Pleural Effusion

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Background

A pleural effusion is an abnormal collection of fluid in the pleural space resulting from excess fluid production or decreased absorption or both.[1] It is the most common manifestation of pleural disease, with etiologies ranging from cardiopulmonary disorders to symptomatic inflammatory or malignant diseases requiring urgent evaluation and treatment. Approximately 1.5 million pleural effusions are diagnosed in the United States each year (see the images below). (See Etiology, Epidemiology, Treatment, and Medications.)


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Large, malignant, right-sided pleural effusion.


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Chest radiograph showing left-sided pleural effusion.

Anatomy

The pleural space is bordered by the parietal and visceral pleurae. The parietal pleura covers the inner surface of the thoracic cavity, including the mediastinum, diaphragm, and ribs. The visceral pleura envelops all lung surfaces, including the interlobar fissures. The right and left pleural spaces are separated by the mediastinum.

The pleural space plays an important role in respiration by coupling the movement of the chest wall with that of the lungs in 2 ways. First, a relative vacuum in the space keeps the visceral and parietal pleurae in close proximity. Second, the small volume of pleural fluid, which has been calculated at 0.13 mL/kg of body weight under normal circumstances, serves as a lubricant to facilitate movement of the pleural surfaces against each other in the course of respirations.[2] This small volume of fluid is maintained through the balance of hydrostatic and oncotic pressure and lymphatic drainage, a disturbance of which may lead to pathology.[3]

Etiology

The normal pleural space contains approximately 1 mL of fluid, representing the balance between (1) hydrostatic and oncotic forces in the visceral and parietal pleural vessels and (2) extensive lymphatic drainage. Pleural effusions result from disruption of this balance.

Pleural effusion is an indicator of an underlying disease process that may be pulmonary or nonpulmonary in origin and may be acute or chronic.[4, 5] Although the etiologic spectrum of pleural effusion is extensive, most pleural effusions are caused by congestive heart failure, pneumonia, malignancy, or pulmonary embolism. The following mechanisms play a role in the formation of pleural effusion:

The net result of effusion formation is a flattening or inversion of the diaphragm, mechanical dissociation of the visceral and parietal pleura, and a restrictive ventilatory defect as measured by pulmonary function testing.[6]

Pleural effusions are generally classified as transudates or exudates, based on the mechanism of fluid formation and pleural fluid chemistry. Transudates result from an imbalance in oncotic and hydrostatic pressures, whereas exudates are the result of inflammation of the pleura or decreased lymphatic drainage. In some cases, the pleural fluid may have a combination of transudative and exudative characteristics.

Transudates

Transudates are usually ultrafiltrates of plasma in the pleura due to imbalance in hydrostatic and oncotic forces in the chest. However, they can also be caused by the movement of fluid from peritoneal spaces or by iatrogenic infusion into the pleural space from misplaced or migrated central venous catheters or nasogastric feeding tubes. Transudates are caused by a small, defined group of etiologies, including the following:

Exudates

Exudates are produced by a variety of inflammatory conditions and often require more extensive evaluation and treatment than transudates. Exudates arise from pleural or lung inflammation, impaired lymphatic drainage of the pleural space, transdiaphragmatic movement of inflammatory fluid from the peritoneal space, altered permeability of pleural membranes, and increased capillary wall permeability or vascular disruption. Pleural membranes are involved in the pathogenesis of the fluid formation. The permeability of pleural capillaries to proteins is increased in disease states resulting in an elevated protein content.

The more common causes of exudates include the following:

Epidemiology

Occurrence in the United States

Because pleural effusion is a manifestation of underlying disease, its precise incidence is difficult to determine. However, the incidence in the United States is estimated to be at least 1.5 million cases annually.[11] Congestive heart failure, bacterial pneumonia, malignancy, and pulmonary embolus are responsible for most of these cases.

International occurrence

The estimated prevalence of pleural effusion is 320 cases per 100,000 people in industrialized countries, with a distribution of etiologies related to the prevalence of underlying diseases.[4]

Sex-related demographics

In general, the incidence of pleural effusion is equal between the sexes. However, certain causes have a gender predilection. About two thirds of malignant pleural effusions occur in women, in whom they are associated with breast and gynecologic malignancies.

Pleural effusion associated with systemic lupus erythematosus is also more common in women than in men. In the United States, the incidence of pleural effusion in the setting of malignant mesothelioma is higher in males, probably because of their higher occupational exposure to asbestos.

Pleural effusions associated with chronic pancreatitis are more common in males, with the majority of male cases having alcoholism as the etiology. Rheumatoid effusions also occur more commonly in males than in females.

Race- and age-related demographics

Because pleural effusion is a manifestation of underlying disease, racial differences will most likely reflect racial variation in incidence of the causative disorder.

Pleural effusions usually occur in adults. However, they appear to be increasing in children, often in the setting of underlying pneumonia.[12] Fetal pleural effusions have also been reported and under certain circumstances may be treated prior to delivery.[13]

Prognosis

The prognosis in pleural effusion varies in accordance with the condition’s underlying etiology. However, patients who seek medical care earlier in the course of their disease and those who obtain prompt diagnosis and treatment have a substantially lower rate of complications than do patients who do not.

Morbidity and mortality

Morbidity and mortality of pleural effusions are directly related to cause and stage of the underlying disease at the time of presentation, and biochemical findings in the pleural fluid.

Morbidity and mortality rates in patients with pneumonia and pleural effusions are higher than those in patients with pneumonia alone. Parapneumonic effusions, when recognized and treated promptly, typically resolve without significant sequelae. However, untreated or inappropriately treated parapneumonic effusions may lead to empyema, constrictive fibrosis, and sepsis.

Development of a malignant pleural effusion is associated with a very poor prognosis, with median survival of four months and mean survival of less than one year.[14] . The most common associated malignancy in men is lung cancer. The most common associated malignancy in women is breast cancer. Median survival ranges from 3-12 months, depending on the malignancy. Effusions from cancers that are more responsive to chemotherapy, such as lymphoma or breast cancer, are more likely to be associated with prolonged survival, compared with those from lung cancer or mesothelioma.[15, 16]

Cellular and biochemical findings in the fluid may also be indicators of prognosis. For example, a lower pleural fluid pH is often associated with a higher tumor burden and a worse prognosis.[17]

History

A detailed medical history should be obtained from all patients presenting with a pleural effusion, as this may help to establish the etiology. For example, a history of chronic hepatitis or alcoholism with cirrhosis suggests hepatic hydrothorax or alcohol-induced pancreatitis with effusion. Recent trauma or surgery to the thoracic spine raises the possibility of a CSF leak. The patient should be asked about a history of cancer, even remote, as malignant pleural effusions can develop many years after initial diagnosis.

An occupational history should also be obtained, including potential asbestos exposure, which could predispose the patient to mesothelioma or benign asbestos-related pleural effusion. The patient should also be asked about medications they are taking.[4]

The clinical manifestations of pleural effusion are variable and often are related to the underlying disease process. The most commonly associated symptoms are progressive dyspnea, cough, and pleuritic chest pain.

Dyspnea

Dyspnea is the most common symptom associated with pleural effusion and is related more to distortion of the diaphragm and chest wall during respiration than to hypoxemia. In many patients, drainage of pleural fluid alleviates dyspnea despite limited alterations in gas exchange. Drainage of pleural fluid may also allow the underlying disease to be more easily recognized on repeat chest radiographs. Note that dyspnea may be caused by the condition producing the pleural effusion, such as underlying intrinsic lung or heart disease or obstructing endobronchial lesions rather than by the effusion itself.

Cough

Cough in patients with pleural effusion is often mild and nonproductive. More severe cough or the production of purulent or bloody sputum suggests an underlying pneumonia or endobronchial lesion.

Chest pain

The presence of chest pain, which results from pleural irritation, raises the likelihood of an exudative etiology, such as pleural infection, mesothelioma, or pulmonary infarction.[18]

Pain may be mild or severe. It is typically described as sharp or stabbing and is exacerbated with deep inspiration. Pain may be localized to the chest wall or referred to the ipsilateral shoulder or upper abdomen because of diaphragmatic irritation. Pain may diminish in intensity as the pleural effusion increases in size and the inflamed pleural surfaces are no longer in contact with each other.

Additional symptoms

Other symptoms in association with pleural effusions may suggest the underlying disease process. Increasing lower extremity edema, orthopnea, and paroxysmal nocturnal dyspnea may all occur with congestive heart failure.

Night sweats, fever, hemoptysis, and weight loss should suggest TB. Hemoptysis also raises the possibility of malignancy, other endotracheal or endobronchial pathology, or pulmonary infarction. An acute febrile episode, purulent sputum production, and pleuritic chest pain may occur in patients with an effusion associated with pneumonia.

Physical Examination

Physical findings in pleural effusion are variable and depend on the volume of the effusion. Generally, there are no physical findings for effusions smaller than 300 mL. With effusions larger than 300 mL, findings may include the following:

Other physical findings, as follows, may suggest the underlying cause of the pleural effusion:

Approach Considerations

Thoracentesis should be performed for new and unexplained pleural effusions when sufficient fluid is present to allow a safe procedure. Observation of pleural effusion is reasonable when benign etiologies are likely, as in the setting of overt congestive heart failure, viral pleurisy, or recent thoracic or abdominal surgery.

Laboratory testing helps to distinguish pleural fluid transudates from exudates. However, certain types of exudative pleural effusions might be suspected simply by observing the gross characteristics of the fluid obtained during thoracentesis. Note the following:

Normal pleural fluid

Normal pleural fluid has the following characteristics:

Distinguishing Transudates From Exudates

The initial diagnostic consideration is distinguishing transudates from exudates. Although a number of chemical tests have been proposed to differentiate pleural fluid transudates from exudates, the tests first proposed by Light et al have become the criterion standards.[22]

The fluid is considered an exudate if any of the following are found:

The fluid is considered a transudate if all of the above are absent.

These criteria require simultaneous measurement of pleural fluid and serum protein and LDH. However, a meta-analysis of 1448 patients suggested that the following combined pleural fluid measurements might have sensitivity and specificity comparable to the criteria from Light et al for distinguishing transudates from exudates[23] :

Clinical judgment is required when pleural fluid test results fall near the cutoff points.

The criteria from Light et al and these alternative criteria identify nearly all exudates correctly, but they misclassify approximately 20-25% of transudates as exudates, usually in patients on long-term diuretic therapy for congestive heart failure (because of the concentrating effect of diuresis on protein and LDH levels within the pleural space).[24]

Using the criterion of serum minus pleural protein concentration level of less than 3.1 g/dL, rather than a serum/pleural fluid ratio of greater than 0.5, more correctly identifies exudates in these patients.[25]

Although pleural fluid albumin is not typically measured, a gradient of serum albumin to pleural fluid albumin of less than 1.2 g/dL also identifies an exudate in such patients.[26]

In addition, studies suggest that pleural fluid levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are elevated in effusions due to congestive heart failure.[27, 24] Moreover, elevated pleural NT-proBNP was demonstrated to out-perform pleural fluid BNP as a marker of heart failure–related effusion.[28] Thus, at institutions where this test is available, high pleural levels of NT-proBNP (defined in different studies as >1300-4000 ng/L) may help to confirm heart failure as the cause of an otherwise idiopathic chronic effusion.

In a more recent systematic review, pleural fluid cholesterol greater than 55 mg/dL and pleural LDH greater than 200 U/L each had better positive and negative likelihood ratio for distinguishing exudates from transudates than did Light’s criteria.[29]

Pleural Fluid LDH, Glucose, and pH

Pleural fluid LDH

Pleural fluid LDH levels greater than 1000 IU/L suggest empyema, malignant effusion, rheumatoid effusion, or pleural paragonimiasis. Pleural fluid LDH levels are also increased in effusions from Pneumocystis jiroveci (formerly, P carinii) pneumonia. The diagnosis is suggested by a pleural fluid/serum LDH ratio of greater than 1, with a pleural fluid/serum protein ratio of less than 0.5.

Pleural fluid glucose and pH

In addition to the previously discussed tests, glucose and pleural fluid pH should be measured during the initial thoracentesis in most situations.

A low pleural glucose concentration (30-50 mg/dL) suggests malignant effusion, tuberculous pleuritis, esophageal rupture, or lupus pleuritis. A very low pleural glucose concentration (ie, < 30 mg/dL) further restricts diagnostic possibilities, to rheumatoid pleurisy or empyema.

Pleural fluid pH is highly correlated with pleural fluid glucose levels. A pleural fluid pH of less than 7.30 with a normal arterial blood pH level is caused by the same diagnoses as listed above for low pleural fluid glucose. However, for parapneumonic effusions, a low pleural fluid pH level is more predictive of complicated effusions (that require drainage) than is a low pleural fluid glucose level. In such cases, a pleural fluid pH of less than 7.1-7.2 indicates the need for urgent drainage of the effusion, while a pleural fluid pH of more than 7.3 suggests that the effusion may be managed with systemic antibiotics alone.

In malignant effusions, a pleural fluid pH of less than 7.3 has been associated in some reports with more extensive pleural involvement, higher yield on cytology, decreased success of pleurodesis, and shorter survival times.

Handle pleural fluid samples as carefully as arterial samples for pH measurements, with fluid collected in heparinized syringes and ideally transported on ice for measurement within six hours. However, studies have determined that when collected in heparinized syringes, pleural fluid pH does not change significantly even over several hours at room temperature. Consequently, if appropriately collected samples can be processed quickly, pH measurements should not be canceled simply because the sample was not transported on ice.

Pleural Fluid Cell Count Differential

If an exudate is suspected clinically or is confirmed by chemistry test results, send the pleural fluid for total and differential cell counts, Gram stain, culture, and cytology.

Pleural fluid lymphocytosis, with lymphocyte values greater than 85% of the total nucleated cells, suggests TB, lymphoma, sarcoidosis, chronic rheumatoid pleurisy, yellow nail syndrome, and chylothorax. Pleural lymphocyte values of 50-70% of the nucleated cells suggest malignancy.

Pleural fluid eosinophilia (PFE), with eosinophil values greater than 10% of nucleated cells, is seen in approximately 10% of pleural effusions and is not correlated with peripheral blood eosinophilia. PFE is most often caused by air or blood in the pleural space. Blood in the pleural space causing PFE may be the result of pulmonary embolism with infarction or benign asbestos pleural effusion. PFE may be associated with other nonmalignant diseases, including parasitic disease (especially paragonimiasis), fungal infection (coccidioidomycosis, cryptococcosis, histoplasmosis), and a variety of medications.

The presence of PFE does not exclude a malignant effusion, especially in patient populations with a high prevalence of malignancy. The presence of PFE makes tuberculous pleurisy unlikely and also makes the progression of a parapneumonic effusion to an empyema unlikely.

Mesothelial cells are found in variable numbers in most effusions, but their presence at greater than 5% of total nucleated cells makes a diagnosis of TB less likely. Markedly increased numbers of mesothelial cells, especially in bloody or eosinophilic effusions, suggests pulmonary embolism as the cause of effusion.

Pleural Fluid Culture and Cytology

Cultures of infected pleural fluids yield positive results in approximately 60% of cases. This occurs even less often for anaerobic organisms. Diagnostic yields, particularly for anaerobic pathogens, may be increased by directly culturing pleural fluid into blood culture bottles.[30]

Malignancy is suspected in patients with known cancer or with lymphocytic, exudative effusions, especially when bloody. Direct tumor involvement of the pleura is diagnosed most easily by performing pleural fluid cytology.

Heparinized samples (1 mL of 1:1000 heparin per 50 mL of pleural fluid) should be submitted for analysis if the pleural fluid is bloody and they should be refrigerate if samples will not be processed within one hour.

The reported diagnostic yields in cytology vary from 60-90%, depending on the extent of pleural involvement and the type of primary malignancy. Cytology findings are positive in 58% of effusions related to mesothelioma.

The sensitivity of cytology is not highly related to the volume of pleural fluid tested. Sending more than 50-60 mL of pleural fluid for cytology does not increase the yield of direct cytospin analysis,[31, 32] and volumes of approximately 150 mL are sufficient when both cytospin and cell block preparations are analyzed.[32]

Tumor markers, such as carcinoembryonic antigen, Leu-1, and mucin, are suggestive of malignant effusions (especially adenocarcinoma) when pleural fluid values are very high. However, because of low sensitivity, they are not helpful if the values are normal or only modestly increased.

Tuberculous pleuritis

Suspect tuberculous pleuritis in patients with a history of exposure or a positive PPD finding and in patients with lymphocytic exudative effusions, especially if less than 5% mesothelial cells are detected on differential cell counts.

Because most tuberculous pleural effusions probably result from a hypersensitivity reaction to the Mycobacterium rather than from microbial invasion of the pleura, acid-fast bacillus stains of pleural fluid are rarely diagnostic (< 10% of cases). Pleural fluid cultures grow M tuberculosis in less than 65% of cases.

In contrast, the combination of histology and culture of pleural tissue obtained by pleural biopsy increases the diagnostic yield for TB to 90%.

Adenosine deaminase (ADA) activity of greater than 43 U/mL in pleural fluid supports the diagnosis of tuberculous pleuritis. However, the test has a sensitivity of only 78%. Therefore, pleural ADA values of less than 43-50 U/mL do not exclude the diagnosis of TB pleuritis.[33]

Interferon-gamma concentrations of greater than 140 pg/mL in pleural fluid also support the diagnosis of tuberculous pleuritis. Unfortunately, this test is not routinely available.

Additional Laboratory Tests

Additional specialized tests are warranted when specific etiologies are suspected. Measure pleural fluid amylase levels if a pancreatic origin or ruptured esophagus is suspected or if a unilateral, left-sided pleural effusion remains undiagnosed after initial testing. Of note, increased pleural fluid amylase can also be seen with malignancy. An additional assay of amylase isoenzymes can help distinguish a pancreatic source (diagnosed by elevated pleural fluid pancreatic isoenzymes) from other etiologies.

Measure triglyceride and cholesterol levels in milky pleural fluids when chylothorax or pseudochylothorax is suspected.

Consider immunologic studies, including pleural fluid antinuclear antibody and rheumatoid factor, when collagen-vascular diseases are suspected.

CT Scanning and Ultrasonography

A study involving 41 consecutive patients with hepatic hydrothorax indicated that hepatic hydrothorax virtually always presents with ascites that can be revealed by ultrasonography or computed tomography (CT) scanning.[34]

Chest CT scanning with contrast should be performed in all patients with an undiagnosed pleural effusion, if it has not previously been performed, to detect thickened pleura or signs of invasion of underlying or adjacent structures. The two diagnostic imperatives in this situation are pulmonary embolism and tuberculous pleuritis. In both cases, the pleural effusion is a harbinger of potential future morbidity. In contrast, a short delay in diagnosing metastatic malignancy to the pleural space has less impact on future clinical outcomes. CT angiography should be ordered if pulmonary embolism is strongly suggested.

Chest Radiography

Effusions of more than 175 mL are usually apparent as blunting of the costophrenic angle on upright posteroanterior chest radiographs. On supine chest radiographs, which are commonly used in the intensive care setting, moderate to large pleural effusions may appear as a homogenous increase in density spread over the lower lung fields. Apparent elevation of the hemidiaphragm, lateral displacement of the dome of the diaphragm, or increased distance between the apparent left hemidiaphragm and the gastric air bubble suggests subpulmonic effusions. (See the images below.)


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Posteroanterior, upright chest radiograph shows isolated, left-sided pleural effusion and loss of left, lateral costophrenic angle. Image courtesy of ....


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Anteroposterior, upright chest radiograph shows bilateral pleural effusions and loss of bilateral costophrenic angles (meniscus sign). Image courtesy ....


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Chest radiograph, lateral view, shows loss of bilateral, posterior costophrenic angles. Image courtesy of Allen R. Thomas, MD.

Lateral decubitus films more reliably detect smaller pleural effusions. Layering of an effusion on lateral decubitus films defines a freely flowing effusion and, if the layering fluid is 1 cm thick, indicates an effusion of greater than 200 mL that is amenable to thoracentesis. Failure of an effusion to layer on lateral decubitus films indicates the presence of loculated pleural fluid or some other etiology causing the increased pleural density. (See the image below.)


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Left lateral decubitus film showing freely layering pleural effusion.

Diagnostic Thoracentesis

A diagnostic thoracentesis should be performed if the etiology of the effusion is unclear or if the presumed cause of the effusion does not respond to therapy as expected. Pleural effusions do not require thoracentesis if they are too small to safely aspirate or, in clinically stable patients, if their presence can be explained by underlying congestive heart failure (especially bilateral effusions) or by recent thoracic or abdominal surgery.

Depending on the clinician’s experience, a pulmonologist or interventional radiologist can be consulted for assistance with high-risk diagnostic thoracentesis.

Contraindications

Relative contraindications to diagnostic thoracentesis include a small volume of fluid (< 1 cm thickness on a lateral decubitus film), bleeding diathesis or systemic anticoagulation, mechanical ventilation, and cutaneous disease over the proposed puncture site. Reversal of coagulopathy or thrombocytopenia may not be necessary as long as the procedure is performed under ultrasound guidance by an experienced operator.[35] Mechanical ventilation with positive end-expiratory pressure does not increase the risk of pneumothorax after thoracentesis, but it increases the likelihood of severe complications (tension pneumothorax or persistent bronchopleural fistula) if the lung is punctured. An uncooperative patient is an absolute contraindication for this procedure.

Complications

Complications of diagnostic thoracentesis include pain at the puncture site, cutaneous or internal bleeding from laceration of an intercostal artery or spleen/liver puncture, pneumothorax, empyema, reexpansion pulmonary edema, malignant seeding of the thoracentesis tract, and adverse reactions to anesthetics used in the procedure. Pneumothorax complicates approximately 6% of thoracenteses but requires treatment with a chest tube drainage of the pleural space in less than 2% of cases.[29] The use of needles larger than 20 gauge increases the risk of a pneumothorax complicating the thoracentesis. In addition, significant chronic obstructive or fibrotic lung disease increases the risk of a symptomatic pneumothorax complicating the thoracentesis.

Procedure

In patients with large, freely flowing effusions and no relative contraindications to thoracentesis, diagnostic thoracentesis can usually be performed safely, with the puncture site initially chosen based on the chest radiograph and located 1-2 rib interspaces below the level of dullness to percussion on physical examination. In other situations, ultrasonography or chest CT scanning should be used to guide thoracentesis.

Ultrasonography guidance at bedside significantly increases the likelihood of obtaining pleural fluid and reduces the risk of pneumothorax.[29, 36]

After the site is disinfected with chlorhexidine (preferred) or povidone/iodine (no longer recommended) solution and sterile drapes are placed, anesthetize the skin, periosteum, and parietal pleura with 1% lidocaine through a 25-gauge needle. If pleural fluid is not obtained with the shorter 25-gauge needle, continue anesthetizing with a 1.5-inch, 22-gauge needle. For patients with larger amounts of subcutaneous tissue, a 3.5-inch, 22-gauge spinal needle with inner stylet removed can be used to anesthetize the deeper tissues and to aspirate pleural fluid.

Confirm the correct location for thoracentesis by aspirating pleural fluid through the 25- or 22-gauge needle before introducing larger-bore thoracentesis needles or catheters. If pleural fluid is not easily aspirated, stop the procedure and use ultrasonography or chest CT scanning to guide thoracentesis.

When possible, patients should sit upright for thoracentesis. Patients should not lean forward, because this causes pleural fluid to move to the anterior costophrenic space and increases the risk of puncture of the liver or spleen. For debilitated and ventilated patients who cannot sit upright, obtain pleural fluid by puncturing over the eighth rib at the midaxillar to posterior axillary line. To avoid puncturing liver or spleen, the needle should not be inserted below the ninth rib. In such patients, imaging may be required to guide thoracentesis.

Supplemental oxygen is often administered during thoracentesis to offset hypoxemia produced by changes in ventilation-perfusion relationships as fluid is removed and to facilitate reabsorption of pleural air if pneumothorax complicates the procedure.

The frequency of complications from thoracentesis may be lower when a more experienced clinician performs the procedure and when ultrasonographic guidance is used.[37] Consequently, a skilled and experienced clinician should perform thoracentesis in patients who have a higher risk of complications or relative contraindications for thoracentesis and in patients who cannot sit upright.

Postprocedure expiratory chest radiographs to exclude pneumothorax are not needed in asymptomatic patients after uncomplicated procedures (single needle pass without aspiration of air).[38] However, postprocedure inspiratory chest radiographs are recommended to establish a new baseline for patients likely to have recurrent symptomatic effusions.

Idiopathic Exudative Effusions

Despite evaluations with repeated diagnostic thoracenteses, approximately 20% of exudative effusions remain undiagnosed. Clues to the diagnosis that may have been overlooked include (1) occupational exposure to asbestos 10-20 years earlier, which may suggest benign asbestos effusion; (2) medication exposure to nitrofurantoin, amiodarone, or medications associated with a drug-induced lupus syndrome; and (3) hepatic hydrothorax unrecognized in a patient with minimal or undetectable ascites.

Among patients with undiagnosed pleural effusions after the primary evaluation, those who meet all 6 of the following clinical parameters are predicted to have a benign course, and no further evaluation is necessary:

For other patients with undiagnosed exudative effusions, approximately 20% have a specific etiology determined, including malignancy. For such patients, weigh the benefits and risks of pursuing a diagnostic strategy that will involve using progressively more invasive procedures, given the low likelihood of finding a curable etiology. Note the following:

Note that in most medical centers, surgical exploration using thoracoscopy or thoracotomy entails the risks of general anesthesia and is probably warranted only in patients who are symptomatic and anxious for a (potentially incurable) diagnosis.

Biopsy

Pleural biopsy should be considered, only if TB or malignancy is suggested. Medical thoracoscopy with the patient under conscious sedation and local anesthesia has emerged as a diagnostic tool to directly visualize and take a biopsy specimen from the parietal pleura in cases of undiagnosed exudative effusions. As an alternative, closed-needle pleural biopsy is a blind technique that can be performed at the patient's bedside.

Medical thoracoscopy has a higher diagnostic yield for malignancy. Closed-needle pleural biopsy findings aid in diagnosis of only 7-12% of malignant effusions when cytology findings alone are negative. However, the yield of closed-needle pleural biopsy (histology plus culture) is as high as thoracoscopy for tuberculous pleuritis and is a useful alternative procedure for this diagnosis when available.

A randomized comparison of medical thoracoscopy with CT scan–guided cutting-needle pleural biopsy (CT-CNPB), found no statistically significant difference in diagnostic sensitivity between these two approaches. The study included 124 patients with exudative pleural effusion who could not be diagnosed by cytologic analysis. These researchers recommended using CT-ANPB as the primary diagnostic procedure in patients with pleural thickening or lesions observed on CT scans, and using medical thoracoscopy in patients whose CT scans demonstrate only pleural fluid, as well as in those who may have benign pleural pathologies other than TB.[40]

Approach Considerations

Transudative effusions are managed by treating the underlying medical disorder. However, regardless of whether transudative or exudative, large, refractory pleural effusions causing severe respiratory symptoms can be drained to provide symptomatic relief.

The management of exudative effusions depends on the underlying etiology of the effusion. Pneumonia, malignancy, and TB cause most exudative pleural effusions, with the remainder typically deemed idiopathic. Complicated parapneumonic effusions and empyemas should be drained to prevent development of fibrosing pleuritis. Malignant effusions are usually drained to palliate symptoms and may require pleurodesis to prevent recurrence.

Medications cause only a small proportion of all pleural effusions and are associated with exudative pleural effusions. However, early recognition of this iatrogenic cause of pleural effusion avoids unnecessary additional diagnostic procedures and leads to definitive therapy, which is discontinuation of the medication. Implicated drugs include medications that cause drug-induced lupus syndrome (eg, procainamide, hydralazine, quinidine), nitrofurantoin, dantrolene, methysergide, procarbazine, and methotrexate.

A meta-analysis and systemic review of 19 observational studies determined that pleural effusion drainage in patients on mechanical ventilation is safe and appears to improve oxygenation.[41] No data supported or refuted claims of beneficial effects on clinical outcomes, such as duration of ventilation or length of stay.

Parapneumonic effusions

Of the common causes for exudative pleural effusions, parapneumonic effusions have the highest diagnostic priority. Even in the face of antibiotic therapy, infected pleural effusions can rapidly coagulate and organize to form fibrous peels that might require surgical decortication. Therefore, quickly assess pleural fluid characteristics predictive of a complicated course to identify parapneumonic effusions that require urgent tube drainage. These are observed more commonly in indolent anaerobic pneumonias than in typical community-acquired pneumonia.

Indications for urgent drainage of parapneumonic effusions include (1) frankly purulent fluid, (2) a pleural fluid pH of less than 7.0-7.1, (3) loculated effusions, and (4) bacteria on Gram stain or culture.[42]

Patients with parapneumonic effusions who do not meet the criteria for immediate tube drainage should improve clinically within one week with appropriate antibiotic treatment.

Reassess patients with parapneumonic effusions who do not improve or who deteriorate clinically, using chest CT scanning and/or ultrasonography to evaluate the pleural space, and direct further drainage attempts, if needed.

Malignant pleural effusions

Malignant pleural effusions usually signify incurable disease with considerable morbidity and a dismal mean survival of less than one year. For some patients, drainage of large, malignant effusions relieves dyspnea caused by distortion of the diaphragm and chest wall produced by the effusion. Such effusions tend to recur in more than 90% of patients, necessitating repeated thoracentesis, pleurodesis, or placement of indwelling tunneled catheters.[39] Drainage systems using tunneled catheters allow patients to drain their effusions as needed at home.

For patients with lung entrapment from malignant effusions indwelling tunneled catheter drainage systems are the preferred treatment and provide good palliation of symptoms.[43] In patients without lung entrapment, pleurodesis (also known as pleural sclerosis) is another option to prevent recurrence of symptomatic effusions. In a 2012 non-randomized study, 34 patients choosing placement of indwelling catheters for malignant effusions had significantly fewer days spent in the hospital, less recurrence of effusion, and more rapid improvement in quality of life, compared with 31 patients choosing talc pleurodesis.[44]

Tuberculous pleuritis

Tuberculous pleuritis is typically self-limited. However, because 65% of patients with primary tuberculous pleuritis reactivate their disease within five years, empiric anti-TB treatment is usually begun pending culture results when sufficient clinical suspicion is present, such as an unexplained exudative or lymphocytic effusion in a patient with a positive PPD finding.

Chylous effusions

Chylous effusions are usually managed by dietary and surgical modalities. However, studies suggest that somatostatin analogues also may help in reducing the efflux of chyle into the pleural space.

Surgical treatment

Surgical intervention is most often required for parapneumonic effusions that cannot be drained adequately by needle or small-bore catheters. Surgery may also be required to establish a diagnosis and for pleural sclerosis therapy of exudative effusions.

Pleurodesis by insufflating talc directly onto the pleural surface using video-assisted thoracoscopy is an alternative to using talc slurries.

Decortication is usually required for trapped lungs to remove the thick, inelastic pleural peel that restricts ventilation and produces progressive or refractory dyspnea. In patients with chronic, organizing parapneumonic pleural effusions, technically demanding operations may be required to drain loculated pleural fluid and to obliterate the pleural space.

Surgically implanted pleuroperitoneal shunts are another treatment option for recurrent, symptomatic effusions, most often in the setting of malignancy, but they are also used for management of chylous effusions. However, the shunts are prone to malfunction over time, can require surgical revision and are poorly tolerated by patients.

In unusual cases, surgery might be required to close diaphragmatic defects (thereby preventing recurrent accumulation of pleural effusions in patients with ascites) and to ligate the thoracic duct to prevent reaccumulation of chylous effusions.

Consultations

Drainage of complicated effusions usually requires consultation with a pulmonologist, interventional radiologist, or thoracic surgeon, depending on the location of the effusion and the clinical situation.

Therapeutic Thoracentesis

Therapeutic thoracentesis is used to remove larger amounts of pleural fluid to alleviate dyspnea and to prevent ongoing inflammation and fibrosis in parapneumonic effusions. In addition to the precautions listed previously for diagnostic thoracentesis, note three additional considerations when performing therapeutic thoracentesis.

First, to avoid producing a pneumothorax during the removal of large quantities of fluid, remove fluid during therapeutic thoracentesis with a catheter, rather than with a needle, introduced into the pleural space. Various specially designed thoracentesis trays are available commercially for introducing small catheters into the pleural space. Alternatively, newer systems using spring-loaded, blunt-tip needles that avoid lung puncture are also available.

Second, monitor oxygenation closely during and after thoracentesis because arterial oxygen tension might worsen after pleural fluid drainage due to shifts in perfusion and ventilation in the re-expanding lung. Consider use of empiric supplemental oxygen during the procedure.

Third, remove only moderate amounts of pleural fluid to avoid reexpansion pulmonary edema and to avoid causing a pneumothorax. Removal of 400-500 mL of pleural fluid is often sufficient to alleviate shortness of breath. The recommended limit is 1000-1500 mL in a single thoracentesis procedure.

Larger amounts of pleural fluid can be removed if pleural pressure is monitored by pleural manometry and is maintained above -20 cm water.[45] However, this monitoring is rarely used by most proceduralists.

The onset of chest pressure or pain during the removal of fluid indicates a lung that is not freely expanding, and the procedure should be stopped immediately to avoid reexpansion pulmonary edema.[45] In contrast, cough frequently occurs during removal of fluid, and this is not an indication to stop the procedure, unless the cough is causing the patient discomfort.

Mediastinal position and lung entrapment

The position of the mediastinum on the chest radiograph may predict whether a patient is likely to benefit from the procedure. A mediastinal shift away from the pleural effusion indicates a positive pleural pressure and compression of the underlying lung that can be relieved by thoracentesis. (See the images below.)


View Image

Massive right pleural effusion with shift of mediastinum towards left


View Image

Right pleural effusion after partial drainage showing decrease in shift of mediastinum towards left

In contrast, a mediastinal shift towards the side of the effusion indicates an endobronchial obstruction that prevents re-expansion of the lung when the pleural fluid is removed or lung trapped by encasement by chronic pleural thickening. Lung entrapment with malignant effusions is most common with mesothelioma and primary lung cancer.

Attempts at therapeutic thoracentesis usually do not improve dyspnea in patients with lung entrapment, due to the inability of the lung to re-expand. In fact, attempts at drainage of fluid in these patients usually results in a hydropneumothorax. (See the image below.)


View Image

Lung entrapment with right hydropneumothorax and pleural drain in place

Tube Thoracostomy

Although small, freely flowing parapneumonic effusions can be drained by therapeutic thoracentesis, complicated parapneumonic effusions or empyemas require drainage by tube thoracostomy.

Traditionally, large-bore chest tubes (20-36F) have been used to drain the thick pleural fluid and to break up loculations in empyemas. However, such tubes are not always well tolerated by patients and are difficult to direct correctly into the pleural space. On the other hand, small-bore tubes (7-14F) inserted at the bedside or under radiographic guidance have been demonstrated to provide adequate drainage.[46] These tubes cause less discomfort and are more likely to be placed successfully within a pocket of pleural fluid. Using 20-cm water suction and flushing the tube with normal saline every 6-8 hours may prevent occlusion of small-bore catheters.

Insertion of additional pleural catheters, usually under radiographic guidance, or instilling fibrinolytics (eg, streptokinase, urokinase, or alteplase) through the pleural catheter can help to drain multiloculated pleural effusions.

A randomized trial of 210 participants with pleural infection documented that instillation of alteplase and DNase produced significantly greater drainage of pleural effusion, less need for surgical referral or surgical intervention, shorter hospital stays, and a decrease in pleural fluid inflammatory markers compared with placebo.[47]

Pleurodesis

Pleurodesis (also known as pleural sclerosis) involves instilling an irritant into the pleural space to cause inflammatory changes that result in bridging fibrosis between the visceral and parietal pleural surfaces, effectively obliterating the potential pleural space. Pleurodesis is most often used for recurrent malignant effusions, such as in patients with lung cancer or metastatic breast or ovarian cancer. Given the limited life expectancy of these patients, the goal of therapy is to palliate symptoms while minimizing patient discomfort, hospital length of stay, and overall costs.[48, 49]

Patients with poor performance status (Karnofsky score < 70) and a life expectancy of less than 3 months should not be treated with pleurodesis, and can be treated with repeated outpatient thoracentesis as needed to palliate symptoms.[50] Unfortunately, pleural effusions can reaccumulate rapidly, and the risk of complications increases with repeated drainage.

Patients with lung entrapment from malignant effusions are not good candidates for repeated thoracentesis, because they may not relieve dyspnea in such patients, nor for pleurodesis, as the visceral and parietal pleural surfaces cannot stay apposed to allow the bridging fibrosis. The best treatment for effusions in such patients may be the insertion of an indwelling tunneled catheter, which allows patients to remove pleural fluid as needed at home.[51]

A 2006 systematic review found that in pleurodesis, rotating the patient through different positions did not appear necessary to ensure distribution of soluble sclerosing agents throughout the pleural space. In addition, neither protracted drainage after instillation of sclerotics nor the use of larger-bore chest tubes increased the effectiveness of pleurodesis.[52]

Pleurodesis is likely to be successful only if the pleural space is drained completely before pleurodesis and if the lung is fully re-expanded to appose the visceral and parietal pleura after sclerosis. Animal studies suggest that systemic corticosteroids can reduce inflammation during sclerosis and can cause pleurodesis failures.

Sclerosing agents

Various agents, including talc, doxycycline, bleomycin sulfate (Blenoxane), zinc sulfate, and quinacrine hydrochloride, can be employed to sclerose the pleural space and effectively prevent recurrence of the malignant pleural effusion.

Talc is the most effective sclerosing commercially available agent and can be administered as slurry through chest tubes or pleural catheters. Although a systematic review suggested that direct insufflation of talc via thoracoscopy was more effective than talc slurry, both were equally effective in a 2005 prospective trial of malignant effusions.[53] Importantly, talc particles tend to occlude the small drainage holes in small pleural catheters. Therefore, pleural catheters should be at least 10-12F if intended for talc pleurodesis.

Doxycycline and bleomycin are also effective in most patients and can be administered more easily through small-bore catheters, although they are somewhat less effective and substantially more expensive than talc.

All sclerosing agents can produce fever, chest pain, and nausea. Talc rarely causes more serious adverse effects, such as empyema and acute lung injury. The latter appears to be related to the particle size and the amount of talc injected for pleurodesis.

Injection of 50 mL of 1% lidocaine hydrochloride prior to instillation of the sclerosing agent has been advocated help to alleviate pain[39, 54] but is not universally used. Additional analgesia might be required in some cases. Clamp chest tubes for approximately two hours after instillation of the sclerosing agent.

Indwelling Tunneled Pleural Catheters

Tunneled pleural catheters (TPC) were approved by the FDA in 1997 and are a valid alternative for pleurodesis in malignant and some benign effusions.[55] TPC can be inserted as an outpatient procedure and can be intermittently drained at home, minimizing the amount of time spent in the hospital for patients with short prognoses. In contrast to pleurodesis, they can be used for patients with effusions and trapped lungs.[51]

Both talc pleurodesis and TPC improve dyspnea when used for malignant effusions, but talc pleurodesis requires significantly more days spent in the hospital and more pleural procedures.[44, 56] Consequently, TPC is the most cost-effective approach for patients with malignant effusions with expected survival of greater than 3 months.[57] The combined use of thoracoscopic talc poudrage and simultaneous placement of TPC for rapid pleurodesis has been reported to have a 92% success rate and 1.79 days median hospitalization stay following the procedure.[58]

TPC has also been shown to palliate refractory symptoms from recurrent effusions due to class III or IV heart failure, with effectiveness similar to thoracoscopic talc pleurodesis and with significantly fewer hospital days, operative morbidity, and readmissions.[59]

Complications reported from use of TPC include malfunction of the catheter (9.1%), clogging (3.7%), and pain (5.6%).[55] Less common but serious complications associated with TPC are infection (2.8%) or, when used for malignant effusions, tumor invasion of the catheter track (less than 1%). Notably, systemic chemotherapy does not increase the risk of pleural infection and can be used in these patients.[50]

Diet

Restriction of fat intake may help in the treatment of chylous effusions, although management remains controversial. Ongoing drainage of these effusions can rapidly deplete patients of fat and protein stores and lymphocytes. Limiting oral fat intake may slow the accumulation of chylous effusions in some patients. Hyperalimentation or total parenteral nutrition can preserve nutritional stores and limit accumulation of the chylous effusion but probably should be restricted to patients in whom definitive therapy for the underlying cause of the chylous effusion is possible.

Monitoring Pleural Drainage

Record the amount and quality of fluid drained and monitor for an air leak (bubbling through the water seal) at each shift. Large air leaks (steady streams of air throughout the respiratory cycle) may be indications of loose connectors or of a drainage port on the catheter that has migrated out to the skin. Consequently, dressings should be taken down and the position of the catheter inspected at the puncture site. Alternatively, they may indicate large bronchopleural fistulae.

Briefly clamping the catheter at the skin helps to determine whether the air leak is originating from within the pleural cavity (in which case, it stops when the tube is clamped) or from outside the chest (in which case, the leak persists).

Repeat the chest radiographs when drainage decreases to less than 100 mL/day to evaluate whether the effusion has been fully drained. If a large effusion persists radiographically, reevaluate the position of the chest catheter using chest CT scanning to ensure that the drainage ports are still positioned within the pleural collection. If the catheter is positioned appropriately, consider injecting thrombolytics through the chest tube to break up clots that may be obstructing drainage. Alternatively, chest CT scanning may reveal lung entrapment/trapped lung, which is unlikely to respond to further drainage.

Medication Summary

Pharmacologic management of pleural effusion depends on the condition’s etiology. For example, medical management includes nitrates and diuretics for congestive heart failure and pulmonary edema, antibiotics for parapneumonic effusion and empyema, and anticoagulation for pulmonary embolism.

In patients with parapneumonic effusions, empyemas, and effusions associated with esophageal perforation and intra-abdominal abscesses, antibiotics should be administered early when these conditions are suspected.

Antibiotic selection should be based on the suspected causative microorganisms and the overall clinical picture. Considerations include the patient's age, comorbidities, duration of the illness, setting (community vs nursing home), and local organism sensitivities. Various effective single agents and combination antimicrobial therapies exist. Antimicrobial coverage should generally include anaerobic organisms. Options may include clindamycin, extended-spectrum penicillins, and imipenem. Depending on the patient's clinical condition, infectious disease consultation may be appropriate.

Particular attention must be given to potential drug interactions, adverse effects, and pre-existing conditions.

Ampicillin and sulbactam (Unasyn)

Clinical Context:  This combination of ampicillin and a beta-lactamase inhibitor interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. It is an alternative to amoxicillin when the patient is unable to take medication orally.

Ampicillin/sulbactam covers skin, enteric flora, and anaerobes. It is not ideal for nosocomial pathogens.

Imipenem and cilastatin (Primaxin)

Clinical Context:  This drug combination is used for the treatment of multiple organism infections for which other agents do not have wide-spectrum coverage or are contraindicated due to their potential toxicity.

Piperacillin and tazobactam sodium (Zosyn)

Clinical Context:  This consists of antipseudomonal penicillin plus a beta-lactamase inhibitor. It inhibits biosynthesis of the cell wall mucopeptide and is effective during the active multiplication stage.

Clindamycin (Cleocin)

Clinical Context:  Clindamycin is a lincosamide for the treatment of serious skin and soft-tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci). Clindamycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer ribonucleic acid (tRNA) from ribosomes, arresting RNA-dependent protein synthesis.

Piperacillin

Clinical Context:  Piperacillin inhibits biosynthesis of cell-wall mucopeptides and the active multiplication stage; it has antipseudomonal activity.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Nitroglycerin (Nitrostat, Nitro-Bid, Nitro-Dur, Nitrolingual)

Clinical Context:  Nitroglycerin is a first-line therapy for patients who are not hypotensive. It provides excellent and reliable preload reduction. Higher doses provide mild afterload reduction. Nitroglycerin has a rapid onset and offset (both within minutes), allowing rapid clinical effects and rapid discontinuation of effects in adverse clinical situations.

Class Summary

These agents are used for their ability to decrease preload.

Furosemide (Lasix)

Clinical Context:  Furosemide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and distal renal tubule.

Class Summary

Loop diuretics decrease plasma volume and edema by causing diuresis.

Heparin

Clinical Context:  Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. Heparin prevents reaccumulation of a clot after spontaneous fibrinolysis. When unfractionated heparin is used, the activated partial thromboplastin time (aPTT) should not be checked until 6 hours after the initial heparin bolus because an extremely high or low value during this time should not provoke any action.

Class Summary

Anticoagulants prevent recurrent or ongoing thromboembolic disorders by inhibiting thrombogenesis.

Author

Jeffrey Rubins, MD, Professor of Medicine, University of Minnesota Medical School; Director, Palliative Medicine, Hennepin County Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Ryland P Byrd Jr, MD, Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Disclosure: Nothing to disclose.

Additional Contributors

Harold L Manning, MD Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School

Harold L Manning, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Stephen P Peters, MD, PhD, FACP, FAAAAI, FCCP, FCPP Professor of Genomics and Personalized Medicine Research, Internal Medicine, and Pediatrics, Associate Director, Center for Genomics and Personalized Medicine Research, Director of Research, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine

Stephen P Peters, MD, PhD, FACP, FAAAAI, FCCP, FCPP is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society, and Sigma Xi

Disclosure: See below for list of all activities None None

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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Large, malignant, right-sided pleural effusion.

Chest radiograph showing left-sided pleural effusion.

Posteroanterior, upright chest radiograph shows isolated, left-sided pleural effusion and loss of left, lateral costophrenic angle. Image courtesy of Allen R. Thomas, MD.

Anteroposterior, upright chest radiograph shows bilateral pleural effusions and loss of bilateral costophrenic angles (meniscus sign). Image courtesy of Allen R. Thomas, MD.

Chest radiograph, lateral view, shows loss of bilateral, posterior costophrenic angles. Image courtesy of Allen R. Thomas, MD.

Left lateral decubitus film showing freely layering pleural effusion.

Massive right pleural effusion with shift of mediastinum towards left

Right pleural effusion after partial drainage showing decrease in shift of mediastinum towards left

Lung entrapment with right hydropneumothorax and pleural drain in place

Large, malignant, right-sided pleural effusion.

Chest radiograph showing left-sided pleural effusion.

Left lateral decubitus film showing freely layering pleural effusion.

Lung entrapment with right hydropneumothorax and pleural drain in place

Massive right pleural effusion with shift of mediastinum towards left

Right pleural effusion after partial drainage showing decrease in shift of mediastinum towards left

Anteroposterior, upright chest radiograph shows bilateral pleural effusions and loss of bilateral costophrenic angles (meniscus sign). Image courtesy of Allen R. Thomas, MD.

Chest radiograph, lateral view, shows loss of bilateral, posterior costophrenic angles. Image courtesy of Allen R. Thomas, MD.

Posteroanterior, upright chest radiograph shows isolated, left-sided pleural effusion and loss of left, lateral costophrenic angle. Image courtesy of Allen R. Thomas, MD.