Management of nonmalignant pleural effusions in adults

INTRODUCTION — Pleural effusions are diagnosed in about 1.5 million individuals in the United States annually [1]. Among the causes, pleural infection, heart failure, and malignancy are the most common. Nonmalignant pleural effusions (NMPEs) have a wide variety of etiologies (table 1 and table 2 and table 3) and cause significant morbidity and mortality [2,3]. There are no established guidelines to facilitate management of NMPEs and most management strategies rely on expert experience and data derived from patients with malignancy. Since the majority of patients with NMPEs have significant comorbidities, a multidisciplinary approach is often necessary for management.

Management of NMPE is discussed in this topic review. Treatment of malignant pleural effusions is discussed elsewhere. (See "Management of malignant pleural effusions".)

ETIOLOGIES — Because of the lack of definition and heterogeneity in etiology of NMPEs (table 1 and table 2 and table 3), there are few large-scale epidemiological data describing the incidence or etiologies of NMPE. However, in our experience, NMPEs due to pleural infection (eg, parapneumonic effusion) and congestive heart failure are the most common. Less common etiologies include NMPEs due to chronic liver disease, kidney disease, asbestos, rheumatoid arthritis, lupus pleuritis, pancreatitis, pulmonary embolism, and cardiac surgery. Rare etiologies include drugs, hypothyroidism, chylothorax, and cholesterol pleural effusion. Occasionally, no etiology is initially apparent (ie, idiopathic NMPE). Noteworthy, is that patients can often have more than one etiology for their effusion (eg, malignancy and congestive heart failure) [4].

Data that support this distribution include the following:

●One prospective study of 356 consecutive unselected patients with NMPE reported that 40 percent of NMPE were due to pleural infection and 24 percent were due to congestive heart failure. Most effusions were exudative in nature (73 percent) and unilateral (88 percent) [3].

●In another prospective study of 308 patients who underwent thoracentesis, excluding patients with malignant pleural effusions, the vast majority of patients had congestive heart failure [2]. In patients with NMPEs, most unilateral effusions were exudates and most bilateral effusions were transudates.

The diagnostic evaluation of a pleural effusion is discussed separately. (See "Pleural fluid analysis in adults with a pleural effusion" and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion".)

INITIAL TREATMENT — Initial treatment of patients with a symptomatic NMPE involves treating the primary disorder and draining the pleural effusion. NMPE is associated with a high mortality such that prompt management is critical [2,3]. (See 'Prognosis' below.)

Treat primary disorder — In most cases the underlying disorder should be treated by starting or optimizing therapy. Treatment varies depending upon the etiology but may involve antibiotics for pneumonia, diuretics for heart failure, diuresis and transjugular intrahepatic portosystemic shunt (TIPS) for hepatic hydrothorax, ultrafiltration for fluid overload in patients with kidney failure, or nonsteroidal anti-inflammatories for lupus pleuritis. (See "Management and prognosis of parapneumonic pleural effusion and empyema in adults" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Hepatic hydrothorax", section on 'Management' and "Overview of the management of chronic kidney disease in adults", section on 'Volume overload' and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Treatment'.)

Drainage for symptomatic patients — Most experts agree that patients with a symptomatic NMPE, should undergo a drainage procedure. In most cases, this involves thoracentesis under ultrasound guidance, though chest tube placement or placement of an indwelling pleural catheter (IPC) may be required. Choosing among these options is individualized and is often institution- or operator-dependent. Technical details and complications of both procedures are described separately. (See "Ultrasound-guided thoracentesis" and "Large volume (therapeutic) thoracentesis: Procedure and complications" and "Thoracostomy tubes and catheters: Indications and tube selection in adults and children".)

Asymptomatic patients with NMPE do not typically require therapeutic pleural intervention. For example, following cardiac surgery many patients have small asymptomatic pleural effusions that do not typically require drainage. Such patients generally undergo observation clinically and radiologically (eg, every three to six weeks). The only indication for thoracentesis in asymptomatic patients with NMPE is for diagnostic purposes or if a complication such as hemorrhage or infection is suspected. A potential downside of not draining a moderate effusion in an asymptomatic patient is the creation of a visceral pleural peel and the development of nonexpandable lung (NEL). As there are minimally invasive ways to palliate patients with NEL (eg, placement of an IPC), it may not be necessary to drain asymptomatic effusions in patients with a known underlying diagnosis.

Assessing the contribution of the pleural effusion to symptoms is challenging. Typical symptoms include dyspnea, chest pain, or cough. In the absence of previous drainage, this decision requires considerable clinical judgement. In many cases, the degree of symptoms and estimated size of the effusion help facilitate this decision. For example, a small- to moderate-sized pleural effusion in a patient admitted with acute heart failure may not need drainage if they are diuresing adequately and symptoms are improving. In contrast, a patient with significant dyspnea and a large pleural effusion due to underlying pneumonia should have their effusion drained. (See "Management and prognosis of parapneumonic pleural effusion and empyema in adults", section on 'Approach to drainage'.)

When a drainage procedure is indicated, it should be performed as soon as is feasible, typically within 12 to 24 hours of presentation. This is especially true in patients in whom the pleural space may be infected (eg, complicated parapneumonic effusion, tuberculous pleuritis, or empyema) or patients with severe symptoms in whom drainage may avoid intubation and mechanical ventilation.

In general, the volume of fluid that can be removed safely is unknown, but 1 to 1.5 L is often quoted as the maximum amount that should be removed in one session to minimize the risk of complications, such as re-expansion pulmonary edema (RPE); however, some data suggest that RPE does not appear to be associated with the volume of fluid removed [5]. However, larger volumes may be removed when the benefits of symptom relief are felt to outweigh the risks. While pleural manometry may guide large-volume thoracentesis, it is not always readily available, and routine pleural pressure monitoring during large-volume thoracentesis does not appear to reduce symptoms of chest discomfort during drainage [6]. We reserve use of manometry for those in whom NEL is suspected. Large-volume thoracentesis and manometry are discussed separately. (See "Large volume (therapeutic) thoracentesis: Procedure and complications" and "Measurement and interpretation of pleural pressure (manometry): Indications and technique".)

Noting the clinical response to drainage is important. It will identify the most likely etiology for patients in whom symptoms improve with drainage; those who demonstrate relief should respond to future drainage procedures should the dyspnea and pleural effusion recur or should additional drainage be needed. In contrast, those who do not respond may need to be investigated for an alternate explanation of their symptoms (eg, NEL, rapid reaccumulation of hepatic hydrothorax, severe underlying lung or cardiac disease, or pulmonary embolism). Drainage also distinguished patients with expandable lung from those with NEL, which will direct options for pleural palliation (ie, IPC placement versus attempts at pleurodesis).

Follow-up — In most cases, treatment of the underlying disorder and drainage of the pleural effusion may result in complete or partial resolution of both symptoms and the effusion. There are no data or guidelines supporting a suitable interval follow-up. However, it is reasonable to perform chest radiography or ultrasound at an interval timepoint when the underlying etiology is expected to improve. For example, this might be days for acute congestive heart failure, weeks for chronic congestive heart failure or pneumonia, or months for lupus pleuritis. Patients should be followed for complete resolution of both symptoms and the pleural effusion. If clinical or radiologic resolution is incomplete, then inadequate primary therapy or an alternate etiology should be sought. Patients who develop worsening symptoms during follow up should be reimaged to look for recurrence or complications (eg, hemorrhage or infection). (See 'Management of persistent or first recurrent pleural effusion' below.)

MANAGEMENT OF PERSISTENT OR FIRST RECURRENT PLEURAL EFFUSION — Most patients with NMPE are responsive to drainage and treatment of the primary disorder. However, a significant proportion persist or recur. In this population, prior to proceeding with definitive therapy to prevent recurrence (eg, pleurodesis or indwelling pleural catheter [IPC] placement), symptomatic pleural effusions should be redrained; the underlying cause of the NMPE reconfirmed; and nonexpandable lung [NEL], pleural infection, hepatic hydrothorax, and malignancy excluded. This approach is largely based upon expert experience since there are no data or guidelines to facilitate this decision. (See 'Repeat thoracentesis' below and 'Clinical re-evaluation and additional testing' below.)

Pleural effusions due to congestive heart failure (CHF) and hepatic hydrothorax are among the most common etiologies that result in recurrent or persistent pleural effusions. As an example, one retrospective study in patients with NMPE reported that among patients who needed an IPC for management of their effusion, almost half were due to CHF and 43 percent were due to hepatic hydrothorax [7]. Another retrospective study of 23 patients with NMPE who underwent IPC placement reported similar results (57 percent due to heart failure and 35 percent due to hepatic hydrothorax) [8]; an additional small proportion had recurrent NMPE due to trauma and idiopathic pleuritis (<10 percent). Both of these studies may have underrepresented patients with NMPEs who are not suited to IPC (eg, patients with parapneumonic effusion).

Repeat thoracentesis — In most patients with persistent or recurrent symptomatic NMPE, repeat therapeutic thoracentesis under ultrasound guidance is generally the first-line option. Repeat thoracentesis is best suited to patients who experienced relief from drainage on presentation, patients with NMPEs that reaccumulate slowly (eg, once every four weeks or more), and patients with a grim prognosis (eg, expected survival less than two to four weeks). Together with optimization of medical therapy, this approach may be sufficient to avoid a definitive form of therapy (eg, pleurodesis or IPC placement) and provides the opportunity for additional pleural fluid analysis and/or pleural biopsy, if needed. In contrast, repeated drainage is generally avoided in asymptomatic patients and in patients who did not experience relief of symptoms with previous drainage. In the latter, investigations targeted at the reason for persistent symptoms is needed (eg, NEL, rapid reaccumulation from hepatic hydrothorax, severe underlying lung or cardiac disease, pulmonary embolism, or deconditioning).

In general, multiple thoracenteses are typically not recommended (more than two to three). The rationale for avoiding frequent thoracenteses is based upon the theoretical risk of introducing infection and inducing loculations as well as avoiding multiple unnecessary procedures when the effusion is clearly recurrent and requires definitive management. Recurrence of this degree should prompt reinvestigation of the etiology, particularly in patients with idiopathic NMPE [9,10]. (See 'Clinical re-evaluation and additional testing' below and 'Pleurodesis' below and 'Indwelling pleural catheter' below.)

Repeat thoracentesis can be performed at the bedside or in an office setting. Technical details regarding thoracentesis and details regarding use of manometry to guide the volume of fluid that can be removed safely and provide a diagnosis of NEL are provided separately. (See "Ultrasound-guided thoracentesis" and "Large volume (therapeutic) thoracentesis: Procedure and complications" and "Measurement and interpretation of pleural pressure (manometry): Indications and technique" and "Diagnosis and management of pleural causes of nonexpandable lung".)

Clinical re-evaluation and additional testing — Recurrence of an NMPE despite primary therapy implies that the initial diagnosis was incorrect and another etiology is present or that the initial diagnosis is correct but the underlying therapy is inadequate (eg, poor compliance, resistance to therapy, failure of therapy). Exploring all options is appropriate at this juncture.

In most patients, the etiology of recurrence is clear and usually due to CHF. However, other important diagnoses to exclude are NEL, active pleural infection (eg, complicated parapneumonic effusion), pleural malignancy, and hepatic hydrothorax. Uncommon and rare etiologies of NMPE should also be kept in mind (eg, chylothorax, cholesterol effusion, effusions due to medications (table 3)), testing for which is largely determined by clinical suspicion. (See 'Exclude nonexpandable lung' below and 'Exclude active pleural infection' below and 'Exclude malignancy' below and 'Exclude other alternate diagnoses' below.)

In patients with recurrent NMPE, we suggest the following clinical evaluation:

●Another in-depth history should be taken looking for symptoms suggestive of an occult cancer, history of asbestos exposure, past or current drug history, possible pneumonia or chest trauma in the recent past, and risk factors for or symptoms of chronic liver disease, heart failure, and connective tissue disease.

●Patients should be re-examined for lymphadenopathy, abdominal masses, spider nevi or other signs of occult liver disease, yellow nails, elevated jugular venous pressure, fine inspiratory crackles, lower extremity edema, or the presence of a ventriculoperitoneal or ventriculopleural shunt.

●All previous existing data should be reviewed including:

•Pleural fluid analyses – Clinicians should re-examine Light's criteria for transudates and exudates from data derived from previous analyses. Whether nonroutine tests such as cytology, pH, cholesterol, triglyceride, amylase, or rheumatoid factor were performed should also be determined. When indicated, repeat diagnostic thoracentesis should be performed to confirm the transudative or exudative nature of the fluid and to look for unusual etiologies (eg, chylothorax, cholesterol pleural effusion). A pleural fluid albumin gradient >1.2 g/dL can also help identify patients whose clinical picture is suggestive of CHF but whose pleural fluid analysis is an exudate by Light's criteria whereas the pleural fluid-serum albumin ratio <0.6 can identify those with hepatic hydrothorax [11]. Details regarding Light's criteria and initial testing are discussed separately. (See "Pleural fluid analysis in adults with a pleural effusion".)

•Chest computed tomography (CT) – Chest CT can reveal potential alternate explanations for a recurrent pleural effusion and if not already done, should be performed irrespective of whether the effusion has been drained or not [12]. Contrast is typically necessary for identifying pleural-based abnormalities (ie, "pleural-phased" contrast) and may also be needed to evaluate hilar or mediastinal disease associated with the effusion [13,14]. Abnormalities that may be diagnostically useful include a lung or pleural abnormality (to suggest primary or metastatic cancer or NEL), bronchiectasis (to support yellow nail syndrome), consolidation (to suggest parapneumonic effusion), cystic lung disease (to suggest chylous effusion from lymphangioleiomyomatosis), interstitial lung disease or nodules (to suggest underlying connective tissue disorder), subphrenic masses or ascites (to suggest an abdominal source or hepatic hydrothorax), bilateral hilar lymphadenopathy (to suggest sarcoidosis), enlarged pulmonary arteries (to suggest pulmonary hypertension), a misplaced catheter, or venous obstruction. (See "Imaging of pleural effusions in adults" and "Imaging of pleural plaques, thickening, and tumors".)

•Transthoracic echocardiography – If not already done, performing an echocardiogram in patients with recurrent NMPE of unclear etiology is appropriate. Echocardiography may reveal evidence of systolic or diastolic heart failure or valvular heart disease to explain a NMPE. Left-sided cardiac function or valvular disease that is disproportionate to the size of the effusion(s) may suggest the presence of pulmonary hypertension or another etiology. A "snowstorm" appearance of the left ventricle myocardium can be suggestive of amyloidosis. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

●New data should be obtained when indicated. This includes routine laboratory tests, kidney and liver function tests, pleural manometry (if available), and repeat pleural fluid analysis and/or thoracoscopic biopsy. In most cases, such testing excludes the important diagnoses discussed in the sections below. Further testing depends upon the clinical suspicion for specific etiologies. (See "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion".)

Reevaluate for congestive heart failure — Since most cases of recurrent NMPE are due to CHF, reconfirming that diagnosis using existing and/or new testing should be performed. This initially involves obtaining an electrocardiograph (EKG), N-terminal pro-brain natriuretic peptide (NT-BNP) level, and a transthoracic echocardiogram (TTE). However, if the diagnosis of CHF is unclear (eg, when cardiac function is disproportionate to the size of the effusion), additional testing such as transesophageal echocardiography, exercise testing, and pulmonary artery catheterization may be needed to determine if serious valvular heart disease or pulmonary hypertension is present. (See "Heart failure: Clinical manifestations and diagnosis in adults".)

Exclude active pleural infection — A parapneumonic effusion is a pleural effusion associated with an underlying pneumonia. Pleural infection can also occur without underlying pneumonia, such as in the case of pleural tuberculosis or trauma (table 4). In addition to Gram stain and culture of the pleural fluid, diagnostic yield can be significantly increased when the pleural fluid is inoculated into blood-culture bottles [15] or when pleural tissue is sent for culture [16]. In patients with recurrent NMPE, actively excluding infection is important because the mainstay of therapy is antibiotics and drainage rather than closure of the pleural space (ie, pleurodesis), which is contraindicated in this population. Diagnosis and management of parapneumonic pleural effusion are discussed separately. (See "Management and prognosis of parapneumonic pleural effusion and empyema in adults".)

In some cases when active infection has resolved, the patients may present with the signs and symptoms of NEL. (See 'Exclude nonexpandable lung' below and "Diagnosis and management of pleural causes of nonexpandable lung" and "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Stage 3 (chronic organization)'.)

Exclude nonexpandable lung — NEL refers to the inability of the lung to fully re-expand after thoracentesis. NEL has historically been separated into trapped lung and lung entrapment. Trapped lung can be due to the development of a fibrous pleural peel that encases the visceral pleura and prevents the lung from expanding fully while lung entrapment is due to an inflammatory process.

NEL occurs most commonly following treatment of an underlying inflammatory or infectious condition of the pleura. It may be suggested when a therapeutic thoracentesis does not improve dyspnea and when fluid is replaced by air after thoracentesis on chest imaging ("pneumothorax ex vacuo"). In most cases, the diagnosis is suggested clinically and radiologically (eg, CT may show visceral pleural thickening, septations, loculations, or scar tissue) and it can be confirmed with pleural manometry, if available.

Importantly, in patients with recurrent NMPE due to NEL, therapeutic thoracentesis is not beneficial; dyspnea is not typically relieved following thoracentesis and the pleural effusion will rapidly reaccumulate despite thoracentesis [17]. In addition, pleurodesis is not typically feasible in patients with NEL since adequate apposition of the visceral and parietal pleura cannot be achieved. Thus, clinicians should not proceed with pleurodesis for patients with recurrent NMPE unless NEL has been reasonably excluded or treated (eg, with decortication). In the patient with NEL who does have symptomatic improvement following initial thoracentesis, IPC placement may be a good option for palliation. Further details regarding diagnosis and management of NEL are provided separately. (See "Diagnosis and management of pleural causes of nonexpandable lung".)

Exclude malignancy — In patients with recurrent NMPE, it is crucial to obtain adequate pleural biopsies to rule out malignancy before proceeding with pleurodesis. Although the yield is likely to be higher in patients with exudative pleural effusions, malignancy can be seen in approximately 5 percent of recurrent transudative effusions [18-20].

Thoracoscopic inspection of the pleural space followed by pleural biopsy is considered the gold standard for the diagnosis of pleural malignancy (multiple biopsies are usually performed in one setting). The optimal target site may be identified on previous chest CT/positron emission tomography (PET) imaging or pleural inspection. Cytology is not as sensitive or specific compared with thoracoscopic biopsy; sensitivity of pleural fluid cytology on initial thoracentesis is approximately 60 percent, which increases to approximately 90 percent after the third thoracentesis (likely due to progression of disease). In addition, yields differ depending upon the type of malignancy that affects the pleural membranes. As such, negative pleural fluid cytology does not rule out malignancy. Additionally, malignant pleural mesothelioma can be difficult to diagnose from pleural fluid cytology and often requires tissue biopsy. The approach to suspected pleural malignancy is provided separately. (See "Selection of modality for diagnosis and staging of patients with suspected non-small cell lung cancer", section on 'Pleural (T2, T3, M1a)' and "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Diagnosis and histology'.)

The rationale for excluding malignancy at this point in patients with recurrent NMPE is that, if found, delay in diagnosis, staging, and initiation of therapy is avoided. In addition, attempting a pleural biopsy after pleurodesis in patients in whom malignant involvement of the pleural space is undiagnosed is fraught with difficulty (due to adhesions and hemorrhage). Management of malignant pleural effusion is provided separately. (See "Management of malignant pleural effusions" and "Imaging of pleural effusions in adults" and "Imaging of pleural plaques, thickening, and tumors".)

Exclude hepatic hydrothorax — In patients with recurrent NMPE, hepatic hydrothorax is one of the more common etiologies. Clinical evaluation and liver function tests may help exclude this as a possibility. Right upper quadrant ultrasound and biopsy may be needed for those without a known diagnosis of cirrhosis. (See "Hepatic hydrothorax" and "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis".)

Exclude other alternate diagnoses — Depending on the clinical suspicion, most other diagnoses may require further imaging (eg, chest magnetic resonance imaging, PET, ultrasonography), hemodynamic testing (pulmonary arterial catheter, exercise testing), laboratory testing (eg, thyroid function tests, 24 hour urine for protein), serologic testing (for connective tissue disorders), or repeat pleural fluid analysis (eg, for triglycerides, cholesterol, chylomicrons, amylase level, rheumatoid factor, fungal, mycobacterial, or parasitic culture) (table 1 and table 2 and table 3 and table 5 and table 6). Obtaining special testing depends upon the suspicion for the underlying disorder. Investigating pleural effusion of unclear etiology and treating special populations with NMPE are discussed separately. (See "Imaging of pleural effusions in adults" and "Diagnostic evaluation of the hemodynamically stable adult with a pleural effusion" and 'Special populations' below.)

Maximize primary therapy — Once the primary diagnosis(es) has been established, attempts should be made to ensure compliance and optimization of therapy for the underlying disease. As examples:

●Patients with extensive volume overload from long standing heart failure with chronic kidney function impairment may benefit from maximizing diuretic medications. In some cases, ultrafiltration or dialysis may be useful. In rare cases, evaluation for implantable devices or cardiac transplantation may also be indicated. (See "Management of refractory heart failure with reduced ejection fraction".)

●Patients with advanced liver disease and hepatic hydrothorax may need optimization of their diuretic therapy, and consideration should also be given to transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation. (See "Hepatic hydrothorax".)

Resolution of pleural effusions in some cases may take weeks or months (eg, tuberculous effusions, hypothyroidism, chylous effusion from lymphangioleiomyomatosis, parapneumonic effusions, cholesterol effusions, effusions from cardiac surgery). In such cases, examining imaging for signs of continued resolution may facilitate the decision of whether to proceed with increasing medical therapy or pleural intervention.

If it is assured that medical therapy has been optimized and the NMPE persists or recurs, definitive therapy to prevent recurrence is needed. (See 'Refractory effusions' below.)

REFRACTORY EFFUSIONS — Patients with symptomatic NMPEs that recur despite repeated thoracentesis (eg, >2 to 3) and optimal medical therapy should undergo indwelling pleural catheter (IPC) placement and/or pleurodesis. While in the past pleurodesis was the preferred option, the emergence of IPCs have changed practice such that either of these options are now equally appropriate. For patients with a grim prognosis (eg, less than two to four weeks) or those who decline pleurodesis and IPC, repeat therapeutic thoracentesis is an option. Pleuroperitoneal or pleurovenous shunts or surgical pleurectomy are last resort options that are rarely used or needed.

Choosing among the options — There are no guidelines and few data to guide the clinician when choosing among these options, and as such, we recommend that therapeutic options be discussed in a multidisciplinary fashion (ie, with pulmonary, thoracic and transplant surgery, and hepatology). The principles that underlie this choice are generally similar to those in patients with recurrent malignant pleural effusion. However, specific to patients with NMPE, when the risk of pleural space infection is considered high (eg, hepatic hydrothorax), then pleurodesis might be preferred, unless pleural fluid output is too high (eg, >300 mL per day) [21,22]. Further details regarding this choice are provided separately. (See "Management of malignant pleural effusions", section on 'Choosing among the options'.)

Pleurodesis — Pleurodesis refers to obliteration of the pleural space by the induction of pleural inflammation and fibrosis using a chemical sclerosant (ie, chemical pleurodesis usually using talc) or manual abrasion (ie, mechanical pleurodesis). Chemical pleurodesis may be performed through a chest tube (ie, talc slurry) at the bedside, or thoracoscopically (ie, talc poudrage). In contrast, mechanical pleurodesis is only performed thoracoscopically.

Patient selection — Pleurodesis is best suited to patients with expandable lung whose pleural fluid reaccumulates over the course of days to weeks rather than months; repeat therapeutic thoracentesis is unlikely to be adequate in this group. However, pleurodesis is also an option for patients with slowly accumulating pleural effusions who prefer to avoid the inconvenience of repeat thoracentesis or an IPC. Patients with a grim prognosis are not suitable for pleurodesis. Pleurodesis can make future thoracic surgery challenging, which should be taken into consideration when making the decision to proceed with this procedure.

Pleurodesis type — There is significant variation in practice regarding the type of pleurodesis (chemical versus mechanical; slurry versus poudrage), chest tube size (large- versus small-bore) and number, and sclerosing agent used (talc versus other). Choosing among these options is often institution- and operator-dependent. Based upon available data derived from patients with malignant pleural effusions, we prefer chemical pleurodesis using talc slurry delivered at the bedside via a small-bore chest tube or talc poudrage. Technical aspects and complications of chemical pleurodesis and data supporting chemical pleurodesis in patients with malignant pleural effusion are discussed in greater detail elsewhere. (See "Chemical pleurodesis for the prevention of recurrent pleural effusion" and "Management of malignant pleural effusions", section on 'Chemical pleurodesis alone (bedside or thoracoscopic)'.)

Efficacy — Supported by case series, several types of NMPEs have been successfully managed by chemical pleurodesis, including those due to chronic ambulatory peritoneal dialysis [23-26], yellow nail syndrome [27-29], chylothorax [30-33], nephrotic syndrome [34], lupus pleuritis [32,35], heart failure [36-39], and hepatic hydrothorax [40,41]. Based upon data from several case series, chemical pleurodesis appears to be effective at managing most patients with NMPEs [23-25,27,28,30-32,34,42-46]. As examples:

●In a retrospective study of 68 patients with NMPE, talc pleurodesis via chest tube was reported to be successful in 77 percent of patients [46].

●In a series of 24 patients with NMPE, chemical pleurodesis was successful in 80 percent of patients [44].

●In another series of 16 patients with NMPE, talc pleurodesis was completely successful in 12 (75 percent) and partially successful in another 3 (19 percent) [45].

The success rate may be lower in patients with hepatic hydrothorax (47 percent) and the morbidity and mortality greater, although the latter may be due to the nature of the underlying disorder rather than the procedure [47]. (See "Hepatic hydrothorax", section on 'Pleurodesis'.)

Importantly, the pleural space needs to be dry for optimal results. Thus, as much fluid as is possible should be removed prior to the application of sclerosant, which may explain the higher failure rate in those with hepatic hydrothorax. In the latter, some experts advocate the use of multiple chest tubes and large-volume paracentesis in order to keep the pleural space dry during the time of pleurodesis.

Indwelling pleural catheter — IPCs are tunneled catheters that provide a means by which fluid is intermittently drained from the pleural space without repeated thoracentesis [48,49]. They are typically left in place for several weeks or for as long as needed or tolerated (weeks to months) and can be left in place indefinitely. IPC placement has the advantage of inducing spontaneous pleurodesis in 40 percent of patients or more. Spontaneous pleurodesis typically occurs within the first six weeks of placement, however success rates are not as high and complications are slightly higher than when used in patients with malignant pleural effusion [50,51]. IPCs can be an outpatient or inpatient procedure. Technical details and complications of IPC placement are provided separately. (See "Management of malignant pleural effusions", section on 'Indwelling pleural catheter (IPC)'.)

Patient selection — IPC is an excellent option for patients who decline, fail, or are not candidates for pleurodesis (eg, frail patients, patients with limited life expectancy [eg, up to six months]) [8,52-54]. However, the patient, a loved-one, or a home healthcare aid needs to be able to perform intermittent drainage (eg, every day or every other day). Selecting patients for IPC and complications of their use (eg, infection) are discussed separately. (See "Management of malignant pleural effusions", section on 'Choosing among the options' and "Management of malignant pleural effusions", section on 'Indwelling pleural catheter (IPC)'.)

Efficacy — Compared with patients who have malignant pleural effusions, data in the NMPE population that support IPC use are limited to case series [7,8,50-57]. As examples:

●In a meta-analysis of thirteen retrospective studies (total 325 patients, half of whom had congestive heart failure), the estimated average rate of spontaneous pleurodesis was 51 percent [50].

●Another randomized study found no difference in the mean dyspnea score when IPC was compared with repeat thoracentesis in patients with refractory NMPE [58]. While thoracentesis resulted in fewer complications, IPCs reduced the number of invasive pleural procedures required.

●In a single-center retrospective study of 54 patients with NMPE, IPC use resulted in adequate symptom relief in 93 percent of patients without need for additional intervention (other than the intermittent drainage itself) [7]. The median length of insertion was six weeks, and the median survival was 3.2 months. Pleurodesis was achieved in 46 percent of those who survived for longer than one month. Approximately one-quarter developed complications, mostly mechanical obstruction of the IPC, and less commonly, infection. Patients with hepatic hydrothorax had the highest rate of complications (37 percent).

●In another retrospective study of 23 patients with NMPE who underwent IPC placement, spontaneous pleurodesis occurred after an average of 111 days [8]. Time to spontaneous pleurodesis was shorter in those with NMPE due to heart failure and longer in those with NMPE due to hepatic hydrothorax. This was longer than that experienced by patients with malignant pleural effusions (36 days).

●In one retrospective study of eight patients who had end-stage kidney disease, IPC use resulted in improved dyspnea by two weeks after insertion, and spontaneous pleurodesis occurred in over one-third [59].

●Several case series also report success of IPC use in patients with hepatic hydrothorax, the details of which are discussed separately [21,40,51,60-65]. (See "Hepatic hydrothorax", section on 'Refractory hydrothorax' and "Palliative care for patients with end-stage liver disease".)

Others — For patients with NMPEs who remain symptomatic and wish to minimize 'catheter days' after IPC or who have recurrence of symptoms after pleurodesis, management options include combining IPC with pleurodesis or repeat pleurodesis attempts.

Success rates may be higher when IPCs are combined with pleurodesis. As an example, one study of 36 patients with refractory NMPE from congestive heart failure reported that successful pleurodesis was achieved in 80 percent of patients when an IPC was placed following talc poudrage pleurodesis [56]. In contrast, the success rate was only 25 percent in patients who only had an IPC alone. Another randomized study found no difference in the mean dyspnea score when repeat thoracentesis was compared with IPC [58].

Last resorts are pleuroperitoneal or pleurovenous shunts for internal drainage or surgical pleurectomy [66-68]. Shunts have two one-way valves that allow unidirectional flow away from the pleural space to the peritoneum or the subclavian vein. Pleurectomy involves resection of visceral and parietal pleura. Both procedures are surgically invasive therapies that are technically difficult to perform. They are rarely done and data that support their use in patients with NMPE are limited. Pleurovenous shunting (eg, Denver shunt) resulted in successful palliation in 12 patients with right-sided NMPE for the one-year observation period of the study [66]. Only one patient had a shunt occlusion after four weeks and another had an early but unrelated death.

A more detailed discussion of these techniques for patients with malignant pleural effusion is provided separately. (See "Management of malignant pleural effusions", section on 'Repeat or combination procedures' and "Management of malignant pleural effusions", section on 'Shunt' and "Management of malignant pleural effusions", section on 'Pleurectomy'.)

SPECIAL POPULATIONS — Treatment of NMPEs that deserve consideration of specific treatment approaches, other than that outlined in this topic, is discussed separately:

●Parapneumonic effusions and empyema (see "Management and prognosis of parapneumonic pleural effusion and empyema in adults")

●Chylothorax (see "Management of chylothorax")

●Cholesterol pleural effusions (see "Clinical presentation, diagnosis, and management of cholesterol pleural effusions")

●Hepatic hydrothorax (see "Hepatic hydrothorax")

●Nonexpandable lung (see "Diagnosis and management of pleural causes of nonexpandable lung")

PROGNOSIS — Few data are published that report the prognosis in patients with NMPEs. The prognosis likely varies with the underlying reason for the effusion and the response to treatment, although data suggest that the one-year mortality ranges from 25 to 55 percent. For those with refractory bilateral transudative effusions mortality is as high as 68 percent at one year and likely reflects the severity of underlying cardiac or liver disease [2].

●One retrospective study of 356 patients with NMPE reported that patients with cardiac, kidney, and hepatic failure had one-year mortality rates of 50 percent, 46 percent, and 25 percent, respectively [3]. Indicators of a poor prognosis were bilateral effusions (hazard ratio [HR] 3.55, 95% CI 2.22-5.68) and transudative effusions (HR 2.78; 95% CI 1.81-4.28).

●In a prospective cohort of 308 patients with both malignant and nonmalignant etiologies for their pleural effusion, the 30-day and one-year mortality in those with NMPEs was 29 and 55 percent respectively [2]. Patients with bilateral pleural effusion had a higher risk of death at 30 days (17 versus 47 percent; HR 2.58, 95% CI 1.44-4.63) and at one year (36 versus 69 percent; HR 2.32, 95% CI 1.55-3.48) compared with patients who had a unilateral effusion.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pleural effusion (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Etiologies – Nonmalignant pleural effusions (NMPEs) have a wide variety of etiologies (table 1 and table 2 and table 3) and are associated with significant morbidity and mortality [2,3]. NMPEs due to pleural infection (eg, parapneumonic effusions) and congestive heart failure (CHF) are the most common etiologies. Less common etiologies include chronic liver disease or kidney function impairment, asbestos, rheumatoid arthritis, lupus pleuritis, pancreatitis, pulmonary embolism, and cardiac surgery. Other etiologies are rare. (See 'Etiologies' above.)

●Initial management – Most management strategies rely on expert experience and data derived from patients with malignant pleural effusions. Many patients with NMPEs have comorbidities such that a multidisciplinary approach is often necessary for optimal management. As initial therapy for patients with symptomatic NMPE, we perform the following (see 'Initial treatment' above):

•Treat the underlying disorder and drain the effusion – In most patients, we start or optimize therapy for the underlying disorder and drain the pleural effusion. Drainage is typically performed using needle thoracentesis under ultrasound guidance. Patients who are asymptomatic do not typically need to be treated. (See 'Drainage for symptomatic patients' above.)

•Follow-up – In most patients, this approach results in complete or partial resolution of the pleural effusion. All patients should be followed clinically and radiologically until symptoms and the effusion resolve. There are no data or guidelines supporting a suitable interval follow-up. However, it is reasonable to perform chest radiography or ultrasound at an interval timepoint when the underlying etiology is expected to improve (eg, days for acute heart failure, weeks for chronic heart failure). Recurrence of symptoms should prompt immediate reimaging.

●Persistent or recurrent NMPE – Our approach to persistent or recurrent NMPE is the following:

•Repeat drainage and pleural fluid analysis – For symptomatic patients who have persistent or a first recurrence of NMPE, we suggest that the effusion be redrained rather than proceeding directly to a definitive therapy (eg, pleurodesis or indwelling pleural catheter [IPC]) (Grade 2C). Repeat pleural fluid analysis should also be performed to reconfirm the suspected diagnosis or rule out more serious pathologies. (See 'Management of persistent or first recurrent pleural effusion' above.)

•Reevaluation of the etiology – In addition, the underlying cause of the NMPE should be reconfirmed. Since this is typically CHF, the clinician should review or obtain an electrocardiograph (EKG), N-terminal pro-brain natriuretic peptide (NT-proBNP) level, and a transthoracic echocardiogram (TTE). However, when the diagnosis of CHF is unclear, additional testing, such as transesophageal echocardiography, exercise testing, and pulmonary artery catheterization, may be needed to determine whether serious valvular heart disease or pulmonary hypertension is present. (See 'Clinical re-evaluation and additional testing' above and 'Reevaluate for congestive heart failure' above.)

•Important conditions to exclude – Nonexpandable lung (NEL), pleural infection, hepatic hydrothorax, and malignancy should also be excluded. This involves review of existing data and obtaining new data such as routine laboratory tests, kidney and liver function tests, pleural manometry (if available), chest CT, and repeat pleural fluid analysis and/or thoracoscopic biopsy. (See 'Clinical re-evaluation and additional testing' above and 'Exclude nonexpandable lung' above and 'Exclude active pleural infection' above and 'Exclude malignancy' above and 'Exclude hepatic hydrothorax' above.)

•Additional testing – Selecting additional tests depends upon the suspicion for other disorders other than those listed but may include further imaging (eg, chest magnetic resonance imaging, positron emission tomography, ultrasound), laboratory testing (eg, thyroid function tests, 24-hour urine for protein), serologic testing (for connective tissue disorders), or repeat pleural fluid analysis (eg, for triglycerides, cholesterol, chylomicrons, amylase level, rheumatoid factor, fungal, mycobacterial, or parasitic culture) (image 1 and table 2 and table 1 and table 3 and table 5 and table 6). (See 'Clinical re-evaluation and additional testing' above and 'Exclude other alternate diagnoses' above.)

•Further maximize therapy for the underlying disorder – Once the primary diagnosis has been established, attempts should be made to ensure compliance and optimization of therapy for the underlying disease. If it is assured that medical therapy has been optimized and the NMPE persists or recurs, definitive therapy to prevent recurrence is needed. (See 'Maximize primary therapy' above.)

●Refractory NMPE – In patients with symptomatic NMPEs that recur despite repeated thoracentesis (eg, >2 to 3) and optimal medical therapy, we suggest either an IPC or pleurodesis rather than repeat thoracentesis (Grade 2C). Repeat therapeutic thoracentesis may be suitable for those with a grim prognosis or those who decline pleurodesis and IPC. Data to support any of these options are limited to case series and data extrapolated from patients with malignant pleural effusion. (See 'Refractory effusions' above and "Management of malignant pleural effusions", section on 'Choosing among the options'.)

•Pleurodesis – Pleurodesis is best suited to patients with expandable lung whose pleural fluid reaccumulates over the course of days to weeks rather than months. It is also an option for patients with slowly accumulating pleural effusions who prefer to avoid the inconvenience of repeat thoracentesis or an IPC. When choosing a sclerosant, we suggest talc rather than other agents (Grade 2C). Patients with a grim prognosis are not suitable for pleurodesis (eg, <2 weeks). (See 'Pleurodesis' above.)

•IPC – IPC is best suited for patients who fail, decline, or are not candidates for pleurodesis (eg, frail patients, patients with limited life expectancy [eg, up to six months]). IPCs are not suitable for patients who do not have the ability to perform intermittent drainage or patients in whom long-term drainage is anticipated (eg, longer that six months). (See 'Indwelling pleural catheter' above and "Management of malignant pleural effusions", section on 'Indwelling pleural catheter (IPC)'.)

•Combination therapy, surgery – For patients with NMPEs who continue to have high output via their IPC and patients who fail pleurodesis, management options include combining IPC with pleurodesis or repeat pleurodesis attempts. Pleuroperitoneal or pleurovenous shunts or surgical pleurectomy are last resort options that are rarely used or needed.

●Special populations – Treatment of NMPEs that deserve consideration of specific treatment approaches, other than those outlined in this topic, include parapneumonic effusions and empyema, chylothorax, cholesterol pleural effusion, tuberculous pleural effusions, NEL, and hepatic hydrothorax. (See 'Special populations' above.)

●Prognosis – The prognosis likely varies with the underlying cause of the effusion and the response to treatment, although data report one-year mortalities ranging from 25 to 55 percent. Bilateral effusion may be an indicator of poor prognosis. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Peter Doelken, MD, FCCP, who contributed to earlier versions of this topic review.