ESC Guidelines

Guidelines on the Diagnosis and Managementof Pericardial DiseasesExecutive Summary

The Task Force on the Diagnosis and Management of PericardialDiseases of the European Society of Cardiology

Task Force members, Bernhard Maisch, Chairperson* (Germany),Petar M. Seferovic (Serbia and Montenegro), Arsen D. Ristic (Serbia and Montenegro),Raimund Erbel (Germany), Reiner Rienmuller (Austria), Yehuda Adler (Israel),Witold Z. Tomkowski (Poland), Gaetano Thiene (Italy), Magdi H. Yacoub (UK)

ESC Committee for Practice Guidelines (CPG), Silvia G. Priori (Chairperson) (Italy), Maria Angeles Alonso Garcia(Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean (France), JaapDeckers (The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden),Gianfranco Mazzotta (Italy), Jo~ao Morais (Portugal), Ali Oto (Turkey), Otto A. Smiseth (Norway)

Document Reviewers, Gianfranco Mazzotta (CPG Review Coordinator) (Italy), Jean Acar (France), Eloisa Arbustini(Italy), Anton E. Becker (The Netherlands), Giacomo Chiaranda (Italy), Yonathan Hasin (Israel), Rolf Jenni(Switzerland), Werner Klein (Austria), Irene Lang (Austria), Thomas F. Luscher (Switzerland), Fausto J. Pinto(Portugal), Ralph Shabetai (USA), Maarten L. Simoons (The Netherlands), Jordi Soler Soler (Spain), David H.Spodick (USA)

Table of contents

Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . 587Introduction. . . . . . . . . . . . . . . . . . . . . . . . . 588Aetiology and classification of pericardial disease . 588Pericardial syndromes . . . . . . . . . . . . . . . . . . 588

Congenital defects of the pericardium . . . . . . 588Acute pericarditis . . . . . . . . . . . . . . . . . . . 588Chronic pericarditis . . . . . . . . . . . . . . . . . . 591Recurrent pericarditis . . . . . . . . . . . . . . . . 592Pericardial effusion and cardiac tamponade . . 592Constrictive pericarditis . . . . . . . . . . . . . . . 593Pericardial cysts . . . . . . . . . . . . . . . . . . . . 595

Specific forms of pericarditis . . . . . . . . . . . . . . 597Viral pericarditis . . . . . . . . . . . . . . . . . . . . 597Bacterial pericarditis . . . . . . . . . . . . . . . . . 598

Tuberculous pericarditis . . . . . . . . . . . . . 598Pericarditis in renal failure . . . . . . . . . . . . . 600Autoreactive pericarditis and pericardial

involvement in systemic autoimmunediseases . . . . . . . . . . . . . . . . . . . . . . . 600

The post-cardiac injury syndrome:postpericardiotomy syndrome . . . . . . . . . 600

Postinfarction pericarditis . . . . . . . . . . . . . . 601Traumatic pericardial effusion and

haemopericardium in aortic dissection . . . . 601Neoplastic pericarditis . . . . . . . . . . . . . . . . 603Rare forms of pericardial disease . . . . . . . . . 603

Fungal pericarditis . . . . . . . . . . . . . . . . . 603Radiation pericarditis . . . . . . . . . . . . . . . 604Chylopericardium . . . . . . . . . . . . . . . . . 604Drug- and toxin-related pericarditis . . . . . . 605

*Corresponding author: Chairperson: Bernhard Maisch, MD, FESC,FACC, Dean of the Faculty of Medicine, Director of the Department ofInternal Medicine-Cardiology, Philipps University, Marburg, Baldingerst-rasse 1, D-35033 Marburg, Germany. Tel.: +49-6421-286-6462; fax: +49-6421-286-8954.

E-mail address: bermaisch@aol.com (B. Maisch).

0195-668X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.ehj.2004.02.002

European Heart Journal (2004) 25, 587610

Preamble

Guidelines and Expert Consensus documents aim to pres-ent all the relevant evidence on a particular issue in orderto help physicians to weigh the benefits and risks of aparticular diagnostic or therapeutic procedure. Theyshould be helpful in everyday clinical decision-making.

A great number of Guidelines and Expert ConsensusDocuments have been issued in recent years by differentorganisations, the European Society of Cardiology (ESC)and by other related societies. By means of links to websites of National Societies several hundred guidelines areavailable. This profusion can put at stake the authorityand validity of guidelines, which can only be guaranteedif they have been developed by an unquestionable deci-sion-making process. This is one of the reasons why theESC and others have issued recommendations for for-mulating and issuing Guidelines and Expert ConsensusDocuments.

In spite of the fact that standards for issuing goodquality Guidelines and Expert Consensus Documents arewell defined, recent surveys of Guidelines and ExpertConsensus Documents published in peer-reviewed jour-nals between 1985 and 1998 have shown that methodo-logical standards were not complied within the vastmajority of cases. It is therefore of great importancethat guidelines and recommendations are presented informats that are easily interpreted. Subsequently, theirimplementation programmes must also be well con-ducted. Attempts have been made to determine whetherguidelines improve the quality of clinical practice andthe utilisation of health resources.

The ESC Committee for Practice Guidelines (CPG)supervises and coordinates the preparation of newGuidelines and Expert Consensus Documents producedby Task Forces, expert groups or consensus panels. TheCommittee is also responsible for the endorsement ofthese Guidelines and Expert Consensus Documents orstatements.

Introduction

The strength of evidence related to a particular diag-nostic or treatment option depends on the availabledata: (1) level of evidence A: multiple randomised clin-ical trials or meta-analyses; (2) level of evidence B: asingle randomised trial or non-randomised studies; and(3) level of evidence C: consensus opinion of the experts.Indications for various tests and procedures were rankedin three classes:

Class I: Conditions for which there is evidence and/orgeneral agreement that a given procedure ortreatment is useful and effective.

Class II: Conditions for which there is conflicting evi-dence and/or a divergence of opinion aboutthe usefulness/efficacy of a procedure or treat-ment.Class IIa: Weight of evidence/opinion is in

favour of usefulness/efficacy.Class IIb: Usefulness/efficacy is less well estab-

lished by evidence/opinion.Class III: Conditions for which there is evidence and/or

general agreement that the procedure/treat-ment is not useful/effective and in some casesmay be harmful.

Aetiology and classification of pericardialdisease

The spectrum of pericardial diseases consists of con-genital defects, pericarditis (dry, effusive, effusive-constrictive, and constrictive), neoplasm, and cysts. Theaetiological classification comprises: infectious pericar-ditis, pericarditis in systemic autoimmune diseases, type2 (auto) immune process, postmyocardial infarctionsyndrome, and auto-reactive (chronic) pericarditis(Table 1).13

Pericardial syndromes

Congenital defects of the pericardium

Congenital defects of the pericardium (1/10.000 autop-sies) comprise partial left (70%), right (17%) or total bi-lateral (rare) pericardial absence. Additional congenitalabnormalities occur in 30% of patients.4 Most patientswith a total pericardial absence are asymptomatic. Ho-molateral cardiac displacement and augmented heartmobility impose an increased risk for traumatic aorticdissection.5 Partial left side defects can be complicatedby herniation and strangulation of the heart through thedefect (chest pain, shortness of breath, syncope or sud-den death). Surgical pericardioplasty (Dacron, Gore-tex,or bovine pericardium) is indicated for imminent stran-gulation.6

Acute pericarditis

Acute pericarditis is dry, fibrinous or effusive, indepen-dent from its aetiology. The diagnostic algorithm can bederived from Table 2.818 A prodrome of fever, malaise,and myalgia is common, but elderly patients may not befebrile. Major symptoms are retrosternal or left precor-dialchest pain (radiates to the trapezius ridge, can bepleuritic or simulate ischemia, and varies with posture)and shortness of breath. The pericardial friction rub canbe transient, mono-, bi- or triphasic. Pleural effusionmay be present. Heart rate is usually rapid and regular.

Pericardial effusion in thyroid disorders . . . 605Pericardial effusion in pregnancy . . . . . . . 605

Uncited references . . . . . . . . . . . . . . . . . . . . 605Acknowledgements . . . . . . . . . . . . . . . . . . . . 605References . . . . . . . . . . . . . . . . . . . . . . . . . 605

588 ESC Guidelines

Table 1 Review of aetiology, incidence and pathogenesis of pericarditis13

Aetiology Incidence (%) Pathogenesis

Infectious pericarditis Multiplication and spread of the causativeagent and release of toxic substances in peri-cardial tissue cause serous, serofibrinous orhaemorrhagic (bacterial, viral, tuberculous,fungal) or purulent inflammation (bacterial)

Viral (Coxsackie A9, B1-4, Echo 8, Mumps,EBV, CMV, Varicella, Rubella, HIV, Parvo B19,etc.)

3050a

Bacterial (Pneumo-, Meningo-, Gonococcosis,Hemophilus, Treponema pallidum, Borreliosis,Chlamydia, Tuberculosis, etc.)

510a

Fungal (Candida, Histoplasma, etc.) RareParasitary (Entameba histolytica, Echinococcus,Toxoplasma. . .)

Rare

Pericarditis in systemic autoimmune diseases Cardiac manifestations of the basic disease,often clinically mild or silentSystemic lupus erythematosus 30b

Rheumatoid arthritis 30b

Spondylitis ankylosans 1b

Systemic sclerosis >50b

Dermatomyositis RarePeriarteritis nodosa RareReiters syndrome 2bFamilial Mediterranean fever 0.7b

Type 2 (auto)immune process Secondary, after infection/surgeryRheumatic fever 2050b Mostly in acute phasePostcardiotomy syndrome 20b 1014 days after surgeryPostmyocardial infarction syndrome 15b DDg P. epistenocardicaAutoreactive (chronic) pericarditis 23.1a Common form

Pericarditis and pericardial effusion in diseases of surrounding organsAcute MI (P. epistenocardica) 520b 15 days after transmural MIMyocarditis 30b Accompanying epimyocarditisAortic aneurysm Rare Dissection: haemorrhagic PELung infarction RarePneumonia RareOesophageal diseases RareHydropericardium in CHF RareParaneoplastic pericarditis Frequent No direct neoplastic infiltrate

Pericarditis in metabolic disordersRenal insufficiency (uraemia) Frequent Viral/toxic/autoimmuneMyxedema 30b Serous, cholesterol rich PEAddisons disease Rare Membranous leak?Diabetic ketoacidosis RareCholesterol pericarditis Very rare Transudation of cholesterol

(sterile serofibrinous PE)Pregnancy Rare

Traumatic pericarditisDirect injury (penetrating thoracic injury,oesophageal perforation, foreign bodies)

Rare

Indirect injury (Non-penetrating thoracic injury,mediastinal irradiation)

Rare Less frequent after introduction of topicalconvergent irradiation

Neoplastic pericardial disease 35a

Primary tumours RareSecondary metastatic tumours Frequent

Lung carcinoma 40c Serous or fibrinous, frequently haemorrhagiceffusion

Breast carcinoma 22c Accompanying disease during the infiltration ofmalignant cells

Gastric and colon 3c

Other carcinoma 6c

Leukemia and lymphoma 15c

Melanoma 3c

Sarcoma 4c

Other tumours 7c

ESC Guidelines 589

Microvoltage and electrical alternans are reversible aftereffusion drainage.19 Echocardiography is essential todetect effusion, concomitant heart or paracardial dis-ease.11;12

Perimyocarditis is evidenced by global or regionalmyocardial dysfunction, elevations of troponins I and T,MB creatine-kinase, myoglobin and tumour necrosis fac-tor. Auscultation of a new S3 heart sound, convexly el-evated J-ST segment in the ECG, fixation of Indium-111-

labelled antimyosin antibodies, and structural changes inMRI are indicative, but only endomyocardial/epimyo-cardial biopsy is diagnostic.7;8

Hospitalisation is warranted to determine the aeti-ology and observe for tamponade as well as the effectof treatment. Nonsteroidal anti-inflammatory drugs(NSAID) are the mainstay (level of evidence B, class I).Indomethacine should be avoided in elderly patientsdue to its flow reduction in the coronaries. Ibuprofen is

Table 2 Diagnostic pathway and sequence of performance in acute pericarditis (level of evidence B for all procedures)

Technique Characteristic findings Reference

Obligatory (indication class I)Auscultation Pericardial rub (mono-, bi-, or triphasic) 7

ECGa Stage I: anterior and inferior concave ST segment elevation. PR segmentdeviations opposite to P polarity.

7,19

Early stage II: ST junctions return to the baseline, PR deviated.Late stage II: T waves progressively flatten and invertStage III: generalised T wave inversionsStage IV: ECG returns to prepericarditis state.

Echocardiography Effusion types BD (Horowitz) (Fig. 1) 9,10Signs of tamponade (see Section Pericardial effusion and cardiac tamponde)

Blood analyses (a) ESR, CRP, LDH, leukocytes (inflammation markers) 11(b) Troponin I, CK-MB (markers of myocardial lesion)b

Chest X-ray Ranging from normal to water bottle heart shadow. Revealing additionalpulmonary/mediastinal pathology.

12

Mandatory in tamponade (indication class I), optional in large/recurrent effusions or if previous tests inconclusive (indicationclass IIa) in small: effusions (indication class IIb)Pericardiocentesis anddrainage

PCR and histochemistry for aetiopathogenetic classification of infection orneoplasia

2,8,13

Optional or if previous tests inconclusive (indication class IIa)CT Effusions, peri-, and epicardium 14MRI Effusions, peri-, and epicardium 14Pericardioscopy, pericardial biopsy Establishing the specific aetiology 2,8,15,16

a Typical lead involvement: I, II, aVL, aVF, and V3-V6. The ST segment is always depressed in aVR, frequently in V1, and occasionally in V2. Oc-casionally, stage IV does not occur and there are permanent T wave inversions and flattenings. If ECG is first recorded in stage III, pericarditis cannotbe differentiated by ECG from diffuse myocardial injury, biventricular strain, or myocarditis. ECG in Early repolarization is very similar to stage I.Unlike stage I, this ECG does not acutely evolve and J-point elevations are usually accompanied by a slur, oscillation, or notch at the end of the QRSjust before and including the J point (best seen with tall R and T waves large in early repolarisation pattern). Pericarditis is likely if in lead V6 the Jpoint is >25% of the height of the T wave apex (using the PR segment as a baseline).b Cardiac troponin I was detectable in 49% and >1.5 ng/ml in 22% of 69 patients with acute pericarditis (only in those with ST elevation in ECG)investigated by Bonnefoy et al.17 In another study18 troponin I was detected in 10/14 patients with a median peak concentration of 21.4 mg/ml(range 0.5 to >50 ng/ml). CK-MB was elevated in 8/14 patients with the median peak of 21 U/l (range 1343), corresponding to the relative index of10.2% of the total CK activity.

Table 1 (continued)

Aetiology Incidence (%) Pathogenesis

Idiopathic 3.5a, in other series >50a Serous, fibrinous, sometimes haemorrhagic PEwith suspect viral or autoimmune secondaryimmunopathogenesis

CHF, congestive heart failure; DDg, differential diagnosis; MI, myocardial infarction; P., pericarditis; PE, pericardial effusion.a Percentage related to the population of 260 subsequent patients undergoing pericardiocentesis, pericardioscopy and epicardial biopsy (Marburgpericarditis registry 19882001).1b Percentage related to the incidence of pericarditis in the specific population of patients (e.g., with systemic lupus erythematosus).c Percentage related to the population of patients with neoplastic pericarditis.

590 ESC Guidelines

preferred for its rare side-effects, favourable impact onthe coronary flow, and the large dose range.7 De-pending on severity and response, 300800 mg every68 hours may be initially required and can be con-tinued for days or weeks, best until the effusion hasdisappeared. Gastrointestinal protection must be pro-vided. Colchicine (0.5 mg bid) added to an NSAID or asmonotherapy also appears to be effective for the initialattack and the prevention of recurrences (level of ev-idence B, class IIa indication).20 It is well tolerated withfewer side effects than NSAIDs. Systemic corticosteroidtherapy should be restricted to connective tissue dis-eases, autoreactive or uremic pericarditis. Intraperi-cardial application avoids systemic side effects and ishighly effective (level of evidence B, class IIa indica-tion).2 For tapering of prednisone, ibuprofen or col-chicine should be introduced early.20 Indications forpericardiocentesis are listed in Focus box 1.7;2130 Re-

covered patients should be observed for recurrences orconstriction.

Chronic pericarditis

Chronic (>3 months) pericarditis includes effusive (in-flammatory or hydropericardium in heart failure), adhe-sive, and constrictive forms.7 Symptoms are usually mild(chest pain, palpitations, fatigue), related to the degreeof cardiac compression and pericardial inflammation.The diagnostic algorithm is similar as in acute pericar-ditis (Table 2). The detection of the curable causes (e.g.,tuberculosis, toxoplasmosis, myxedema, autoimmune,and systemic diseases) allows successful specific ther-apy. Symptomatic treatment and indications for peri-cardiocentesis are as in acute pericarditis. For frequentand symptomatic recurrences balloon pericardiotomy orpericardiectomy should be considered (level of evidenceB, indication IIb).23;31

Focus box 1 PericardiocentesisPericardiocentesis is life saving in cardiac tamponade (level of evidence B, class I indication) and indicated in ef-fusions >20 mm in echocardiography (diastole)23 but also in smaller effusions for diagnostic purposes (pericardialfluid and tissue analyses, pericardioscopy, and epicardial/pericardial biopsy)(level of evidence B, class IIa indica-tion).2;8;15;16 Aortic dissection is a major contraindication.22 Relative contraindications include uncorrected coag-ulopathy, anticoagulant therapy, thrombocytopenia

Recurrent pericarditis

The term recurrent pericarditis encompasses (1) theintermittent type (symptom free intervals withouttherapy) and (2) the incessant type (discontinuation ofanti-inflammatory therapy ensures a relapse). Massivepericardial effusion, overt tamponade or constrictionare rare. Evidence for an immunopathological processinclude: (1) the latent period lasting for months; (2) thepresence of anti-heart antibodies; (3) the quick re-sponse to steroid treatment and the similarity and co-existence of recurrent pericarditis with other autoim-mune conditions (lupus, serum sickness, polyserositis,postpericardiotomy/postmyocardial infarction syn-drome, celiac disease, dermatitis herpetiformis, fre-quent arthralgias, eosinophilia, allergic drug reaction,and history of allergy). Potential underlying geneticdisorders were also reported: autosomal dominant in-heritance with incomplete penetrance32 and sex-linkedinheritance (recurrent pericarditis associated with ocu-lar hypertension).33

Symptomatic management relies on exercise restric-tion and the regimen used in acute pericarditis. Col-chicine was effective when NSAIDs and corticosteroidsfailed to prevent relapses.20;3435 During 1004 months ofcolchicine treatment, only 13.7% new recurrences oc-curred.20 During the 2333 months of follow-up, 60.7% ofthe patients remained recurrence-free. The recom-mended dose is 2 mg/day for one or two days, followedby 1 mg/day (level of evidence B, indication I). Corti-costeroids should be used only in patients with poorgeneral condition or in frequent crises7 (level of evi-dence C, indication IIa). A common mistake is to use adose too low to be effective or to taper the dose toorapidly. The recommended regimen is: prednisone11.5 mg/kg, for at least one month. If patients do notrespond adequately, azathioprine (75100 mg/day) orcyclophosphamide can be added.36 Corticoids should betapered over a three-month period. If symptoms stillrecur, return to the last dose that suppressed themanifestations, maintain that dose for 23 weeks andthen recommence tapering. Towards the end of thetaper, introduce anti-inflammatory treatment with col-chicine or NSAID. Renewed treatment should continuefor at least three months. Pericardiectomy is indicatedonly in frequent and highly symptomatic recurrencesresistant to medical treatment (level of evidence B,indication IIa).37 Before pericardiectomy, the patientshould be on a steroid-free regimen for several weeks.Post pericardiectomy recurrences were also demon-strated, possibly due to incomplete resection of thepericardium.

Pericardial effusion and cardiac tamponade

Pericardial effusion may appear as transudate (hydro-pericardium), exudate, pyopericardium or haemoperi-cardium. Large effusions are common with neoplastic,tuberculous, cholesterol, uremic pericarditis, myx-edema, and parasitoses.38 Effusions that develop slowlycan be remarkably asymptomatic, while rapidly accu-

mulating smaller effusions can present with tamponade.Loculated effusions are more common when scarring hassupervened (e.g., postsurgical, posttrauma, purulentpericarditis). Massive chronic pericardial effusions arerare (23.5% of all large effusions).39 Cardiac tamponadeis the decompensated phase of cardiac compressioncaused by effusion accumulation and the increased in-trapericardial pressure. In surgical tamponade intra-pericardial pressure is rising rapidly, in the matter ofminutes to hours (i.e. haemorrhage), whereas a low-in-tensity inflammatory process is developing days to weeksbefore cardiac compression occurs (medical tampon-ade). Heart sounds are distant. Orthopnoea, cough anddysphagia, occasionally with episodes of unconsciousnesscan be observed. Insidiously developing tamponade maypresent with the signs of its complications (renal failure,abdominal plethora, shock liver and mesenteric ische-mia). In 60% of the patients, the cause of pericardialeffusion may be a known medical condition.40 Tampon-ade without two or more inflammatory signs (typicalpain, pericardial friction rub, fever, diffuse ST segmentelevation) is usually associated with a malignant effusion(likelihood ratio 2.9). Electrocardiography may demon-strate diminished QRS and T-wave voltages, PR-segmentdepression, ST-T changes, bundle branch block, andelectrical alternans (rarely seen in the absence of tam-ponade).7 In chest radiography large effusions are de-picted as globular cardiomegaly with sharp margins(water bottle silhouette).12 On well-penetrated lateralradiographies, or cine films, pericardial fluid is suggestedby lucent lines within the cardiopericardial shadow(epicardial halo).12;41;42 This sign is useful for the fluo-roscopic guidance of pericardiocentesis.27 The separa-tion of pericardial layers can be detected inechocardiography, when the pericardial fluid exceeds1535 ml (Fig. 1).43 The size of effusions can be gradedas: (1) small (echo-free space in diastole

typical echolucent areas may disappear, so that cardiactamponade may be overlooked. Transesophageal echo-cardiography is here particularly useful58 as well as inidentifying metastases and pericardial thickening.59 CT,spin-echo and cine MRI can also be used to assess the sizeand extent of simple and complex pericardial effusions.51

Effusions measured by CT/MRI tend to be larger than inechocardiography.24;60 Up to one-third of patients withasymptomatic large pericardial chronic effusion developunexpected cardiac tamponade.23 Triggers for tampon-ade include hypovolemia, paroxysmal tachyarrhythmiaand intercurrent acute pericarditis. Diagnostic criteriafor cardiac tamponade are listed in Table 35260 andFocus box 2.61;62

Pericardiocentesis is not necessary when the diagnosiscan be made otherwise or the effusions are small or re-

solving under anti-inflammatory treatment. Haemody-namic compromise and cardiac tamponade is an absoluteindication for drainage (Focus box 1). Patients with de-hydration and hypovolemia may temporarily improvewith intravenous fluids. Whenever possible, treatmentshould be aimed at the underlying aetiology. Even inidiopathic effusions extended pericardial catheterdrainage (3 2 days, range 113 days) was associatedwith a lower recurrence rates (6% vs. 23%) than in thosewithout catheter drainage during the follow-up of3.8 4.3 years.25 Resistant neoplastic processes requireintrapericardial treatment,63 percutaneous balloon per-icardiotomy31 or rarely pericardiectomy. Surgical ap-proach is recommended only in patients with very largechronic effusion in whom repeated pericardiocentesisand/or intrapericardial therapy were not successful.64

Constrictive pericarditis

Constrictive pericarditis is a rare but severely disablingconsequence of the chronic inflammation of the peri-cardium, leading to an impaired filling of the ventriclesand reduced ventricular function. Until recently, in-creased pericardial thickness has been considered anessential diagnostic feature of constrictive pericarditis.However, in the large surgical series from the Mayo clinicconstriction was present in 18% of the patients withnormal pericardial thickness.65 Tuberculosis, mediastinalirradiation, and previous cardiac surgical procedures arefrequent causes of the disease, which can present inseveral pathoanatomical forms66 (Fig. 2). Constrictivepericarditis may rarely develop only in the epicardiallayer in patients with previously removed parietal peri-cardium.67 Transient constrictive pericarditis is uncom-mon but important entity, since these patients are notindicated for pericardiectomy.68 Patients complainabout fatigue, peripheral oedema, breathlessness, andabdominal swelling, which may be aggravated by a pro-tein-loosing enteropathy. Typically, there is a long delaybetween the initial pericardial inflammation and theonset of constriction. In decompensated patients venouscongestion, hepatomegaly, pleural effusions, and ascitesmay occur. Haemodynamic impairment of the patientcan be additionally aggravated by a systolic dysfunctiondue to myocardial fibrosis or atrophy. Clinical, echocar-diographic, and haemodynamic parameters can be de-rived from Table 4.50;65;66;6971 Differential diagnosis hasto include acute dilatation of the heart, pulmonary em-

Focus box 2 Determination of pulsus paradoxusPulsus paradoxus is defined as a drop in systolic blood pressure >10 mmHg during inspiration whereas diastolic bloodpressure remains unchanged. It is easily detected by feeling the pulse.61;62 During inspiration, the pulse may dis-appear or its volume diminishes significantly. Clinically significant pulsus paradoxus is apparent when the patient isbreathing normally. When present only in deep inspiration it should be interpreted with caution. The magnitude ofpulsus paradoxus is evaluated by sphygmomanometry. If the pulsus paradoxus is present, the first Korotkoff sound isheard only during expiration. The blood pressure cuff is therefore inflated above the patients systolic pressure.During deflation, the first Korotkoff sound is intermittent. Correlation with the patients respiratory cycle identifiesa point at which the sound is audible during expiration, but disappears in inspiration. As the cuff pressure drops,another point is reached when the first blood pressure sound is audible throughout the respiratory cycle. The dif-ference is the measure of pulsus paradoxus.

Fig. 1 Horowitz classification of pericardial effusions.43 Type A: Noeffusion; Type B: Separation of epicardium and pericardium (316 ml);Type C 1: Systolic and diastolic separation of epicardium and pericardium(small effusion >16 ml); Type C 2: Systolic and diastolic separation ofepicardium and pericardium with attenuated pericardial motion; Type D:Pronounced separation of epicardium and pericardium with large echo-free space; Type E: Pericardial thickening (>4 mm). Copyrights AmericanHeart Association.

ESC Guidelines 593

Table

3Diagn

osisofca

rdiactamponad

e

Clinical

presentation

Eleva

tedsystemic

venouspressure

a,hyp

otensionb,pulsusparad

oxu

sc,tach

ycardia

d,dyspnoeaortach

ypnoeawith

clear

lungs

Precipitatingfactors

Drugs

(cyclosporine,an

tico

agulants,thrombolytics,etc.),rece

ntca

rdiacsurgery,indwellinginstrumentation,

bluntch

est

trau

ma,

malignan

cies,

connectivetissuedisease,renalfailure,septica

emia

e

ECG

Can

benorm

alornon-specifica

llych

ange

d(ST-T

wav

e),

electrica

lalternans(Q

RS,

rarely

T),

bradycardi(end-stage

),Electromech

anical

dissociation(ago

nal

phase)

Chest

X-ray

Enlargedca

rdiacsilhouettewithclear

lungs.

Mmode/2

Dech

oca

rdiogram

Diastolicco

llap

seofthe(1)an

teriorRVfreewall52f ,

RAco

llap

se53,LA

54andve

ryrarely

LV55

collapse,increasedLV

diastolicwallthickn

ess

pseudohyp

ertrophy

56,VCIdilatation(noco

llapse

ininspirium),

sw

ingingheart5

7

Doppler

Tricu

spid

flow

increasesan

dmitralflow

decreasesduringinspiration(reve

rsein

exp

iration)

Systolican

ddiastolicflowsarereduce

din

systemic

veinsin

exp

irium

andreve

rseflow

withatrialco

ntractionis

increased58

M-m

odeco

lourDoppler

Largerespiratory

fluctuationsin

mitral/tricuspid

flows5

9

Cardiacca

theterisation

(1)Confirm

ationofthediagn

osisan

dquan

tifica

tionofthehae

modyn

amic

compromise60

RApressure

iseleva

ted(preservedsystolicxdescentan

dabsentordim

inisheddiastolicydescent)

Intrap

erica

rdialpressure

isalso

eleva

tedan

dvirtually

identica

lto

RApressure

(both

pressuresfallin

inspiration)

RVmid-diastolicpressure

eleva

tedan

dequal

totheRAan

dperica

rdialpressures(nodip-and-plateau

configu

ration)

Pulm

onaryartery

diastolicpressure

isslightlyeleva

tedan

dmayco

rrespondto

theRVpressure.

Pulm

onaryca

pillary

wedge

pressure

isalso

eleva

tedan

dnearlyequalto

intraperica

rdialandrigh

tatrialpressure.

LVsystolican

dao

rtic

pressuresmay

benorm

alorreduce

d.

(2)Docu

mentingthat

perica

rdialaspirationis

followedbyhae

modyn

amic

improve

mentg

(3)Detectionoftheco

existinghae

modyn

amic

abnorm

alities(LVfailure,co

nstriction,pulm

onary

hyp

ertension)

(4)Detectionofassociatedca

rdiova

sculardiseases(cardiomyo

pathy,

coronaryartery

disease)

RV/L

Van

giograp

hy

Atrialco

llap

sean

dsm

allhyp

eractiveve

ntricularch

ambers.

Coronaryan

giograp

hy

Coronaryco

mpressionin

diastole.

Computertomograp

hy

Novisualisationofsubepicardialfatalongboth

ventricles,

whichshow

tube-likeco

nfigu

rationan

dan

teriorlydrawn

atrias

LA,left

atrium,LV

,left

ventricle,RA,righ

tatrium,RV,righ

tve

ntricle,VCI,inferiorve

naca

va.

aJu

gularve

nousdistensionis

less

notable

inhyp

ovo

lemic

patients

orin

surgical

tamponad

e.

Aninspiratory

increaseorlack

offallofthepressure

intheneck

veins(Kussmaulsign

),whenve

rifiedwith

tamponad

e,orafterperica

rdialdrainag

e,indicateseffusive

-constrictivedisease.

bHeartrate

isusually

>100

beats/min,butmay

belowerin

hyp

othyroidism

andin

uremic

patients.

cPulsusparad

oxu

sis

absentin

tamponad

eco

mplica

tingatrial

septaldefect

61an

din

patients

withsign

ifica

ntao

rtic

regu

rgitation.

dOccasional

patients

arehyp

ertensive

especially

iftheyhav

epre-existinghyp

ertension.6

2

eFe

brile

tamponad

emay

bemisdiagn

osedas

septicshock.

fRightve

ntricularco

llap

seca

nbeab

sentin

eleva

tedrigh

tve

ntricularpressure

andrigh

tve

ntricularhyp

ertrophy6

3orin

righ

tve

ntricularinfarction.

gIfafterdrainag

eofperica

rdialeffusionintrap

erica

rdialpressure

doesnotfallbelow

atrial

pressure,theeffusive

-constrictivediseaseshould

beco

nsidered.

594 ESC Guidelines

bolism, right ventricular infarction, pleural effusion,chronic obstructive lung diseases72 and restrictive car-diomyopathy. The best way to distinguish constrictivepericarditis from restrictive cardiomyopathy is theanalysis of respiratory changes with or without changesof preload by Doppler and/or tissue Doppler echocardi-ography,73 but physical findings, ECG, chest radiography,CT and MRI, haemodynamics, and endomyocardial biopsymay be helpful as well.7

Pericardiectomy is the only treatment for permanentconstriction. The indications are based upon clinicalsymptoms, echocardiography findings, CT/MRI, and heartcatheterisation. There are two standard approaches,both aiming at resecting the diseased pericardium as faras possible:7477 (1) The antero-lateral thoracotomy (fifthintercostal space) and (2) median sternotomy (fasteraccess to the aorta and right atrium for extracorporealcirculation). A primary installation of cardiopulmonarybypass is not recommended (diffuse bleeding followingsystemic heparinisation). If severe calcified adhesionsbetween peri- and epicardium or a general affection ofthe epicardium (outer porcelain heart) are presentsurgery carries a high risk of either incomplete success orsevere myocardial damage. An alternative approach insuch cases may be a laser shaving using an Excimerlaser.75 Areas of strong calcification or dense scaring maybe left as islands to avoid major bleeding. Pericardiec-tomy for constrictive pericarditis has a mortality rate of612%.75;77 The complete normalization of cardiac hae-modynamics is reported in only 60% of the patients.74;76

The deceleration time (DT) may remain prolonged78 andpostoperative respiratory variations of mitral/tricuspid

flow are found in 925%.76;79 Left ventricular ejectionfraction can increase due to a better ventricular fill-ing.76;78 Major complications include acute perioperativecardiac insufficiency and ventricular wall rupture.80 Car-diac mortality and morbidity at pericardiectomy is mainlycaused by the pre-surgically unrecognised presence ofmyocardial atrophy or myocardial fibrosis (Fig. 2).66 Ex-clusion of patients with extensive myocardial fibrosisand/or atrophy reduced the mortality rate for pericardi-ectomy to 5%. Postoperative low cardiac output80 shouldbe treated by fluid substitution and catecholamines, highdoses of digitalis, and intraaortic balloon pump in mostsevere cases. If indication for surgery was establishedearly, long-term survival after pericardiectomy corre-sponds to that of the general population.75;76 However, ifsevere clinical symptoms were present for a longer periodbefore surgery, even a complete pericardiectomy maynot achieve a total restitution.

Pericardial cysts

Congenital pericardial cysts are uncommon; they may beunilocular or multilocular, with the diameter from 15cm.81 Inflammatory cysts comprise pseudocysts as wellas encapsulated and loculated pericardial effusions,caused by rheumatic pericarditis, bacterial infection,particularly tuberculosis, trauma and cardiac surgery.Echinococcal cysts usually originate from ruptured hy-datid cysts in the liver and lungs. Most patients areasymptomatic and cysts are detected incidentally onchest roentgenograms as an oval, homogeneous radio-dense lesion, usually at the right cardiophrenic angle.82

Fig. 2 Pathoanatomical forms of constrictive pericarditis vs. restrictive cardiomyopathy. (a) Annular form of pericardial constriction with bilateralthickening of the pericardium along the atrial ventricular grooves with normal configuration of both ventricles and enlargement of both atria. (b) Leftsided form of pericardial constriction with thickened pericardium along the left ventricle and right sided bending of the interventricular septum withtube-like configuration of mainly left ventricle and enlargement of both atria. (lateral sternotomy and partial pericardiectomy is indicated). (c) Rightsided form of pericardial constriction with thickened pericardium along the right ventricle and left sided bending of the interventricular septum withtube-like configuration of mainly right ventricle and enlargement of both atria (median sternotomy and partial pericardiectomy is indicated). (d) My-ocardial atrophy and global form of pericardial constriction with bilateral thickening of the pericardium along both ventricles separated from the rightmyocardial wall by a thin layer of subepicardial fat. Tube-like configuration of both ventricles and enlargement of both atria, however, thinning of theinterventricular septum and posterolateral wall of the left ventricle below 1 cm is suggesting myocardial atrophy (pericardiectomy is contraindicated).(e) Perimyocardial fibrosis and global form of pericardial constriction with bilateral thickening of the pericardium along both ventricles, however, theright sided thickened pericardium cannot be separated from the wave-like thin form of right sided ventricular wall suggesting perimyocardial fibrosis(pericardiectomy is contraindicated). (f) Global form of pericardial constriction with bilateral thickening of the pericardium along both ventriclesseparated from the right myocardial wall by a thin layer of subepicardial fat. Tube-like configuration of both ventricles and enlargement of both atria(median sternotomy and pericardiectomy is indicated). (g) Restrictive cardiomyopathy with normal thin pericardium along both ventricles that shownormal configuration and with enlargement of both atria.

ESC Guidelines 595

Table

4Diagn

ostic

approac

hin

constrictiveperica

rditis

Clinical

presentation

Seve

rech

ronic

systemic

venousco

nge

stionassociatedwithlow

cardiacoutput,

includingjugu

larve

nousdistension,

hyp

otensionwithalow

pulsepressure,ab

dominal

distension,oedemaandmuscle

wasting

ECG

Can

benorm

al,orreve

allow

QRSvo

ltag

e,ge

neralize

dT-w

aveinve

rsion/fl

attening,

LAab

norm

alities,

atrial

fibrillation,

atriove

ntricularblock,intrav

entricularco

nductiondefects,

orrarely

pseudoinfarctionpattern

Chest

X-ray

Perica

rdialca

lcifica

tions,

pleuraleffusions

Mmode/2

Dech

oca

rdiogram

Perica

rdialthicke

ningan

dca

lcifica

tionsa

aswellas

theindirect

sign

sofco

nstriction:

RA&LA

enlargementwithnorm

alap

pearan

ceoftheve

ntricles,

andnorm

alsystolicfunction

Early

pathologica

loutw

ardan

dinwardmove

mentoftheinterventricularseptum

(dip-plateau

phenomenon)

72

Flatteringwav

esat

theLV

posteriorwall

LVdiameteris

notincreasingaftertheearly

rapid

fillingphase

VCIan

dthehepatic

veinsaredilatedwithrestrictedrespiratory

fluctuationsb

Doppler

Restrictedfillingofboth

ventricleswithrespiratory

variation>25%ove

rtheAV-valves)

69c

TEE

Measurementoftheperica

rdialthickn

ess

50

CT/M

RI

Thicke

nedan

d/o

rca

lcifiedperica

rdium,tube-likeco

nfigu

rationofoneorboth

ventricles,

narrowingofoneorboth

atrio-

ventriculargroove

s,co

nge

stionoftheca

valve

ins6

6enlargementofoneorboth

atria

Cardiacca

theterisation

Dip

andplateau

orsquareroutesign

inthepressure

curveoftherigh

tan

d/o

rleft

ventricle

EqualisationofLV

/RVend-diastolicpressuresin

therange

of5mmHgorless

72d

RV/L

Van

giograp

hy

ThereductionofRV&LV

size

andincreaseofRA&LA

size

Duringdiastole

arapid

early

fillingwithstopoffurtherenlargement(dip-plateau

)

Coronaryan

giograp

hy

Inallpatients

ove

r35

yearsan

din

patients

withahistory

ofmediastinal

irradiation,rega

rdless

oftheag

e

LA,left

atrium,LV

,left

ventricle,RA,righ

tatrium,RV,righ

tve

ntricle,VCI,inferiorve

naca

va,TEE

tran

soesophag

eal

ech

oca

rdiograp

hy

aThicke

ningoftheperica

rdium

isnotalway

sequal

toco

nstriction(absentin

18%of14

3surgically

prove

nca

ses).Whenclinical,ech

oca

rdiographic,orinva

sive

haemodyn

amic

featuresindicate

constriction,

perica

rdiectomyshould

notbedeniedonthebasis

ofnorm

alperica

rdialthickn

ess.6

5

bDiagn

osisis

difficu

ltin

atrial

fibrillation.Hepatic

diastolicve

inflow

reve

rsal

inexp

irium

isobservedeve

nwhentheflow

velocity

pattern

isinco

nclusive

.69

cPatients

withincreasedatrial

pressuresormixedco

nstrictionan

drestrictiondemonstrate

However, the patients can also present with chest dis-comfort, dyspnoea, cough or palpitations, due to thecompression of the heart. Echocardiography is useful,but additional imaging by computed tomography (densityreadings) or magnetic resonance is often needed.83 Thetreatment for congenital and inflammatory cysts is per-cutaneous aspiration and ethanol sclerosis.84;85 If this isnot feasible, video assisted thoracotomy or surgical re-section may be necessary. The surgical excision of ec-chinococcal cysts is not recommended. Percutanousaspiration and instillation of ethanol or silver nitrateafter pre-treatment with Albendazole (800 mg/day 4weeks) is safe and effective.85

Specific forms of pericarditis

Viral pericarditis

Viral pericarditis is the most common infection of thepericardium. Inflammatory abnormalities are due to di-rect viral attack, the immune response (antiviral or an-ticardiac), or both.3;86 Early viral replication inpericardial and epimyocardial tissue elicits cellular andhumoral immune responses against the virus and/or car-diac tissue. Viral genomic fragments in pericardial tissuemay not necessarily replicate, yet they serve as a sourceof antigen to stimulate immune responses. Deposits ofIgM, IgG, and occasionally IgA, can be found in the peri-cardium and myocardium for years.86 Various virusescause pericarditis (entero-, echo-, adeno-, cytomegalo-,Ebstein Barr-, herpes simplex-, influenza, parvo B19,

hepatitis C, HIV, etc). Attacks of enteroviral pericarditisfollow the seasonal epidemics of Coxsackie virus A+B andEchovirus infections.87 Cytomegalovirus pericarditis hasan increased incidence in immunocompromised and HIVinfected hosts.88 Infectious mononucleosis may alsopresent with pericarditis. The diagnosis of viral pericar-ditis is not possible without the evaluation of pericardialeffusion and/or pericardial/epicardial tissue, preferablyby PCR or in-situ hybridisation (level of evidence B, classIIa indication) (Focus boxes 34). A four-fold rise in serumantibody levels is suggestive but not diagnostic for viralpericarditis (level of evidence B, class IIb indication).

Treatment of viral pericarditis is directed to resolvesymptoms (see acute pericarditis), prevent complica-tions, and eradicate the virus. In patients with chronic orrecurrent symptomatic pericardial effusion and con-firmed viral infection the following specific treatment isunder investigation: (1) CMV pericarditis: hyperimmu-noglobulin - 1 time per day 4 ml/kg on day 0, 4, and 8; 2ml/kg on day 12 and 16; (2) Coxsackie B pericarditis:Interferon alpha or beta 2,5 Mio. IU/m2 surface area s.c.3 per week; (3) adenovirus and parvovirus B19 peri-myocarditis: immunoglobulin treatment: 10 g intrave-nously at day 1 and 3 for 68 hours.113

Pericardial manifestation of human immunodeficiencyvirus (HIV) infection can be due to infective, non-infec-tive and neoplastic diseases (Kaposi sarcoma and/orlymphoma). Infective (myo)pericarditis results from thelocal HIV infection and/or from the other viral (cyto-megalovirus, herpes simplex), bacterial (S. aureus, K.pneumoniae, M. avium, and M. tuberculosis) and fungalcoinfections (Cryptococcus neoformans).114 In progres-

Focus box 3 Analyses of pericardial effusionAnalyses of pericardial effusion can establish the diagnosis of viral, bacterial, tuberculous, fungal, cholesterol, andmalignant pericarditis.7 It should be ordered according to the clinical presentation. Cytology and tumour markers(carcinoembryonic antigen (CEA), alpha-feto protein (AFP), carbohydrate antigens CA 125, CA 72-4, CA 15-3, CA 19-9, CD-30, CD-25, etc.) should be performed in suspected malignant disease. In suspected tuberculosis acid-fastbacilli staining, mycobacterium culture or radiometric growth detection (e.g., BACTEC-460), adenosine deaminase(ADA), interferon (IFN)-gamma, pericardial lysozyme, and as well as PCR analyses for tuberculosis should be per-formed (indication I, level of evidence B).11;89100 Differentiation of tuberculous and neoplastic effusion is virtuallyabsolute with low levels of ADA and high levels of CEA.94 In addition, very high ADA levels have prognostic value forpericardial constriction.95 However, it should be noted that PCR is as sensitive (75% vs. 83%), but more specific (100%vs. 78%) than ADA estimation for tuberculous pericarditis.99 In suspected bacterial infection at least three culturesof pericardial fluid for aerobes and anaerobes as well as the blood cultures are mandatory (level of evidence B,indication I). PCR analyses for cardiotropic viruses discriminate viral from autoreactive pericarditis (indication IIa,level of evidence B).2 Analyses of the pericardial fluid specific gravity (>1015), protein level (>3.0 g/dl; fluid/serumratio >0.5), LDH (>200 mg/dL; serum/fluid >0.6), and glucose (exudates vs. transudates 77.9 41.9 vs.96.1 50.7 mg/dl) can separate exudates from transudates but are not directly diagnostic (class IIb).14 However,purulent effusions with positive cultures have significantly lower fluid glucose levels (47.3 25.3 vs. 102.5 35.6mg/dl) and fluid to serum ratios (0.28 0.14 vs. 0.84 0.23 mg/dl), than non-infectious effusions.11 White cellcount (WBC) is highest in inflammatory diseases, particularly of bacterial and rheumatologic origin. A very low WBCcount is found in myxedema. Monocyte count is highest in malignant effusions and hypothyroidisms (79 27% and74 26%), while rheumatoid and bacterial effusions have the highest proportions of neutrophils (78 20% and69 23%). Compared with controls, both bacterial and malignant pericardial fluids have higher cholesterol levels(49 18 vs. 121 20 and 117 33 mg/dl).11

Grams stains in pericardial fluid have a specificity of 99%, but a sensitivity of only 38% for exclusion of the in-fection in comparison to bacterial cultures.14 Combination of epithelial membrane antigen, CEA and vimentin im-munocytochemical staining can be useful to distinguish reactive mesothelial and adenocarcinoma cells.101

ESC Guidelines 597

sive disease the incidence of echocardiographically de-tected pericardial effusion is up to 40%.115 Cardiactamponade is rare.116 During the treatment with retro-viral compounds, lipodystrophy can develop (best dem-onstrated by MRI) with intense paracardial fat depositionleading to heart failure. Treatment is symptomatic,while in large effusions and cardiac tamponade pericar-diocentesis is necessary. The use of corticoid therapy iscontraindicated except in patients with secondary tu-berculous pericarditis, as an adjunct to tuberculostatictreatment (level of evidence A, indication I).117

Bacterial pericarditis

Purulent pericarditis in adults is rare (Table 5), but alwaysfatal if untreated.118121 Mortality rate in treated patientsis 40%, mostly due to cardiac tamponade, toxicity, andconstriction. It is usually a complication of an infectionoriginating elsewhere in the body, arising by contiguousspread or haematogenous dissemination.131 Predisposingconditions are pericardial effusion, immunosuppression,chronic diseases (alcohol abuse, rheumatoid arthritis,etc), cardiac surgery and chest trauma. The disease ap-pears as an acute, fulminant infectious illness with shortduration. Percutaneous pericardiocentesis must bepromptly performed. Obtained pericardial fluid shouldundergo urgent Gram, acid-fast and fungal staining, fol-lowed by cultures of the pericardial and body fluids (levelof evidence B, indication I). Rinsing of the pericardialcavity, combined with effective systemic antibiotictherapy is mandatory (antistaphylococcal antibiotic plusaminoglycoside, followed by tailored antibiotic therapyaccording to pericardial fluid and blood cultures).119 In-trapericardial instillation of antibiotics (e.g., gentamy-cin) is useful but not sufficient. Frequent irrigation of thepericardial cavity with urokinase or streptokinase, usinglarge catheters, may liquefy the purulent exudate,120;121

but open surgical drainage through subxiphoid pericardi-otomy is preferable.118 Pericardiectomy is required inpatients with dense adhesions, loculated and thick pu-rulent effusion, recurrence of tamponade, persistent in-

fection, and progression to constriction.119 Surgicalmortality is up to 8%.

Tuberculous pericarditisIn the last decade TBC pericarditis in the developedcountries has been primarily seen in immunocompro-mised patients (AIDS).123 The mortality rate in untreatedacute effusive TBC pericarditis approaches 85%. Peri-cardial constriction occurs in 3050%.122;125 The clinicalpresentation is variable: acute pericarditis with orwithout effusion; cardiac tamponade, silent, often largepericardial effusion with a relapsing course, toxicsymptoms with persistent fever, acute constrictivepericarditis, subacute constriction, effusive-constric-tive, or chronic constrictive pericarditis, and pericardialcalcifications.3;89 The diagnosis is made by the identifi-cation of Mycobacterium tuberculosis in the pericardialfluid or tissue, and/or the presence of caseous granulo-mas in the pericardium.3;123 Importantly, PCR can iden-tify DNA of Mycobacterium tuberculosis rapidly from only1 lL of pericardial fluid.127;128 High adenosine deaminaseactivity and interferon gamma concentration in pericar-dial effusion are also diagnostic, with a high sensitivityand specificity (Focus box 3): Both pericardioscopy andpericardial biopsy have also improved the diagnosticaccuracy for TBC pericarditis.15 Pericardial biopsy en-ables rapid diagnosis with better sensitivity than peri-cardiocentesis (100 vs. 33%).

Pericarditis in a patient with proven extracardiac tu-berculosis is strongly suggestive of TBC aetiology (severalsputum cultures should be taken).3;126 The tuberculinskin test may be false negative in 2533% of tests122 andfalse positive in 3040% of patients.123 More accurateenzyme-linked immunospot (ELISPOT) test detects T-cells specific for Mycobacterium tuberculosis antigen.132

Perimyocardial TBC involvement is also associated withhigh serum titres of antimyolemmal and antimyosin an-tibodies.133 The diagnostic yield of pericardiocentesis inTBC pericarditis ranges from 3076% according to themethods applied for the analyses of pericardial effu-sion.122;127 Pericardial fluid demonstrates high specific

Focus box 4 Pericardioscopy and epicardial/pericardial biopsyIntroduction of pericardioscopy and contemporary pathology, virology, and molecular biology techniques haveimproved the diagnostic value of epicardial/pericardial biopsy.2;8;15;16;102108 Pericardioscopy makes possible to in-spect pericardial surface, select the biopsy site, and take numerous samples safely.16 Targeted pericardial/epi-cardial biopsy during pericardioscopy was particularly useful in the diagnosis of neoplastic pericarditis.15;16;102104 Nomajor complications occurred in any of the flexible pericardioscopy studies. Mortality reported in the studies withrigid endoscopes was 2.1%,15 and 3.5%103 due to induction of anaesthesia in patients with very large pericardialeffusions.

Histology of epicardial/pericardial biopsies can establish the diagnosis in patients with neoplastic pericarditis andtuberculosis.16;63;102;103 Diagnosis of viral pericarditis can be established by PCR techniques with much higher sen-sitivity and specificity in comparison to viral isolation from fluid and tissue.107111 Immunohistochemistry, especiallyIgG-, IgM- and IgA- and complement fixation contribute significantly to the diagnostic value of epicardial biopsy.2

Specificity of immunoglobulin fixation in autoreactive pericarditis is 100%. Complement fixation was found primarilyin patients with the autoreactive form and rarely in patients with neoplastic pericarditis.8 Malignant mesotheliomascan be distinguished from pulmonary adenocarcinomas by immunohistochemical staining for CEA, surfactant apo-protein, Lewis a, and Tn antigen.112

598 ESC Guidelines

Table

5Differential

diagn

osisofthespecificform

sofperica

rditis11

813

0

Viral

Bac

terial

Tuberculous

Autoreac

tive

Cardiotropic

microbial

agents

Entero-,

ech

o-,

adeno-,

cytomega

lo,

Ebstein

Barr,

herpessimplex,

influenza,parvo

B19

,hepatitis

A,B,C

virus,

HIV

Stap

hyloco

cci,pneumoco

cci,

streptoco

cci,Neisseria,

proteus,

gram

nega

tive

rods,

Legionella

Mycobac

terium

tuberculosis

Autoim

muneproce

ssin

theab

sence

of

viralandbacterialage

nts

Etiologica

levidence

by

PCRorin

situ

hyb

ridisation

(evidence

leve

lB,indicationIIa)

Gram-stain,bac

terial

culture,

PCRforBorreliaan

dch

lamyd

iapneumoniae(evidence

leve

lB,

indicationI)

Ziehl-Neelsen,au

ramin

0stain,

culture,PCR(evidence

leve

lB,

indicationI)

Ig-bindingto

peri-andepicardium,

nega

tive

PCRforca

rdiotropic

agents,

epicarditis

(evidence

leve

lB,

indicationIIa)

Incidence

(%)Western

countries

305

105per10

0,00

0patients

25%

Aspect

ofPE

Serous/serosanginous

Purulent

Serosanginous

Serous

Protein

content

>3g/

dL

High

High/interm

ediate

Interm

ediate

Leuko

cyte

count(PE)

>50

00/m

l10

000/

ml

Interm

ediate

>8000

Interm

ediate

40

U/m

l)

Activatedlymphocytesan

dmac

rophag

es(sparse)ADA-nega

tive

Peri-an

depicardialbiopsy

Lymphocyticperi-/epicarditis,

PCRpositive

forca

rdiotropic

virus

Leuko

cyticepicarditis

Caseousgran

uloma,

PCR

Lymphocyticperi-/epicarditis,PCR

nega

tive

Mortalityifuntreated

Dependingonag

entan

dtamponad

e10

0%85

%In

untreatedtamponad

eIntrap

erica

rdialtreatment

Drainag

e,ifneeded,no

intrap

ercardialco

rticoids

Drainag

ean

drinsing(saline)

gentamycin

80mgi.p.,

Drainag

e,ifneeded

Drainag

e,i.p.triamcinolon(evidence

B,indicationIIa)

Perica

rdiotomy/

perica

rdiectomy

Rarely

needed

Promptlyneeded(evidence

leve

lB,indicationI)

Rarely

needed

Rarely

needed

Systemic

treatment

I.V.im

munoglobulins,

IFN

(inenteroviralperica

rditis)s.c.

I.V.an

tibiotics

Tuberculostatic+prednisone

NSA

IDs,

Colchicine,prednisolone/

azathioprin

Constriction

Rare

Frequent

Frequent(30

50%)

Rare

ESC Guidelines 599

gravity, high protein levels, and high white-cell count(from 0.754 109/l).123

Various antituberculous drug combinations of differ-ent lengths (6, 9, 12 months) have been ap-plied.94;122;123;126 However, only patients with proven orvery likely TBC pericarditis should be treated. Preventionof constriction in chronic pericardial effusion ofundetermined aetiology by ex iuvantibus antitubercu-lar treatment was not successful.134 The use of steroidsremains controversial.126;130;135137 A meta analysis ofpatients with effusive and constrictive TBC pericardi-tis136;137 suggested that tuberculostatic treatment com-bined with steroids might be associated with fewerdeaths, less frequent need for pericardiocentesis orpericardiectomy (level of evidence A, indicationIIb).126;129 If given, prednisone should be administered inrelatively high doses (12 mg/kg per day) since rifam-picin induces its liver metabolism.7 This dose is main-tained for 57 days and is progressively reduced todiscontinuation in 68 weeks. If, in spite of combinationtherapy, constriction develops pericardiectomy is indi-cated (level of evidence B, class I indication).

Pericarditis in renal failure

Renal failure is a common cause of pericardial disease,producing large pericardial effusions in up to 20% of pa-tients.138 Two forms have been described: (1) Uremicpericarditis in 610% of patients with advanced renalfailure (acute or chronic) before dialysis has been insti-tuted or shortly thereafter.139 It results from inflamma-tion of the visceral and parietal pericardium andcorrelates with the degree of azotemia (BUN >60 mg/dl). (2) Dialysis-associated pericarditis in up to 13% ofpatients on maintenance haemodialysis,140 and occa-sionally with chronic peritoneal dialysis due to inade-quate dialysis and/or fluid overload.141 Pathologicexamination of the pericardium shows adhesions be-tween the thickened pericardial membranes (bread andbutter appearance). The clinical features may includefever and pleuritic chest pain but many patients areasymptomatic. Pericardial rubs may persist even in largeeffusions or may be transient. Due to autonomic im-pairment in uremic patients, heart rate may remain slow(6080 beats/min) during tamponade, despite fever andhypotension. Anaemia, due to induced resistance toerythropoetin142 may worsen the clinical picture. TheECG does not show the typical diffuse ST/T wave ele-vations observed with other causes of acute pericarditisdue to the lack of the myocardial inflammation.143 If theECG is typical of acute pericarditis, intercurrent infec-tion must be suspected.

Most patients with uremic pericarditis respond rapidlyto haemo- or peritoneal dialysis with resolution of chestpain and pericardial effusion. To avoid haemopericar-dium heparin-free haemodialysis should be used. Hypo-kalemia and hypophosphatemia should be prevented bysupplementing the dialysis solution when appropriate.144

Intensified dialysis usually leads to resolution of thepericarditis within 12 weeks.145 Peritoneal dialysis,which does not require heparinisation, may be thera-

peutic in pericarditis resistant to haemodialysis, or ifheparin-free haemodialysis cannot be performed. NSAIDsand systemic corticosteroids have limited success whenintensive dialysis is ineffective.146 Cardiac tamponadeand large chronic effusions resistant to dialysis must betreated with pericardiocentesis. (level of evidence B,class IIa indication). Large, non-resolving symptomaticeffusions should be treated with intrapericardial instil-lation of corticosteroids after pericardiocentesis or sub-xiphoid pericardiotomy (triamcinolone hexacetonide 50mg every 6 h for 23 days).140;147 Pericardiectomy is in-dicated only in refractory, severely symptomatic pa-tients due to its potential morbidity and mortality. Afterrenal transplantation, pericarditis has also been reportedin 2.4% of patients, within two months.148 Uraemia orinfection (CMV) may be the causes.

Autoreactive pericarditis and pericardialinvolvement in systemic autoimmune diseases

The diagnosis of autoreactive pericarditis is establishedusing the following criteria:2 (1) increased number oflymphocytes and mononuclear cells >5000/mm3 (auto-reactive lymphocytic), or the presence of antibodiesagainst heart muscle tissue (antisarcolemmal) in thepericardial fluid (autoreactive antibody-mediated); (2)inflammation in epicardial/endomyocardial biopsies byP 14 cells/mm2; (3) exclusion of active viral infectionboth in pericardial effusion and endomyocardial/epi-myocardial biopsies (no virus isolation, no IgM-titeragainst cardiotropic viruses in pericardial effusion, andnegative PCR for major cardiotropic viruses); (4) tuber-culosis, Borrelia burgdorferi, Chlamydia pneumoniae,and other bacterial infection excluded by PCR and/orcultures; (5) neoplastic infiltration absent in pericardialeffusion and biopsy samples; (6) exclusion of systemic,metabolic disorders, and uraemia. Intrapericardialtreatment with triamcinolone is highly efficient with rareside effects.2

Pericarditis occurs in systemic autoimmune diseases:rheumatoid arthritis, systemic lupus erythematosus,progressive systemic sclerosis, polymyositis/ dermato-myositis, mixed connective tissue disease, seronegativespondyloarthropathies, systemic and hypersensitivityvasculitides, Behcet syndrome, Wegener granulomatosis,and sarcoidosis.7 Intensified treatment of the underlyingdisease and symptomatic management are indicated(evidence level B, indication I).

The post-cardiac injury syndrome:postpericardiotomy syndrome

Post-cardiac injury syndrome develops within days tomonths after cardiac, pericardial injury or both.7;149 Itresembles the post-myocardial infarction syndrome,both appearing to be variants of a common immuno-pathic process. Unlike post-myocardial infarction syn-drome, post-cardiac injury syndrome acutely provokes agreater antiheart antibody response (antisarcolemmaland antifibrillary), probably related to more extensiverelease of antigenic material.149;150 Pericardial effusion

600 ESC Guidelines

also occurs after orthotopic heart transplantation (21%).It is more frequent in patients receiving aminocaproicacid during the operation.151 Cardiac tamponade afteropen heart surgery is more common following valvesurgery than coronary artery bypass grafting (CABG)alone and may be related to the preoperative use ofanticoagulants.152 Constrictive pericarditis may also oc-cur after cardiac surgery. Warfarin administration inpatients with early postoperative pericardial effusionimposes the greatest risk, particularly in those who didnot undergo pericardiocentesis and drainage of the ef-fusion.153 Symptomatic treatment is as in acute peri-carditis (NSAIDs or colchicine for several weeks ormonths, even after disappearance of effusion).154 Longterm (36 months) oral corticoids or preferably peri-cardiocentesis and intrapericardial instillation of triam-cinolone (300 mg/m2) are therapeutic options inrefractory forms. Redo surgery and pericardiectomy arevery rarely needed. Primary prevention of postperiocar-diotomy syndrome using short-term perioperative steroidtreatment or colchicine is under investigation.155

Postinfarction pericarditis

Two forms of postinfarction pericarditis can be distin-guished: an early form (pericarditis epistenocardica)and a delayed form (Dresslers syndrome).156 Epi-stenocardiac pericarditis, caused by direct exudation,occurs in 520% of transmural myocardial infarctions butis clinically discovered rarely. Dresslers syndrome oc-curs from one week to several months after clinical onsetof myocardial infarction with symptoms and manifesta-tions similar to the post-cardiac injury syndrome. It doesnot require transmural infarction157 and can also appearas an extension of epistenocardiac pericarditis. Its inci-dence is 0.55%158 and is still lower in patients treatedwith thrombolytics (10 mm is most frequentlyassociated with haemopericardium, and two thirds ofthese patients may develop tamponade/free wall rup-ture.163 Urgent surgical treatment is life saving. How-ever, if the immediate surgery is not available orcontraindicated pericardiocentesis an intrapericardialfibrin-glue instillation could be an alternative in subacutetamponade.163;164

Hospitalisation to observe for tamponade, differentialdiagnosis, and adjustments of treatment is needed.Ibuprofen, which increases coronary flow, is the agent ofchoice.165 Aspirin, up to 650 mg every 4 hours for 2 to 5days has also been successfully applied. Other nonste-roidal agents risk thinning the infarction zone.164;166

Corticosteroid therapy can be used for refractory symp-toms only but could delay myocardial infarction healing(level of evidence B, class IIa indication).7

Traumatic pericardial effusion andhaemopericardium in aortic dissection

Direct pericardial injury can be induced by accidents oriatrogenic wounds.7;167170 Blood loss, vasoconstriction,and haematothorax leading to severe hypotension andshock may mask pulses paradoxus.170 Thoracotomy andsurgical repair should be performed.

Iatrogenic tamponade occurs most frequently inpercutaneous mitral valvuloplasty, during or aftertransseptal puncture, particularly, if no biplane cathe-terisation laboratory is available and a small left atriumis present. Whereas the puncture of the interatrial sep-tum is asymptomatic, the passage of the free wall in-duces chest-pain immediately. If high-pressurecontaining structures are punctured, rapid deteriorationoccurs. However, if only the atrial wall is passed, theonset of symptoms and the tamponade may be delayedfor 4 to 6 hours. Rescue pericardiocentesis is successfulin 95100% with a

Table

6Traumatic

perica

rdialeffusion167

194

Effusiondueto

Incidence

(%)

Mortality(%)

Man

agement

Comment/Reference

Iatroge

nic

Transseptalpuncture

13

30

%ofmyo

cardium

atstak

eorbleedingca

nnotbestopped17

2;17

3

Rotablation

0.1

3Notav

ailable

Seeab

ove

Seeab

ove

172;173

Transluminal

extractionatherectomy

(atheroca

th)

02%

Notav

ailable

Seeab

ove

Seeab

ove

Excim

erlaseran

gioplasty

1.7

3%Notav

ailable

Seeab

ove

Seeab

ove

173

Highpressure

stenting