a mild (A) vs. moderate to large pericardial effusions (B) on echocardiography. Mild pericardial effusion is evident
adjacent to the right atrium in four-chambers view and only posterior in parasternal long-axis view (A). As fluid accumulates, the effusion
becomes circumferential (B). Pe, pericardial effusion; RA, right atrium; Ao, aorta.

be causative agents (Table 2). The more common causes of
pericardial effusions include infections (viral, bacterial, especially
tuberculosis), cancer, connective tissue diseases, pericardial in-
jury syndromes (post-myocardial infarction effusions, post-
pericardiotomy syndromes, post-traumatic pericarditis either
iatrogenic or not), metabolic causes (especially hypothyroidism,
renal failure), myopericardial diseases (especially pericarditis, but
also myocarditis, heart failure), aortic diseases, especially aortic dis-
section extending into the pericardium, and selected drugs (i.e.
minoxidil). Hydropericardium, a non-inflammatory transudative
pericardial effusion, may occur not only in heart failure, but also
advanced hypoalbuminaemia, such as in cirrhosis and nephrotic
Management of pericardial effusion 1189

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Figure 3 Differential diagnosis of pericardial effusion vs. epicardial fat. (A) Echocardiographic view. Anterior pericardial echo-free space.
No effusion was evident adjacent to the right atrium in four-chambers view. (B) Epicardial fat and thickened pericardium with contrast enhance-
ment on CT scan.

Figure 4 Pressure/volume curve of the pericardium with fast accumulating pericardial fluid leading to cardiac tamponade with a smaller
volume (A) compared with the slowly accumulating pericardial fluid reaching cardiac tamponade only after larger volumes (B).

syndrome, when Starling forces promote the accumulation of a
plasma ultrafiltrate across the pericardium as well as other mem-
branes (e.g. pleura and peritoneum).
In the last 20 years, five major surveys have been published on
the characteristics of moderate to large pericardial effusions
(Table 3).17 – 21 Obviously, the relative frequency of different
causes depends on the local epidemiology (especially the preva-
lence of tuberculosis), the hospital setting, and the diagnostic
protocol that has been adopted. Many cases still remain idiopathic
in developed countries (up to 50%), while other common causes
include especially cancer (10– 25%), pericarditis and infectious
causes (15–30%), iatrogenic causes (15 –20%), and connective
tissue disease (5–15%), whereas tuberculosis is the dominant
cause in developing countries (.60%), where tuberculosis is
endemic.22 In the setting of pericarditis with pericardial effusion,
the prevalence of malignant or infectious aetiologies ranges from
15 to 50% depending on published series.12,17 – 21
At present, the largest cohort of patients with moderate (echo-
free space of 10–20 mm during diastole) and large pericardial effu-
sions (echo-free space .20 mm) comes from Spain and includes
322 cases (mean age 56 years, 52% males). Cases were collected
retrospectively from 1990 to 93 and then prospectively from
1994 to 96 in a 637-bed university general hospital in Barcelona.
The authors adopted a three-stage protocol including a basic
evaluation for all (stage I including clinical history, physical examin-
ation, electrocardiography, chest X-ray, echocardiography, evalu-
ation for tuberculosis, measurement of serum antinuclear
antibodies and thyroid hormones, and other targeted studies
according to specific presentation), followed by stage II with peri-
cardiocentesis and pericardial fluid analysis for those with cardiac
tamponade, suspicion of purulent pericarditis, or chronic large
pericardial effusions. Stage III (surgical biopsy of the pericardium)
was limited to those with persistent or recurring tamponade
after pericardiocentesis, and when the effusion lasted for .3
1190
Table 2 Causes of pericardial effusion
Infectious
Viral (most common: Echovirus and Coxsackievirus (usual), Influenza,
EBV, CMV, Adenovirus, Varicella, Rubella, Mumps, HBV, HCV, HIV,
Parvovirus B19 and Human Herpes Virus 6 (increasing reports)
Bacterial [most common: tuberculous (4 –5%), Coxiella burnetii, other
bacterial rare may include Pneumo-, Meningo-, Gonococcosis,
Haemophilus, Staphylococci, Chlamydia, Mycoplasma, Legionella,
Leptospira, and Listeria]
Fungal (rare: Histoplasma more likely in immunocompetent patients,
Aspergillosis, Blastomycosis, Candida more likely in
immunosuppressed host)
Parasitic (very rare: echinococcus, toxoplasma)
................................................................................
Non-infectious
Autoimmune and autoinflammatory
Systemic inflammatory diseases (more common in systemic lupus
erythematosus, Sjögren syndrome, rheumatoid arthritis, systemic
sclerosis, systemic vasculitides, Behçet syndrome, Sarcoidosis,
Familial Mediterranean Fever)
Pericardial injury syndromes (post-myocardial infarction,
post-pericardiotomy syndrome, post-traumatic)
Autoreactive
Cancer
Primary tumours (rare, especially pericardial mesothelioma)
Secondary metastatic tumours (lung, breast cancer, lymphomas, and
melanoma)
Metabolic (Uraemia, Myxedema)
Trauma
Direct injury (penetrating thoracic injury, oesophageal perforation, and
iatrogenic)
Indirect injury (non-penetrating thoracic injury, and radiation injury)
Mediastinal radiation, recent, or remote
Drugs and toxins (rare): Procainamide, hydralazine, isoniazid, and
phenytoin (lupus-like syndrome), Penicillins (hypersensitivity
pericarditis with eosinophilia), Doxorubicin and daunorubicin
(often associated with a cardiomyopathy, may cause a
pericardiopathy). Minoxidil. Immunosuppressive therapies (e.g.
methotrexate, cyclosporine)
Haemodynamic (heart failure, pulmonary hypertension, and
hypoalbuminaemia)
weeks after admission and without an aetiologic diagnosis. The
most common diagnoses included: acute idiopathic pericarditis
(20%), iatrogenic effusions (16%), cancer (13%), and chronic
idiopathic pericardial effusion (9%). In 60% of cases, the cause of
pericardial effusion was a known medical condition.18
Clinical presentation
The clinical presentation of pericardial effusion is varied according
to the speed of pericardial fluid accumulation as mentioned in the
introduction, and the aetiology of the effusion with possible symp-
toms that may be related to the causative disease. The rate of peri-
cardial fluid accumulation is critical for the clinical presentation. If
pericardial fluid is quickly accumulating such as for wounds or
M. Imazio and Y. Adler
iatrogenic perforations, the evolution is dramatic and only small
amounts of blood are responsible of a quick rise of intrapericardial
pressure and overt cardiac tamponade in minutes. On the contrary
a slowly accumulating pericardial fluid allows the collection of a
large effusion in days to weeks before a significant increase in peri-
cardial pressure becomes responsible of symptoms and signs.3
Classical symptoms include dyspnoea on exertion progressing to
orthopnoea, chest pain, and/or fullness. Additional occasional
symptoms due to local compression may include nausea (dia-
phragm), dysphagia (oesophagus), hoarseness (recurrent laryngeal
nerve), and hiccups (phrenic nerve). Non-specific symptoms
include also cough, weakness, fatigue, anorexia and palpitations
and reflect the compressive effect of the pericardial fluid on con-
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tiguous anatomic structures or reduced blood pressure and sec-
ondary sinus tachycardia.23
The classical findings of cardiac tamponade have been described
by the thoracic surgeon Beck in 1935.24 Beck identified a triad in-
cluding hypotension, increased jugular venous pressure, and a small
and quiet heart. This triad was classically identified in ‘surgical tam-
ponade’ with acute cardiac tamponade due to intrapericardial
haemorrhage because of trauma, myocardial or aortic rupture.
The Beck triad may be lacking in patients with ‘medical tamponade’
with slowly accumulating pericardial fluid. Hypotension is absolute
or relative. Acute cardiac tamponade is usually associated with low
blood pressure (,90 mmHg) but may be only slightly reduced in
subacute, chronic tamponade. Hypertensive patients may have
normal to mildly elevated blood pressure concomitant to cardiac
tamponade.25 Fever is a non-specific sign that may be associated
with pericarditis either infectious or immune-mediated (i.e. system-
ic inflammatory diseases).
On physical examination classical signs include neck vein disten-
tion with elevated jugular venous pressure at bedside examination,
pulsus paradoxus, and diminished heart sounds on cardiac auscul-
tation. Pericardial friction rubs are rarely reported, they can be
usually detected in patients with concomitant pericarditis. Rubs
which occur during the maximal movement of the heart within
its pericardial sac, are said to be generated by friction between
the two inflamed layers of the pericardium. However, this com-
monly offered explanation for its mechanism may be an oversimpli-
fication as patients with a pericardial effusion may also have an
audible friction rub, and there is no precise correlation between
pericardial rubs and size of the effusion, although pericardial rubs
may be easier to hear in patients without a pericardial effusion,
but this finding is not universal and is not well-documented
(Supplementary material online, Reference E). In a report of 100
patients with acute pericarditis, a pericardial rub was present in
85% of cases without an effusion (Supplementary material online,
Reference F). This prevalence is considerably higher than the
35% incidence of friction rubs reported in another series (Supple-
mentary material online, Reference G).
Pulsus paradoxus has been described for the first time by Kuss-
maul in 1873 as a palpable reduction of radial pulse on inspiration
in patients with cardiac tamponade.26 The so-called paradox was
the ‘waxing and waning’ of the peripheral pulse, in contrast to
the unvarying strength of the apical cardiac impulse. Pulsus para-
doxus is classically defined as an inspiratory reduction of at least
10 mmHg of the systolic blood pressure (Figure 5). It can be
Management of pericardial effusion 1191

Table 3 Aetiologic diagnosis of moderate to large pericardial effusions according to major published series

Feature Corey et al.17 Sagrista-Sauleda et al.18 Levy et al.19 Reuter et al.20 Ma et al.21
...............................................................................................................................................................................
Patients 57 322 204 233 140
Study years 1993 1990– 96 1998–2002 1995– 2001 2007– 09
Country USA Spain France South Africa China
Effusion size .5 mm .10 mm NR NR Moderate to largea
Cardiac NR 37 NR NR NR
tamponade
Evaluation Subxiphoid TB, ANA, TSH, BCx, TSH, ANA, Q HIV, sputum, TB, BCx, Pericardiocen-tesis
pericardiotomy pericardiocen-tesis, and fever, viral rectal, and blood chemistry,
biopsy throat swabs and serology

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Idiopathic (%) 7 29 48 14 9
Cancer (%) 23 13 15 9 39
Infections (%) 27 2 16 72 29
Connective tissue 12 5 10 5 6
diseases (%)
Metabolic (%) 24 6 11 0 0
Iatrogenic (%) 0 16 0 0 9

A selection of the most frequent aetiological diagnoses is reported (thus overall sum in columns may be ,100%).
NR, not reported; TB, aetiology search for tuberculosis; BCx, blood cultures.
a
All effusions requiring pericardiocentesis.

In the absence of cardiac tamponade reported symptoms and

signs are non-specific and may include: shortness of breath, dys-
pnoea on exertion, fever, chills, chest pain, paroxysmal nocturnal
dyspnoea, orthoponea, cough, and oedema.23 All these symptoms,
and signs may be secondary to the underlying cause of the effusion
(i.e. systemic disease and pericarditis) or the initial mechanical
interference of pericardial fluid with cardiac function or surround-
ing anatomical structures.

Figure 5 The femoral artery pressure curve showing pulsus
paradoxus during cardiac tamponade. A systolic blood pressure
decline is .10 mmHg during inspiration.
easily detected recording the systolic pressure at which Korotkoff
sounds are first audible and the systolic pressure at which they are
audible through the whole respiratory cycle. Pulsus paradoxus is
due to exaggerated ventricular interdependence occurring in
cardiac tamponade when overall volume of cardiac chambers
becomes fixed and any change in the volume of one side of the
heart causes the opposite changes in the other side (i.e. inspiratory
increase of venous return and right chambers with decreased left
chambers volume and reduced systemic blood pressure).
Diagnosis
The diagnosis of pericardial effusion is generally performed by
echocardiography, that also allows the semiquantitative assessment
of the pericardial effusion size and its haemodynamic effects as out-
lined in the paragraph on the initial approach to pericardial effu-
sion. The diagnosis of cardiac tamponade is essentially a clinical
diagnosis requiring echocardiographic confirmation of the initial
diagnostic suspicion. In most patients, cardiac tamponade should
be diagnosed by a clinical examination that shows elevated system-
ic venous pressure, tachycardia, dyspnoea, and paradoxical arterial
pulse. Systemic blood pressure may be normal, decreased, or even
elevated. The diagnosis is confirmed by an echocardiographic dem-
onstration of moderately large or large circumferential pericardial
effusion and in most instances, of right atrial compression, abnor-
mal respiratory variation in right and left ventricular dimensions,
and in tricuspid and mitral valve flow velocities usually associated
with inferior vena cava plethora (Table 4 and Figure 6) (Supplemen-
tary material online, Reference H).27
However, a more complex task is the evaluation of the aeti-
ology. Different diagnostic protocols have been proposed.4,8,17 – 21
1192 M. Imazio and Y. Adler

Nevertheless, the diagnostic work-up should be guided by the
epidemiology and the clinical presentation to avoid performing
an extensive and blinded testing. As already remarked, developing
countries have a high rate of pericardial effusions correlated to tu-
berculosis (.60, and .80% with HIV infection)28,29 that should be
ruled out in such context, as well as in immigrants and HIV-infected
patients. Non-idiopathic and non-viral aetiologies (especially bac-
terial and neoplastic) are associated with an increased risk of
cardiac tamponade and large effusion, and pericardiocentesis is
mandatory when cardiac tamponade or such aetiologies are
suspected.4,6,7
Analyses of pericardial effusion can establish the diagnosis of in-
fectious and neoplastic pericardial effusions. Cytology and tumour
glucose can separate exudates from transudates, but are not dir-
ectly diagnostic (class IIb). Nevertheless, purulent effusions with
positive cultures have significantly lower fluid glucose levels than
non-infectious effusions. White cell count is highest in inflamma-
tory and infectious diseases, and lowest in myxedema. Technical
advances in instrumentation, introduction of pericardioscopy and
contemporary pathology, virology, and molecular biology techni-
ques have improved the diagnostic value of epicardial/pericardial
biopsy. Pericardioscopy performed through air instead of fluid,
made it possible to inspect large areas of pericardial surface,
select the biopsy site, and take numerous samples. Targeted peri-
cardial/epicardial biopsy during pericardioscopy was particularly
useful in the diagnosis of neoplastic pericarditis. No major compli-

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markers [carcinoembryonic antigen (CEA), alfafeto protein, carbo- cations were reported with the use of flexible pericardioscopies
hydrate antigens CA 125, CA 72-4, CA 15-3, CA 19-9, etc.) should (Supplementary material online, References I and J). Such techniques
be performed in suspected malignant disease. In suspected tuber- and approaches are warranted in skilled tertiary referral centres for
culosis acid-fast bacilli staining, mycobacterium culture or radio- selected cases, when a specific diagnosis, that may require a targeted
metric growth detection (e.g. BACTEC-460), adenosine therapy (i.e. neoplastic pericardial effusion), is suspected and cannot
deaminase (ADA), interferon (IFN)-gamma, pericardial lysozyme, be diagnosed by traditional diagnostic means.
and as well as PCR analyses for tuberculosis should be performed In the 2004 ESC guidelines, a specific definition is provided
(indication class I, level of evidence B). Differentiation of tubercu- for autoreactive pericarditis/pericardial effusion. The diagnosis of
lous and neoplastic effusion is virtually absolute with low levels of autoreactive pericarditis is established using the following criteria:
ADA and high levels of CEA. In addition, high ADA levels may (i) increased number of lymphocytes and mononuclear cells
predict the evolution towards pericardial constriction. In suspected .5000/mm3 (autoreactive lymphocytic), or the presence of anti-
bacterial infections, at least three cultures of pericardial fluid for bodies against heart muscle tissue (antisarcolemmal) in the pericar-
aerobes and anaerobes as well as the blood cultures are manda- dial fluid (autoreactive antibody mediated); (ii) signs of myocarditis
tory (indication class I, level of evidence B). PCR analyses for car- on epicardial/endomyocardial biopsies by .14 cells/mm2; (iii) ex-
diotropic viruses have been suggested (indication class IIa, level of clusion of active viral infection both in pericardial effusion and
evidence B), but are rarely used in clinical practice. Analyses of the endomyocardial/ epimyocardial biopsies (no virus isolation, no
pericardial fluid specific gravity (.1015), protein level (.3.0 g/dL), IgM titer against cardiotropic viruses in pericardial effusion, and
fluid/serum ratio .0.5, LDH .200 mg/dL, serum/fluid .0.6, and negative PCR for major cardiotropic viruses); (iv) tuberculosis,
Borrelia burgdorferi, Chlamydia pneumoniae, and other bacterial
infection excluded by PCR and/or cultures; (v) neoplastic infiltration
absent in pericardial effusion and biopsy samples; (vi) exclusion of sys-
Table 4 Major echocardiographic signs of cardiac temic, metabolic disorders, and uraemia. This is essentially a diagnosis
tamponade (Supplementary material online, of exclusion for pericardial effusions with an autoimmune patho-
Reference H) genesis not related to a known systemic inflammatory disease,
and that may be efficiently treated by corticosteroids.
Sign Sensitivity Specificity
................................................................................ A standard recommended approach for the analysis of pericar-
Large pericardial effusion with swinging n.a. n.a. dial fluid is reported in Table 5.
heart Among specific causes of pericardial effusion, tuberculosis is es-
Diastolic collapse of right atrium (RA) 50– 100% 33– 100% pecially important to be recognized, because it is a dangerous
Duration of RA inversion by the RA .90% 100% disease with a high mortality if untreated, and a high risk of evolu-
inversion time index (duration of tion towards constrictive pericarditis (30–50% of cases). A previ-
inversion/cardiac cycle length); ous history of tuberculosis, an origin from an area, where
for values .0.34
tuberculosis is endemic (i.e. Africa and India), a subacute course,
Diastolic collapse of right ventricle (RV) 48– 100% 72– 100%
low grade fever, weight loss, night sweats, a moderate to large peri-
Variations in E velocities during n.a. n.a.
respiration across the mitral valve,
cardial effusion are all features associated with a high risk of a tu-
tricuspid valve, and pulmonary berculous cause of the effusion. A definite diagnosis of tuberculous
outflow that are greater than 25, 50, effusion requires the demonstration of tuberculosis bacilli in peri-
and 30% cardial fluid or tissue. However, the diagnosis is probable if tuber-
Inferior vena cava (IVC) pletora 97% 40% culosis is shown in patients with the diagnosis of tuberculosis
(dilatation .20 mm and ,50% elsewhere in the body (i.e. pulmonary), or with a lymphocytic peri-
reduction in the diameter of IVC
with respiratory phases)
cardial exudate with elevated ADA levels. The empiric response to
antituberculosis therapy as ex-iuvantibus diagnosis may be accept-
n.a, not available. able only in countries, where tuberculosis is endemic, but not in
Western Europe and North America.4,28
Management of pericardial effusion
Figure 6 Mitral valve flows respiratory changes .25% (A) and inferior vena cava plethora (B; dilatation .20 mm and ,50% reduction
in inferior vena cava diameter) in case of cardiac tamponade.
Table 5 Routine analyses to be performed
on pericardial fluid
Analysis Test
................................................................................
General Specific gravity. 1015, protein
chemistry level .3 g/dL, protein fluid/
serum ratio .0.5,
LDH .200 mg/dL, fluid/serum
ratio .0.6a
Glucose, blood cell count
Cytology Cytology (higher volumes of
fluid, centrifugation, and
rapid analysis improve
diagnostic yield)
Biomarkers Tumour markers (i.e. CEA
.5 ng/mL or CYFRA 21-1
.100 ng/mL)
Adenosine deaminase .40 U/
L, IFN-gamma
Polymerase chain PCR for specific infectious
reaction (PCR) agents (i.e. TBC)
Microbiology Acid-fast bacilli staining,
mycobacterium cultures,
aerobic, and anaerobic
cultures
LDH, lactate dehydrogenase; TBC, tuberculosis.
a
These chemical features have been especially validated for pleural fluid and not
pericardial fluid, although generally used also for pericardial effusion.
The presence of elevated inflammatory markers and other
criteria for pericarditis (chest pain, pericardial rubs, and ECG
changes) suggests pericarditis and management should follow the
triage and management recommended for pericarditis.30
Integrated cardiovascular imaging, including echocardiography,
CT, and CMR may provide valuable aid in the search for the
cause of pericardial effusions.31 – 36 Although echocardiography
remains the primary diagnostic tool for the study of pericardial
1193
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diseases because of its widespread availability, portability, and
limited costs, CT and CMR provide a larger field of view, allowing
the detection of loculated pericardial effusion, pericardial thicken-
ing and masses, as well as associated chest abnormalities. Cardiac
Aetiology magnetic resonance may also provide a combined morphological
or feature and functional evaluation. For both CT and CMR, the pericardium
is ideal for imaging studies, because of a high natural contrast
Exudate between pericardial layers separated by pericardial fluid, and con-
tiguous fat tissue in the mediastinal and subepicardial space. Com-
puted tomography density measurements and the analysis of CMR
signals may enable the initial characterization of pericardial fluid
better than echocardiography. With inflamed pericardium, the
Cancer patient usually has the combination of effusion and pericardial
thickening. On CT, generally, pericardial effusions are of low
density in the range of 0–20 Hounsfield units (HU). When the ef-
fusion contains higher amounts of protein, such as in bacterial
Cancer
infections, or when it is haemorrhagic, its density may rise to
50 HU and more. Inflamed pericardium may also show contrast
TBC enhancement. In CT imaging of the pericardium, difficulty may be
encountered in differentiating fluid from thickened pericardial
TBC tissue. Cardiac magnetic resonance is superior to CT in differenti-
ating fluid, especially highly proteinaceous exudative effusions, from
TBC
thickened pericardium. On the contrary, CT may detect even
Other bacteria
minimal amounts of pericardial calcium, whereas CMR may miss
significant deposits. Computed tomography requires less time
than echocardiography and CMR. However, CT requires the use
of intravenously administered iodinated contrast materials and ion-
izing radiation. Moreover, if performed without ECG gating, CT
may lead to cardiac motion artefacts, that limit the evaluation of
pericardial thickness. However, the use of more recent and
updated CT scanners with a greater spatial and temporal reso-
lution and more sophisticated algorithms for image reconstruction
may allow a significant reduction in CT imaging artefacts. Cardiac
magnetic resonance has a superior ability to characterize pericar-
dial effusions and masses with the use of a combination
of T1-weighted, T2-weighted, and gradient-recalled echo cine
sequences without the use of either iodinated contrast material
or ionizing radiation. However, a possible disadvantage of CMR
with ECG gating is that arrhythmias, often associated with
1194 M. Imazio and Y. Adler

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Figure 7 Evidence of acute pericarditis with mild pericardial effusion on cardiac magnetic resonance (A). The pericardium is thickened
and contrast enhancement is evident on the inflamed pericardium (B, see red arrows).

myopericardial diseases, may cause artefacts. Another disadvantage

of CMR is related to its limited availability and higher costs. Use of Table 6 Empiric anti-inflammatory therapy
i.v. injected gadolinium may be useful for pericarditis detection, for inflammatory pericardial effusions
because gadolinium has been reported to enhance inflamed peri-
cardium (Figure 7), as well as for the detection of concomitant Drug Attack Dose Treatment Level of
myocardial involvement in myopericarditis.4,7,14,34 – 37 length evidencea
.................................................................................
Acetylsalicylic acid 750– 1000 mg t.i.d. 1– 2 weeks B
Ibuprofen 600 mg t.i.d. 1– 2 weeks B
Therapy Indomethacin 50 mg t.i.d. 1– 2 weeks C
The therapy of pericardial effusion should be targeted at the aeti- Prednisone or 0.2–0.5 mg/kg/day First episode: B
steroid at 2 weeks
ology as much as possible.37 – 41 In 60% of cases, the effusion is
equivalent dose Recurrence:
associated with a known disease,18 and the essential treatment is 4 weeks
that of the underlying disease. When pericardial effusion is associated Colchicine 0.5 mg b.i.d First episode: B
with pericarditis, management should follow that of pericarditis.30,37 (≥70 kg) 3 months
Nevertheless, when diagnosis is still unclear or idiopathic, and 0.5 mg once Recurrence: A
inflammatory markers are elevated, a trial of aspirin or a non- (,70 kg) 6 months
steroidal anti-inflammatory drug (NSAID) can be prescribed also
to evaluate the response (Table 6). A viral or idiopathic form is t.i.d., three times daily; b.i.d.,: twice daily; tapering may be considered in case of
normalization of markers of inflammation and significant response to therapy
often responsive to such empiric therapy. For the management (symptoms, regression or reduction of pericardial effusion). A low tapering is
of recurrent inflammatory cases, the first step is considering especially required for corticosteroids (i.e. decrease prednisone 2.5 mg every 2–4
the combination of aspirin or a NSAID plus colchicine,42 while weeks).
a
A in case of multiple randomized trials or meta-analysis, B for a single-randomized
corticosteroids at low to moderate doses may be considered for trial or non-randomized studies, C for consensus opinion of experts.
specific indications (i.e. systemic inflammatory diseases and preg-
nancy),43 and in case of intolerance, contraindications, or failure
of aspirin/NSAID; other therapies are based on less solid evidence:
less toxic and less expensive drugs (e.g. azathioprine or methotrex- Other non-steroidal agents may increase the risk of thinning the
ate) should be preferred, tailoring the therapy for the individual infarction zone. Corticosteroid therapy can be used for refractory
patient and the physician experience.44 symptoms only, but could delay myocardial infarction healing (class
In the 2004 ESC guidelines, ibuprofen is proposed as the favour- IIa indication, level of evidence B). Post-infarction pericardial effu-
ite first choice for empiric anti-inflammatory therapy of pericardi- sion .10 mm may be associated with haemopericardium, and up
tis, due to rare side effects, favourable effect on the coronary flow, to two-thirds of these patients may develop tamponade/free wall
and the large dose range.7 However, other approaches have been rupture. In this setting, urgent surgical treatment is life saving.
published, and aspirin is used as first favourite choice in several However, if the immediate surgery is not available or contraindi-
clinical trials in the setting of acute and recurrent pericardi- cated, pericardiocentesis, and intrapericardial fibrin-glue instillation
tis.4,37,38,42 For patients who already are taking or need aspirin, could provide an alternative immediate treatment, as proposed in
such drug is the best anti-inflammatory choice.37 In the setting of the 2004 ESC guidelines.7
post-myocardial infarction pericarditis, ibuprofen, which increases In the setting of autoreactive pericardial effusion, growing evi-
the coronary flow, is the preferred agent of choice according to dence supports the possible use of intrapericardial therapies to
2004 ESC guidelines.7 Aspirin has been also successfully applied. reduce side effects related to the oral use of corticosteroids
Management of pericardial effusion
(Supplementary material online, Reference K). Systemic corticos-
teroids offer an effective treatment option for autoreactive peri-
carditis; however, their use is limited by adverse effects and they
are an independent risk factor for pericarditis recurrence. In a re-
cently published systematic review (Supplementary material online,
Reference L), one case series and three open-label trials evaluating
intrapericardial triamcinolone for the management of autoreactive
pericarditis were reviewed. Included studies were limited by small
sample sizes (n ¼ 2 –84), lack of control groups, short durations of
follow-up (24 h–12 months), use of adjuvant agents, lack of patient
demographic data, subjective report of symptom relief, and lack
of consistent dose of intrapericardial triamcinolone. Despite
these limitations, available data suggest symptom resolution and
reduced pericarditis recurrence with the administration of intra-
pericardial triamcinolone to patients with autoreactive pericarditis
(Supplementary material online, Reference L).
When a pericardial effusion becomes symptomatic without
evidence of inflammation or when empiric anti-inflammatory
drugs are not successful, drainage of the effusion should be consid-
ered. Pericardiocentesis with prolonged pericardial drainage till
,30 mL/24 h is recommended to promote adherence of pericar-
dial layers and prevent further accumulation of fluid, although
evidence to support this indication is based on case reports, retro-
spective studies, and expert opinion. If pericardiocentesis is not
feasible or fails, the creation of a so-called pericardial window
should be considered either by conventional heart surgery or
video-assisted thoracoscopy. Balloon pericardiotomy is an alterna-
tive to surgical creation of a pericardial window, which has been
shown successful especially in the setting of neoplastic pericardial
disease. The technique involves inserting a deflated single catheter
or double balloon catheters into the pericardial space using a sub-
xiphoid approach under fluoroscopic or echocardiographic guid-
ance. Although successful in preventing recurrence in .80% of
cases, stretching of the pericardium is often painful so appropriate
analgesia is recommended.37,38
The 2004 ESC guidelines gave a class IIa recommendation to
pericardiectomy for frequent and highly symptomatic recurrences
resistant to medical treatment. Other reported indications include
repeated recurrences with cardiac tamponade, and evidence of
serious steroid toxicity.7 Although surgical experiences are not
always concordant, pericardiectomy is generally considered as a
therapeutic option of doubtful efficacy in recurrent idiopathic peri-
carditis or pericardial effusion and should be considered only in ex-
ceptional cases. Chronic permanent constriction remains the
major indication for such intervention.37 However, incessant peri-
carditis, as distinguished from recurrent intermittent pericarditis,
may respond favourably to surgical removal, especially in the pres-
ence of recurrent pericardial effusion.45 An idiopathic chronic peri-
cardial effusion is defined as a collection of pericardial fluid that
persists for .3 months and has no apparent cause; large effusions
have a risk of progression to cardiac tamponade (up to one-third,
according to a Spanish study). On this basis some authors have
advocated the need for pericardiectomy for such cases, whenever
a large effusion recurs after pericardiocentesis.46 Since drainage is
relatively safe and easy in some cases with guided pericardiocen-
tesis, drainage has been recommended for large subacute effusions,
that do not respond to empiric therapy, and are stable after several
1195
weeks (e.g. 6–8 weeks), especially when there are signs of right-
sided collapse, in order to prevent the possible progression of
the effusion towards tamponade following additional events (e.g.
pericarditis, bleeding following chest trauma).47
Unfortunately, there are no proven effective medical therapies
to reduce an isolated effusion; in the absence of inflammation,
NSAID as well as colchicine and corticosteroids are generally
not efficacious.42 Pericardiocentesis alone may be necessary for
the resolution of large effusions but recurrences are also
common and pericardiectomy or less invasive options (i.e. pericar-
dial window) should be considered whenever fluid reaccumulates,
becomes loculated, or biopsy material is required.37 The feasibility
of pericardiocentesis is high (.90%) in patients with anterior effu-
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sion, while the rate of success is ,60% with small, posteriorly
located effusions. Pericardiocentesis with echocardiography guid-
ance is feasible in .95% of cases. The most serious complications
of pericardiocentesis are laceration and perforation of the myocar-
dium and the coronary vessels. In addition, patients can experience
air embolism, pneumothorax, arrhythmias (usually vasovagal brady-
cardia), and puncture of the peritoneal cavity or abdominal viscera.
Internal mammary artery fistulas, acute pulmonary oedema, and
purulent pericarditis were rarely reported. The safety was improved
with echocardiographic or fluoroscopic guidance. Recent large
echocardiographic series reported an incidence of major complica-
tions of 1–1.6%. In a large series of fluoroscopy-guided percutan-
eous pericardiocenteses, cardiac perforations occurred in ,1%,
serious arrhythmias in 0.6%, arterial bleeding in 1.1%, pneumothorax
in 0.6%, infection in 0.3%, and a major vagal reaction in 0.3%.6,7 The
need for intervention in all cases remains controversial and requires
the understanding of the possible benefit/risk ratio (i.e. possible
trigger of recurrences).48
Special considerations should be done for the management of
neoplastic pericardial effusions (Supplementary material online,
References L and M –Q). Malignant pericardial effusion and
cardiac tamponade are known complications of many advanced
malignancies, such as breast cancer, lung cancer, lymphomas, and
leukaemias. There are many treatment options available, ranging
from simple drainage to thoracic surgery. It is essential that treating
physicians choose a treatment plan in the context of the cancer
stage, the patient’s prognosis, the success rates and risks of the
various modalities, and local availability and expertise. Given the
poor prognosis of most patients presenting with malignant pericar-
dial effusions, reducing symptoms and improving the quality of life
are the primary goals of treatment. Management of these patients
requires multidisciplinary approaches with cooperation between
cardiologists, cardiac surgeons, oncologists, radiotherapists, and
palliative care physicians.38 Immediate relief of symptoms may be
obtained with percutaneous drainage or with a surgical approach.
For long-term prevention of recurrences, various approaches have
been proposed: extended drainage, pericardial window (either sur-
gical or percutaneous balloon pericardiostomy), sclerosing local
therapy, local and/or systemic chemotherapy, or radiation
therapy. The outcomes of various therapeutic approaches vary
for different tumour types. Lymphoma and leukaemias can be suc-
cessfully treated with systemic chemotherapy; for solid tumours,
percutaneous drainage and the use of systemic and/or local scler-
osing and antineoplastic therapy seems to offer the best chance of
1196
success. The use of ‘pure’ sclerosing agents has been replaced by
agents with both sclerosing and antineoplastic activity (bleomycin
or thiotepa), which seems to be quite effective in breast cancer,
at least when associated with systemic chemotherapy. Local chemo-
therapy with platinum, mitoxantrone, and other agents may lead to
good local control of the disease, but the addition of systemic
chemotherapy is probably relevant to improve survival. The ration-
ale of local instillation of antineoplastic agents is to cure the metas-
tases, rather than simply prevent effusion by mechanical means.
Intrapericardial treatment tailored to the type of cancer indicates
that cisplatin is more effective in secondary lung cancer, whereas
thiotepa seems to be effective in breast cancer.7 Surgical or percu-
taneous pericardiostomy and radiation therapy may be useful in re-
curring effusions or cases not responsing to other treatments
(Supplementary material online, References P and Q).40
Prognosis and follow-up
The prognosis of pericardial effusion is essentially related to the
aetiology, and, thus, it is important to identify specific aetiology
that requires targeted therapies. The size of the effusion is corre-
lated to the prognosis, because moderate to large effusions are
more common for specific aetiologies, such as bacterial, neoplastic
or related to a systemic inflammatory disease.4,12,30 Bacterial aeti-
ologies as well as post-radiation pericardial diseases, pericardial
injury syndromes have an increased risk of developing
Figure 8 A simplified algorithm for pericardial effusion triage and management. CRP, C-reactive protein.
M. Imazio and Y. Adler
complications either early or intermediate (cardiac tamponade,
recurrences) or late (constrictive pericarditis).49 Idiopathic pericar-
dial effusion and pericarditis have an overall good prognosis with a
very low risk of complications especially if the effusion is mild to
moderate. In contrast with these observations, a recently published
prospective study has shown that even with mild pericardial effu-
sion the overall prognosis may be worse than in age- and sex-
matched controls.50
Large idiopathic chronic effusion (.3 months) have a 30 –35%
risk of progression to cardiac tamponade.46 Also subacute (4–6
weeks) large effusions not responsive to conventional therapy
and with echocardiographic signs of right chambers collapse may
have an increased risk of progression according to some authors
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who recommend preventive drainage in such cases.47
Idiopathic pericarditis has a very low documented risk of con-
strictive pericarditis despite even several recurrences: here the risk
is related to the aetiology and not the number of recurrences.49
The follow-up of pericardial effusion is mainly based on the
evaluation of symptoms and the echocardiographic size of the ef-
fusion, as well as additional features such as inflammatory markers
(i.e. C-reactive protein). There are no specific recommendations
from pericardial diseases guidelines. A mild idiopathic effusion
(,10 mm) is usually asymptomatic, has generally a good prognosis
and does not require specific monitoring. Moderate to large effu-
sions (.10 mm) may worsen and especially severe effusions may
evolve towards cardiac tamponade in up to one-third of cases as
Management of pericardial effusion
already mentioned. We usually recommend to tailor the follow-up
to the aetiology, adopted therapies (usually a control after 1– 2
weeks and then after 1 month and 6 months), and monitoring
the possible evolution towards worsening pericardial effusion,
cardiac tamponade, and constrictive pericarditis. For idiopathic
moderate effusions, an appropriate timing for echocardiographic
follow-up may be an echocardiogram every 6 months. For a
severe effusion, an echocardiographic follow-up may be every
3–6 months. A tailored follow-up is warranted also considering
the relative stability or evolution of the size (i.e. a worsening effu-
sion may require a closer timing also guided by symptoms).4
Conclusions
Relatively, few data have been published on the management of
pericardial effusion and there is a lack of contemporary prospect-
ive series with unselected patients with pericardial effusions of dif-
ferent entity (small vs. moderate vs. large). Ongoing prospective
studies, registries, and new updated guidelines from medical soci-
eties will provide more evidence based data to guide the manage-
ment of pericardial effusion. A simplified algorithm for the triage
and management of pericardial effusion is illustrated in Figure 8.
Supplementary material
Supplementary material is available at European Heart Journal
online.
Conflict of interest: none declared.
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