Effusive-Constrictive Pericarditis

Effusive-constrictive pericarditis is a rare clinical syndrome characterized by concurrent pericardial effusion and pericardial constriction, ^{[1, 2]} with constrictive hemodynamics being persistent after the pericardial effusion is removed. Thus, its hallmark is the persistence of postpericardiocentesis elevated right atrial pressure. ^[1]  Effusive-constrictive pericarditis is defined as failure of the right atrial pressure to fall by 50% or to a postpericardiocentesis level below 10 mmHg. ^{[3, 4]}  This condition may also be diagnosed with noninvasive imaging. ^[3]

The mechanism of effusive-constrictive pericarditis is thought to be visceral pericardial constriction. ^[4] Pericardial effusions vary in size and age and may be transudative, exudative, sanguineous, or chylous. An effusion persisting for months to years may evolve into effusive-constrictive pericarditis. ^{[5, 6, 7, 8, 9, 10, 11, 12, 13, 14]}

Patients with effusive-constrictive pericarditis may present with symptoms similar to those of heart failure and volume overload, ^[2] caused by a limitation of intercardiac end-diastolic volume. These findings are secondary not only to the pericardial effusion but also to the pericardial constriction. Symptoms, as well as history and physical findings, vary, and a moderate to large pericardial effusion may occur.

The effusive-constrictive variant of pericarditis was first described in the 1960s. Hancock popularized this definition of a constrictive physiology with a coexisting pericardial effusion. ^[7]

Sagrista-Sauldea et al reported on 15 subjects among 190 consecutive patients with clinical tamponade who underwent pericardiocentesis and concurrent catheterization, who were identified as having effusive-constrictive pericarditis. ^[15] The etiologies of the effusive-constrictive pericarditis were infectious causes, irradiation, cardiac surgery, and idiopathic.

Most cases of effusive-constrictive pericarditis are due to idiopathic factors, ^{[4, 15]}  which is a general reflection of the frequency of idiopathic pericardial disease. ^[4]

Pericardial effusion

The pericardium consists of two layers, a parietal layer and a visceral layer. The visceral pericardium is composed of one or two cell layers of mesothelial cells and adheres closely with the epicardium. The parietal pericardium is separated from the visceral pericardium by a small amount of fluid that serves as a lubricant. Any supraphysiologic accumulation of this fluid is identified as a pericardial effusion. ^{[5, 6, 16, 17, 18]} In general, a pericardial effusion should be evaluated to determine its etiology and hemodynamic significance.

Progression from pericardial effusion to effusive-constrictive pericarditis occurs in an estimated 1.4%-14% of cases. ^[19]

Hemodynamics

Jugular venous and arterial pressures may be within the reference range, with or without signs of cardiac tamponade. Effusive-constrictive pericarditis is believed to evolve as part of a clinical continuum initiated by pericarditis or a pericardial effusion; thus, its etiologies mirror those of pericarditis, pericardial tamponade, and chronic constrictive pericarditis.

The hemodynamic definition of this syndrome is the continued elevation of right atrial, end-diastolic right ventricular, and left ventricular diastolic pressures after the removal of pericardial fluid returns the pericardial pressure to zero (or near zero). ^{[5, 7, 15]}

Treatment considerations

Recognition of effusive-constrictive pericarditis is clinically important because treatment with pericardiocentesis or a pericardial window may be inadequate; this is because neither treatment would address the visceral pericardium. Rather, a visceral pericardiectomy may be indicated for optimal therapy since it is the visceral pericardium that is constricting.

Importantly, however, not all cases of effusive-constrictive pericarditis progress to chronic constrictive pericarditis. In some clinical situations, relief from the effusion can be obtained by means of pericardiocentesis or a pericardial window, with medical treatment being used to manage the underlying condition. ^{[2, 3]}  The constriction may be transitory and surgical pericardiectomy may be avoided. These situations usually occur in the first months of a chronic effusion and close monitoring is required. Surgery may be required for persistent cases. ^[3]

Patient education

Although the symptoms of effusive-constriction are nonspecific, patients should be counseled to report any new or worsened dyspnea, ascites, weight loss or gain, peripheral edema, fever, or chest pain or pressure.

Constrictive pericarditis and cardiac tamponade both restrict filling of the cardiac chambers, thereby increasing systemic and pulmonary filling pressures. In tamponade, single forward flow occurs during systole (prominent x descent in atrial pressure tracings), whereas in constriction, a biphasic pressure tracing is greater during diastole (prominent y descent).

Patients with effusive-constrictive pericarditis may have tamponade-like pressure tracings, which change to constrictive-like tracings after pericardiocentesis. This is because the visceral, rather than the parietal, pericardium is constrictive.

In rare cases, a loculated effusion may lead to constriction with regional tamponade of 1 or more cardiac chambers. Almost any form of chronic pericardial effusion has the potential to organize into an effusive-constrictive state even though the absolute number of cases is relatively low. ^[8]

A study by Ntsekhe et al found that in patients with tuberculous pericardial effusion, right atrial pressure and interleukin-10 (IL-10) levels were higher in those with effusive-constrictive pericarditis. The study included 68 patients with tuberculous pericardial effusion, 36 of whom had effusive-constrictive pericarditis. The investigators determined that the latter group had a right atrial pressure of 17.0 mmHg, versus 10.0 mmHg in the other patients, prior to pericardiocentesis. In addition, the serum and pericardial concentrations of IL-10 were 38.5 and 84.7 pg/mL, respectively, in the patients with effusive-constrictive pericarditis, compared with 0.2 and 20.4 pg/mL, respectively, for the patients with nonconstrictive tuberculous pericardial effusion. ^[20]

Effusive-constrictive pericarditis may be part of a clinical continuum. Stages of infective pericarditis have been observed that range from acute pericarditis and tamponade with effusion to constrictive pericarditis without effusion. Effusive-constrictive pericarditis is likely a middle phase in this evolution. Therefore, suspicion for this entity should be high in cases of indolent, subacute pericarditis, as well in cases of chronic pericardial effusion.

Effusive-constrictive pericarditis likely occurs at any point along a clinical continuum that ranges from the occurrence of an effusion to the development of chronic pericardial constriction. Leading causes of effusive-constrictive pericarditis include the following:

• Idiopathic factors (most cases) ^{[4, 15]}

• Irradiation

• Cardiac surgery

• Neoplasm - Most commonly lung, breast, or hematologic

• Infectious disease - Particularly in immunocompromised states (most commonly tuberculosis and fungal disease, although Streptococcus species have been reported) ^{[21, 22]}

• Myocardial infiltration

• Connective tissue disease

• Uremia

Cases of effusive-constrictive pericarditis in the United States are most often secondary to irradiation, cardiac surgery, uremia, or malignancy or are idiopathic. ^[10] In developing countries, the disorder is usually secondary to infectious causes (eg, tuberculosis). ^[23] In a prospective study of 1184 patients with pericarditis, Sagrista-Sauldea et al reported that 6.9% of 218 patients with tamponade had confirmed effusive-constrictive pericarditis. ^[15]

The disorder’s etiology can often be suspected from the clinical setting in which the effusion occurs. The differential diagnosis of effusive-constrictive pericarditis requires a consideration of all of the causes for pericardial effusions and pericardial tamponade and then a determination of whether a particular patient has constrictive physiology.

There are limited data regarding the prognosis and optimal management of effusive-constrictive pericarditis. ^{[1, 19]}  However, pericardiectomy rates of 40% to 100% have been reported, as well as a mortality of up to 50%. ^[2]

Mortality associated with effusive-constrictive disease is directly related to its etiology. For example, patients with metastatic carcinoma in the pericardial space usually have a prognosis that is much poorer than that of patients with postviral or idiopathic pericardial effusion with constriction. Noncardiac metastatic effusions are often end-stage, with reported mortality rates of 47% and 80% at 3 and 6 months, respectively.

Constrictive physiology increases the risk of morbidity in patients with effusive-constrictive pericarditis, but no definitive statistics are available.

The most effective therapy for effusive-constrictive pericarditis is pericardiectomy with complete removal of the parietal and visceral membranes. However, the perioperative mortality rate for this procedure can be high. Indeed, only experienced surgeons should undertake visceral pericardiectomy, ^[24]  and pericardiectomy should be reserved for refractory cases. ^[1]

When visceral pericardiectomy is not chosen as the plan of care, the underlying disease may progress and cause recurrent and/or worsening effusive-constrictive syndrome or constrictive pericarditis.

Symptoms of effusive-constrictive pericarditis can be hard to interpret but may include atypical or typical chest pain, chest heaviness, or pressure. Other symptoms include dyspnea on exertion, fatigability, or peripheral edema.

Many patients are asymptomatic until the advanced disease stages. In more severe cases, impaired mental status may be evident as a result of decreased cardiac output.

Specific etiologies of effusive-constrictive pericarditis may have characteristic antecedent histories that can suggest pericardial disease (eg, tuberculosis, renal failure, malignancy, radiation therapy, cardiovascular surgery). ^[6]

Physical findings may exist on a continuum, including findings common with cardiac tamponade. ^[25] Findings may include hypotension, jugular venous distension, and diminished heart sounds (classic Beck triad). (The classic description of percussible cardiac dullness at the apex may be unreliable.)

Other common findings can include the following:

• Pulsus paradoxus (paradoxical pulse)

• Jugular venous pulse with a prominent x descent and absent y descent

• Tachycardia

• Tachypnea

• Hepatomegaly

• Ascites

• Peripheral edema

• Pleural effusion (in the absence of left-sided congestive signs)

• Renal dysfunction

• Liver dysfunction and/or auscultation of a pericardial friction rub

Careful attention to all physical findings is required to find clues to the underlying etiology of the pericardial disease.

Because effusive-constrictive pericarditis is rare, the differential diagnosis is guided by few published series and case reports. Differentials to consider include the following:

• Postradiation syndromes

• Neoplasias (metastatic)

• Hematologic neoplasias

• Immunocompromised states with infection

• Connective tissue disease

• Uremia

• Breast Cancer

• Cardiac tamponade

• Restrictive cardiomyopathy

• Hypothyroidism

• Myocardial infarction

• Penetrating chest trauma

• Pericardial effusion

• Acute pericarditis

• Constrictive pericarditis

• Uremic pericarditis

• Tuberculosis

Laboratory studies for effusive-constrictive pericarditis include tests of serum complete blood count (CBC) with differential and serum chemistries, with additions depending on the suspected etiology.

The most important laboratory studies are those performed on pericardial fluid (always under the assumption that pericardiocentesis is clinically indicated). The following tests should always be sent on an initial pericardiocentesis ^[26] :

• Hematocrit and cell count with differential

• Culture - Including tuberculosis

• Glucose

• Total protein

• Enzymes - Lactate dehydrogenase, adenosine deaminase

• Gram staining

• Cytology

The need for other, more specific laboratory tests, including the following, is determined by the priorities of the differential diagnosis:

• Suspected tuberculous pericarditis - Purified protein derivative (PPD) of tuberculin, appropriate staining of pericardial fluid

• Suspected infectious pericarditis - Serum aerobic and anaerobic blood cultures, viral titers, or polymerase chain reaction (PCR) assay of pericardial fluid

• Suspected malignancy - Pericardial fluid for tumor markers or carbohydrate antigens (CAs; eg, CA-125)

• Suspected human immunodeficiency virus (HIV) pericarditis - Serum HIV testing

• Suspected hypothyroid-related pericarditis - Serum thyroid function testing

• Suspected connective tissue disease - Serum connective tissue serologies

The chest radiograph may consistently show an enlarged cardiac silhouette when the pericardial effusion is greater than 250 mL. The cardiac silhouette may be flask shaped and the lung fields may show no evidence of congestion, consistent with the absence of a congestive cardiomyopathy. ^[27]

These findings must be interpreted with caution, as they may also be observed in severe aortic insufficiency, congestive heart failure with severe tricuspid insufficiency, severe volume overload, and mitral regurgitation. The distinguishing characteristic is pulmonary vascular congestion, which may be present with any of these conditions and is usually absent in pericardial disease.

A small effusion may have a normal cardiac silhouette, but this does not eliminate the diagnosis of effusive-constrictive pericarditis.

Echocardiography is the most efficient way to detect an effusion because it has excellent sensitivity and specificity. ^{[23, 28, 29]} Pericardial fluid is easily observed as an echolucent region (echo-free space) between the visceral pericardium (epicardium) and the parietal pericardium.

The size of the effusion may be estimated, even if the effusion is localized. For example, small effusions usually must be observed in 2 views, particularly behind the left ventricle. Moderate effusions are visualized circumferentially, and large effusions exceed 1cm in thickness on all views.

Doppler investigation may demonstrate overlapping features of both cardiac tamponade and constrictive pericarditis. ^[30] There may be an increased respiratory variation of mitral and tricuspid inflow, consistent with constrictive pericarditis. Other echocardiographic findings consistent with constrictive pericarditis include abnormal septal and posterior wall motion, noted in the M-mode by using a parasternal short-axis view; a normal velocity of propagation (V p) in color M-mode; and a normal or supranormal early relaxation (Ea) on tissue Doppler imaging. More recently, a study that reviewed pre- and postpericardiocentesis echo-Doppler findings compared with those of cardiac tamponade showed that effusive-constrictive pericarditis has higher medial and lateral e' velocities (augmented early diastolic mitral septal annular velocities). ^[31] Both effusive-constrictive pericarditis and tamponade had reduced hepatic vein diastolic forward flow velocities, which both increased after pericardiocentesis. Inspiratory and expiratory mitral E/A ratios (early to late diastolic filling ratios) in effusive-constrictive pericarditis were increased but less so compared to that of constrictive pericarditis, whereas the early diastolic mitral inflow was less than that of the late diastolic mitral inflow in tamponade. ^[31]

Echocardiography can also be used to distinguish a pericardial effusion from a pleural effusion, with pericardial effusions being anterior to the descending aorta.

In addition, evidence for cardiac tamponade may be inferred from an echocardiogram. For example, early diastolic collapse of the right ventricular free wall and/or late diastolic collapse of the right atrium may be observed.

The diagnosis of effusive-constrictive pericarditis cannot be made primarily on the basis of computed tomography (CT) scan or magnetic resonance imaging (MRI) findings. However, CT scanning and MRI may provide excellent images of the pericardium and associated mediastinal structures.

CT scanning and MRI can be used to effectively image and confirm a thickened pericardium or detect a pericardial effusion if visualization with echocardiography is suboptimal.

Cardiac magnetic resonance imaging (CMRI) enables the evaluation of the functional and flow changes in pericardial constriction. In addition, it allows for the detection of acute pericardial inflammation, fusion and thickening of the pericardial layers, and pericardial effusion. In one study, Aquaro and colleagues used a multiparametric CMRI approach in diagnosing patients with constrictive pericarditis, transient constrictive pericarditis, and effusive-constrictive pericarditis. ^[32] However, some patients with effusive-constrictive pericarditis have normal pericardial thickness; in such cases, the disease must be diagnosed hemodynamically.

The use of ¹⁸ F-2-deoxyglucose (FDG) positron emission tomography (PET) scanning has been reported for the evaluation of pericardial inflammation and malignancy. Clinically, this imaging modality can be used to rule out malignancy and to help assess active areas of inflammation to gauge not only potential response to treatments such as anti-inflammatory agents but also to possibly help select the optimal site for biopsy if indicated. ^[33]

An electrocardiogram (ECG) may not show any specific findings for effusive-constrictive pericarditis. However, the ECG may show changes in the ST segment, T wave, or PR segment and/or demonstrate low QRS voltage associated with pericarditis and/or effusion. Nonspecific ST- and T-wave abnormalities may be present.

With a large effusion, a cardiac rocking motion may be observed on the ECG as electrical alternans.

Pericardiocentesis

Pericardiocentesis as a diagnostic test may have a low yield, yet as a therapeutic procedure its diagnostic benefit is much improved. The risks and benefits of any invasive procedure must be considered before the start of testing.

Pericardial biopsy

Clinical circumstances determine when a biopsy is performed because the procedural risk is increased. Factors include how symptomatic the patient is and how likely a finding would change clinical management. Positron emission tomography (PET) scanning may be utilized in this circumstance to identify the optimal biopsy site.

Pericardioscopy is a developing technique that allows direct viewing of the epicardium with the possibility for biopsy. This is currently an experimental technique. ^[34]

Histologic findings

Pericardial biopsy samples may be examined for malignancy and inflammation by traditional and immunohistologic means. In advanced laboratories, PCR assay or in situ hybridization may be used to analyze for microbial deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). Combined examination of pericardial fluid and biopsy results provides the greatest yield.

The diagnosis of effusive-constrictive pericarditis may be suspected clinically, but it is definitively established by recording right heart and intrapericardial pressures before and after pericardiocentesis. ^[5]

Before pericardial fluid is removed, cardiac tamponade (or near tamponade) hemodynamic physiology must be present to make the diagnosis of effusive-constrictive pericarditis. Hemodynamic pressure recordings will indicate that intrapericardial pressures, right atrial pressure, and end-diastolic right and left ventricular pressures are elevated and equal (or nearly equal). There is usually an inspiratory decrease in right-heart filling pressures. A prominent x descent and an absent y descent may also be noted.

Pericardiocentesis should decrease intrapericardial pressure to zero but may fail to restore cardiac hemodynamics to normal. This is because the visceral constrictive component of the syndrome causes a persistent elevation and equalization of intracardiac diastolic pressures. This constrictive physiology unveils a biphasic pressure tracing in the right atrium, now with a prominent y descent and dip-and-plateau right ventricular pressure tracings, with absent or minimal respiratory variation.

Put another way, persistent constriction after pericardiocentesis suggests a constrictive visceral pericardium and, therefore, the diagnosis of effusive-constrictive pericarditis.

Diagnostic consideration

Because effusive-constrictive pericarditis is rare, intrapericardial pressures are not routinely measured during pericardiocentesis in clinical practice. This protocol may result in failure to recognize intrapericardial pressure as near zero. The consequences of this oversight include missing the diagnosis of effusive-constrictive pericarditis.

Although potentially curative therapy for hemodynamically compromising effusive-constrictive pericarditis requires surgical intervention, medical management directed at the underlying etiology may be effective, as dictated by clinical circumstances. However, no randomized, blinded clinical trials have been completed to guide medical therapy, which is primarily supportive. In the setting of clear evidence of pericardial inflammation, a trial anti-inflammatory treatment is indicated. ^[4]

Rilonacept, and interleukin-1 (IL-1) cytokine trap, was approved by the US Food and Drug Administration (FDA) in March 2021 to treat pericarditis and to reduce the risk for recurrence in patients aged 12 years and older. ^[35] Approval of rilonacept was supported by results from the RHAPSODY clinical trial (N = 61). Among 30 patients who received rilonacept, 2 patients (7%) had pericarditis recurrence, compared to 23 of 31 patients (74%) in the placebo group. ^[36]  

Depending on putative etiology, steroids, nonsteroidal anti-inflammatory agents, or antibiotics may be needed. ^[37]

Schatz et al showed the benefit of Anakinra, a non-glycosylated recombinant form of the interleukin-1 receptor antagonist, in a case of refractory pericardial disease associated with rheumatoid arthritis. ^[38]

Intravascular volume status must not be decreased excessively in the presence of tamponade physiology; diuretics must not be applied indiscriminately. Alternatively, after pericardial drainage, diuretics may be useful with constrictive physiology and evidence of volume overload.

Pericardiocentesis or surgical drainage of the effusion is performed as dictated by the patient's clinical situation. These procedures are undertaken in circumstances of tamponade or hemodynamic compromise or when a purulent effusion is suspected, as well as in cases in which there is a large, persistent effusion or diagnostic uncertainty exists. ^[39]

The most effective therapy for effusive-constrictive pericarditis is pericardiectomy, with complete removal of the parietal and visceral membranes. The perioperative mortality rate for this procedure can be high, therefore a complete pericardiectomy is primarily reserved in the setting of refractory symptoms or clinical evidence of chronic constrictive pericarditis. ^[4] Surgery can be risky and requires considerable thought before it may be recommended. Difficulties include the length of the procedure, infection potential, morbidity secondary to the wide exposure required, other medical problems that are often present in these patients, and the technical expertise required to perform the surgery.

In patients who may have a high mortality risk with thoracotomy yet have a significant chance of effusion recurrence with needle drainage alone, a pericardial-peritoneal window is an effective treatment for recurrent pericardial effusions. ^[40]

Inpatient care

If hemodynamic compromise is possible, inpatient care is required to monitor the patient. Moreover, necessary pericardial procedures usually involve hospitalization.

Transfer is required when necessary diagnostic or therapeutic modalities such as echocardiography, pericardiocentesis, or cardiothoracic surgery are not available at the treating facility.

Outpatient care

The priorities of outpatient care reflect the treatments required for specific etiologies and include monitoring patients for signs of worsening constrictive physiology or for the development of cardiac tamponade.

In general, patients are given maintenance therapy with a diuretic to maintain euvolemia. Other medications depend on the specific etiology being treated.

A cardiologist can assist with echocardiographic interpretation, pericardiocentesis, and invasive hemodynamics. A cardiothoracic surgeon may help when a pericardial window or pericardiectomy is being considered.

In complicated cases, such as those involving tuberculous pericarditis or purulent uremic pericarditis, multidisciplinary involvement may be required. Specialists in infectious disease, nephrology, cardiology, and/or cardiothoracic surgery may be consulted.

No specific dietary changes are recommended. However, patients with effusive-constrictive pericarditis often have chronic underlying diseases for which adequate nutrition is especially important. Moreover, euvolemia is a goal, and salt restriction may be indicated.

The patient’s activities are generally limited by the underlying disease or the decreased cardiac output that may occur with effusive-constriction, but no specific activity prohibitions exist.

European Society of Cardiology (ESC)

The ESC released updated guidelines for the diagnosis and treatment of constrictive pericarditis in 2015, which are summarized below. ^[3]  All of these recommendations are based on class I, level C evidence, unless noted otherwise.

• Transthoracic echocardiography as well as frontal and lateral chest radiography with adequate technical characteristics are recommended in all patients with suspected constrictive pericarditis.
• Computed tomography (CT) scanning and/or cardiac magnetic resonance imaging (CMRI) are indicated as second-level imaging techniques to assess calcifications (CT scanning), pericardial thickness, and degree and extension of pericardial involvement.
• Cardiac catheterization is indicated when noninvasive diagnostic methods do not provide a definite diagnosis of constriction.
• The mainstay of treatment of chronic constriction is pericardiectomy.
• Medical therapy for specific etiologies of pericarditis is recommended to prevent progression of constriction, as well as for advanced cases or in the setting of a high risk of surgery or mixed forms with myocardial involvement.
• Empiric anti-inflammatory therapy may be considered in cases with transient or a new diagnosis of constriction with concomitant evidence of pericardial inflammation on CT/CMRI or results of laboratory studies suggestive of inflammation (eg, elevated C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]) (class IIb, level C evidence).