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Pleural Effusion

by Richard W. Light, MD

Pleural effusions are accumulations of fluid within the pleural space. They have multiple causes and usually are classified as transudates or exudates. Detection is by physical examination and chest x-ray; thoracentesis and pleural fluid analysis are often required to determine cause. Asymptomatic transudates require no treatment. Symptomatic transudates and almost all exudates require thoracentesis, chest tube drainage, pleurodesis, pleurectomy, or a combination.

Normally, 10 to 20 mL of pleural fluid, similar in composition to plasma but lower in protein (< 1.5 g/dL), is spread thinly over visceral and parietal pleurae, facilitating movement between the lungs and chest wall. The fluid enters the pleural space from systemic capillaries in the parietal pleurae and exits via parietal pleural stomas and lymphatics. Pleural fluid accumulates when too much fluid enters or too little exits the pleural space.

Etiology

Pleural effusions are usually categorized as transudates or exudates based on laboratory characteristics of the fluid (see Table: Criteria for Identifying Exudative Pleural Effusions). Whether unilateral or bilateral, a transudate can usually be treated without extensive evaluation, whereas the cause of an exudate requires investigation. There are numerous causes (see Table: Causes of Pleural Effusion).

Transudative effusions are caused by some combination of increased hydrostatic pressure and decreased plasma oncotic pressure. Heart failure is the most common cause, followed by cirrhosis with ascites and by hypoalbuminemia, usually due to the nephrotic syndrome.

Exudative effusions are caused by local processes leading to increased capillary permeability resulting in exudation of fluid, protein, cells, and other serum constituents. Causes are numerous; the most common are pneumonia, cancer, pulmonary embolism, viral infection, and TB. Yellow nail syndrome is a rare disorder causing chronic exudative pleural effusions, lymphedema, and dystrophic yellow nails—all thought to be the result of impaired lymphatic drainage.

Criteria for Identifying Exudative Pleural Effusions

Test

Exudate

Sensitivity (%)

Specificity (%)

Light’s criteria ( 1 of the following 3):

98

77

  • Fluid LDH*

2/3 ULN for serum LDH

66

100

  • Pleural fluid:serum total protein ratio

0.5

91

89

  • Pleural fluid:serum LDH ratio

0.6

93

82

Fluid total protein

3 g/dL

90

90

Fluid cholesterol

60 mg/dL

43 mg/dL

54

75

92

80

Pleural fluid:serum cholesterol ratio

0.3

89

71

Serum protein – pleural fluid protein

3.1 g/dL

87

92

*Correction for increase in LDH due to RBC lysis = measured LDH 0.0012 × RBC count/μL.

Preferred test for patients who are prescribed diuretics after development of effusion if Light’s exudative criteria are met, but none of the biochemical measurements are > 15% above the cutoff levels for Light’s criteria.

ULN = upper limit of normal.

Data modified from Light RW: Pleural effusion. New England Journal of Medicine 346:1971–1977, 2002.

Chylous effusion (chylothorax) is a milky white effusion high in triglycerides caused by traumatic or neoplastic (most often lymphomatous) damage to the thoracic duct. Chylous effusion also occurs with the superior vena cava syndrome.

Chyliform (cholesterol or pseudochylous) effusions resemble chylous effusions but are low in triglycerides and high in cholesterol. Chyliform effusions are thought to be due to release of cholesterol from lysed RBCs and neutrophils in long-standing effusions when absorption is blocked by the thickened pleura.

Hemothorax is bloody fluid (pleural fluid Hct > 50% peripheral Hct) in the pleural space due to trauma or, rarely, as a result of coagulopathy or after rupture of a major blood vessel, such as the aorta or pulmonary artery.

Empyema is pus in the pleural space. It can occur as a complication of pneumonia, thoracotomy, abscesses (lung, hepatic, or subdiaphragmatic), or penetrating trauma with secondary infection. Empyema necessitatis is soft-tissue extension of empyema leading to chest wall infection and external drainage.

Trapped lung is a lung encased by a fibrous peel caused by empyema or tumor. Because the lung cannot expand, the pleural pressure becomes more negative than normal, increasing transudation of fluid from parietal pleural capillaries. The fluid characteristically is borderline between a transudate and an exudate; ie, the biochemical values are within 15% of the cutoff levels for Light’s criteria (see Table: Criteria for Identifying Exudative Pleural Effusions).

Iatrogenic effusions can be caused by migration or misplacement of a feeding tube into the trachea or perforation of the superior vena cava by a central venous catheter, leading to infusion of tube feedings or IV solution into the pleural space.

Causes of Pleural Effusion

Cause

Comments

Transudate

Heart failure

Bilateral effusions in 81%; right-sided in 12%; left-sided in 7%

With left ventricular failure, there is increased interstitial fluid, which crosses the visceral pleura and enters the pleural space

Cirrhosis with ascites (hepatic hydrothorax)

Right-sided effusions in 70%; left-sided in 15%; bilateral in 15%

Ascitic fluid migration to the pleural space through diaphragmatic defects

Effusion present in about 5% of patients with clinically apparent ascites

Hypoalbuminemia

Uncommon

Bilateral effusions in > 90%

Decreased intravascular oncotic pressure causing transudation into the pleural space

Associated with edema or anasarca elsewhere

Nephrotic syndrome

Usually bilateral effusions; commonly subpulmonic

Decreased intravascular oncotic pressure plus hypervolemia causing transudation into the pleural space

Hydronephrosis

Retroperitoneal urine dissection into the pleural space, causing urinothorax

Constrictive pericarditis

Increases IV hydrostatic pressure

In some patients, accompanied by massive anasarca and ascites due to a mechanism similar to that for hepatic hydrothorax

Atelectasis

Increases negative intrapleural pressure

Peritoneal dialysis

Mechanism similar to that for hepatic hydrothorax

Pleural fluid with characteristics similar to dialysate

Trapped lung

Encasement with fibrous peel increasing negative intrapleural pressure

May be exudative or borderline effusion

Systemic capillary leak syndrome

Rare

Accompanied by anasarca and pericardial effusion

Myxedema

Effusion present in about 5%

Usually transudate if pericardial effusion is also present; either transudate or exudate if pleural effusion is isolated

Exudate

Pneumonia (parapneumonic effusion)

May be uncomplicated or loculated and/or purulent (empyema)

Thoracentesis necessary to differentiate

Cancer

Most commonly lung cancer, breast cancer, or lymphoma but possible with any tumor metastatic to pleurae

Typically causing dull, aching chest pain

Pulmonary embolism

Effusion present in about 30%:

Almost always exudative; bloody in < 50%

Pulmonary embolism suspected when dyspnea is disproportionate to size of effusion

Viral infection

Effusion usually small with or without parenchymal infiltrate

Predominantly systemic symptoms rather than pulmonary symptoms

Coronary artery bypass surgery

Effusions left-sided or larger on the left in 73%; bilateral and equal in 20%; right-sided or larger on the right in 7%

> 25% of the hemithorax filled with fluid 30 days postoperatively in 10% of patients

Bloody effusions related to postoperative bleeding likely to resolve

Nonbloody effusions likely to recur; etiology unknown but probably with an immunologic basis

TB

Effusion usually unilateral and ipsilateral to parenchymal infiltrates if present

Effusion due to hypersensitivity reaction to TB protein

Pleural fluid TB cultures positive in < 20%

Sarcoidosis

Effusion in 1–2%

Extensive parenchymal sarcoid and often extrathoracic sarcoid

Pleural fluid predominantly lymphocytic

Uremia

Effusion in about 3%

In > 50%, symptoms secondary to effusion: Most commonly fever (50%), chest pain (30%), cough (35%), and dyspnea (20%)

Diagnosis of exclusion

Infradiaphragmatic abscess

Causes sympathetic subpulmonic effusion

Neutrophils predominant in pleural fluid

pH and glucose normal

HIV infection

Many possible etiologic factors: Pneumonias (parapneumonic), including Pneumocystis jirovecii pneumonia, other opportunistic infections, TB, and pulmonary Kaposi sarcoma

RA

Effusion typically in elderly men with rheumatoid nodules and deforming arthritis

Must differentiate from parapneumonic effusion

SLE

Effusion possibly first manifestation of SLE

Common with drug-induced SLE

Diagnosis established by serologic tests of blood, not of pleural fluid

Drugs

Many drugs, most notably bromocriptine, dantrolene, nitrofurantoin, IL-2 (for treatment of renal cell cancer and melanoma), and methysergide

Ovarian hyperstimulation syndrome

Syndrome occurring as a complication of ovulation induction with human chorionic gonadotropin (hCG) and occasionally clomiphene

Effusion developing 7–14 days after hCG injection

Effusion right-sided in 52%; bilateral in 27%

Pancreatitis

Acute: Effusion present in about 50%: Bilateral in 77%; left-sided in 16%; right-sided in 8%

Effusion due to transdiaphragmatic transfer of the exudative inflammatory fluid and diaphragmatic inflammation

Chronic: Effusion due to sinus tract from pancreatic pseudocyst through diaphragm into pleural space

Predominantly chest symptoms rather than abdominal symptoms

Patients presenting with cachexia that resembles cancer

Superior vena cava syndrome

Effusion usually caused by blockage of intrathoracic venous and lymphatic flow by cancer or thrombosis in a central catheter

May be an exudate or a chylothorax

Esophageal rupture

Patients extremely sick

Medical emergency

Morbidity and mortality due to infection of the mediastinum and pleural space

Benign asbestos pleural effusion

Effusion occurring > 30 yr after initial exposure

Frequently asymptomatic

Tends to come and go

Must rule out mesothelioma

Benign ovarian tumor (Meigs syndrome)

Mechanism similar to that for hepatic hydrothorax

Surgery sometimes indicated for patients with ovarian mass, ascites, and pleural effusion

For diagnosis, disappearance of ascites and effusion postoperatively required

Yellow nail syndrome

Triad of pleural effusion, lymphedema, and yellow nails, sometimes appearing decades apart

Pleural fluid with relatively high protein but low LDH

Tendency for effusion to recur

No pleuritic chest pain

Effusions with no obvious cause are often due to occult pulmonary emboli, TB, or cancer. Etiology is unknown for about 15% of effusions even after extensive study; many of these effusions are thought to be due to viral infection.

Symptoms and Signs

Some pleural effusions are asymptomatic and are discovered incidentally during physical examination or on chest x-ray. Many cause dyspnea, pleuritic chest pain, or both. Pleuritic chest pain, a vague discomfort or sharp pain that worsens during inspiration, indicates inflammation of the parietal pleura. Pain is usually felt over the inflamed site, but referred pain is possible. The posterior and peripheral portions of the diaphragmatic pleura are supplied by the lower 6 intercostal nerves, and irritation there may cause pain in the lower chest wall or abdomen that may simulate intra-abdominal disease. Irritation of the central portion of the diaphragmatic pleura, innervated by the phrenic nerves, causes pain referred to the neck and shoulder.

Physical examination reveals absent tactile fremitus, dullness to percussion, and decreased breath sounds on the side of the effusion. These findings can also be caused by pleural thickening. With large-volume effusions, respiration is usually rapid and shallow. A pleural friction rub, although infrequent, is the classic physical sign. The friction rub varies from a few intermittent sounds that may simulate crackles to a fully developed harsh grating, creaking, or leathery sound synchronous with respiration, heard during inspiration and expiration. Friction sounds adjacent to the heart (pleuropericardial rub) may vary with the heartbeat and may be confused with the friction rub of pericarditis. Pericardial rub is best heard over the left border of the sternum in the 3rd and 4th intercostal spaces, is characteristically a to-and-fro sound synchronous with the heartbeat, and is not influenced significantly by respiration. Sensitivity and specificity of the physical examination for detecting effusion are probably low.

Diagnosis

  • Chest x-ray

  • Pleural fluid analysis

  • Sometimes CT angiography or other tests

Pleural effusion is suspected in patients with pleuritic pain, unexplained dyspnea, or suggestive signs. Diagnostic tests are indicated to document the presence of pleural fluid and to determine its cause (see Figure: Diagnosis of pleural effusion).

Presence of effusion

Chest x-ray is the first test done to confirm the presence of pleural fluid. The lateral upright chest x-ray should be examined when a pleural effusion is suspected. In an upright x-ray, 75 mL of fluid blunts the posterior costophrenic angle. Blunting of the lateral costophrenic angle usually requires about 175 mL but may take as much as 500 mL. Larger pleural effusions opacify portions of the hemithorax and may cause mediastinal shift; effusions > 4 L may cause complete opacification of the hemithorax and mediastinal shift to the contralateral side.

Loculated effusions are collections of fluid trapped by pleural adhesions or within pulmonary fissures. Lateral decubitus x-rays, chest CT, or ultrasonography should be done if it is unclear whether an x-ray density represents fluid or parenchymal infiltrates or whether suspected fluid is loculated or free-flowing; these tests are more sensitive than upright x-rays and can detect fluid volumes < 10 mL. Loculated effusions, particularly those in the horizontal or oblique fissure, can be confused with a solid pulmonary mass (pseudotumor). They may change shape and size with changes in the patient’s position and amount of pleural fluid.

CT is not routinely indicated but is valuable for evaluating the underlying lung parenchyma for infiltrates or masses when the lung is obscured by the effusion or when the detail on chest x-rays is insufficient for distinguishing loculated fluid from a solid mass.

Cause of effusion

Thoracentesis (see Thoracentesis) should be done in almost all patients who have pleural fluid that is 10 mm in thickness on CT, ultrasonography, or lateral decubitus x-ray and that is new or of uncertain etiology. In general, the only patients who do not require thoracentesis are those who have heart failure with symmetric pleural effusions and no chest pain or fever; in these patients, diuresis can be tried, and thoracentesis avoided unless effusions persist for 3 days.

Thoracentesis and subsequent pleural fluid analysis often are not necessary for pleural effusions that are chronic, have a known cause, and cause no symptoms.

Pearls & Pitfalls

  • Despite common practice, chest x-ray need not be repeated after thoracentesis unless patients develop symptoms suggesting pneumothorax (dyspnea or chest pain) or unless the clinician suspects that air may have entered the pleural space during the procedure.

Whenever possible, thoracentesis is done using ultrasonographic guidance, which increases the yield of fluid and decreases risk of complications such as pneumothorax or puncture of an intra-abdominal organ.

Pleural fluid analysis is done to diagnose the cause of pleural effusion. Analysis begins with visual inspection, which can

  • Distinguish bloody and chylous (or chyliform) from other effusions

  • Identify purulent effusions strongly suggestive of empyema

  • Identify viscous fluid, which is characteristic of some mesotheliomas

Fluid should always be sent for total protein, LDH, cell count and cell differential, Gram stain, and aerobic and anaerobic bacterial cultures. Other tests (glucose, cytology, TB fluid markers [ adenosine deaminase or interferon-γ], amylase, mycobacterial and fungal stains and cultures) are used in appropriate clinical settings.

Fluid chemistries help distinguish transudates from exudates; multiple criteria exist, but not one perfectly discriminates between the 2 types. When Light’s criteria are used (see Table: Criteria for Identifying Exudative Pleural Effusions), serum LDH and total protein levels should be measured as close as possible to the time of thoracentesis for comparison with those in pleural fluid. Light’s criteria correctly identify almost all exudates but misidentify about 20% of transudates as exudates. If transudative effusion is suspected (eg, due to heart failure or cirrhosis) and none of the biochemical measurements are > 15% above the cutoff levels for Light’s criteria, the difference between serum and the pleural fluid protein is measured. If the difference is > 3.1 g/dL, the patient probably has a transudative effusion.

If the diagnosis remains unclear after pleural fluid analysis, CT angiography is indicated to look for pulmonary emboli, pulmonary infiltrates, or mediastinal lesions. Findings of pulmonary emboli indicate the need for long-term anticoagulation; parenchymal infiltrates, the need for bronchoscopy; and mediastinal lesions, the need for transthoracic needle aspiration or mediastinoscopy. However, CT angiography requires patients to hold their breath for 24 sec, and not all patients can comply. If CT angiography is unrevealing, observation is the best course unless the patient has a history of cancer, weight loss, persistent fever, or other findings suggestive of cancer or TB, in which case thoracoscopy may be indicated. Needle biopsy of the pleura can be done when thoracoscopy is unavailable. When tuberculous pleuritis is suspected, the level of adenosine deaminase in the pleural fluid is measured. A level > 40 U/L has a 95% sensitivity and specificity for the diagnosis of tuberculous pleuritis.

Diagnosis of pleural effusion

*Based on presence of fever, weight loss, history of cancer, or other suggestive symptoms.

Treatment

  • Treatment of symptoms and underlying disorder

  • Drainage of some symptomatic effusions

  • Other treatments for parapneumonic and malignant effusions

The effusion itself generally does not require treatment if it is asymptomatic because many effusions resorb spontaneously when the underlying disorder is treated, especially effusions due to uncomplicated pneumonias, pulmonary embolism, or surgery. Pleuritic pain can usually be managed with NSAIDs or other oral analgesics. At times, a short course of oral opioids is required.

Thoracentesis is sufficient treatment for many symptomatic effusions and can be repeated for effusions that reaccumulate. There are no arbitrary limits on the amount of fluid that can be removed. Removal of fluid can be continued until the effusion is drained or the patient develops chest tightness, chest pain, or severe coughing.

Effusions that are chronic, recurrent, and causing symptoms can be treated with pleurodesis or by intermittent drainage with an indwelling catheter (see Pneumothorax : Treatment). Effusions caused by pneumonia and cancer may require additional specific measures.

Parapneumonic effusion and empyema

In patients with adverse prognostic factors (pH < 7.20, glucose < 60 mg/dL, positive Gram stain or culture, loculations), the effusion should be completely drained via thoracentesis (see Thoracentesis) or tube thoracostomy (see Tube Thoracostomy). If complete drainage is impossible, a thrombolytic (fibrinolytic) drug (eg, a tissue plasminogen activator 10 mg) plus a DNAse (eg, dornase alfa 5 mg) in 100 mL saline solution can be administered intrapleurally twice a day for 3 days. If attempts at drainage are unsuccessful, thoracoscopy should be done to lyse adhesions and remove fibrous tissue coating the lung to allow the lung to expand. If thoracoscopy is unsuccessful, thoracotomy with surgical decortication (eg, removal of scar, clot, or fibrous membrane surrounding the lung) is necessary.

Malignant pleural effusion

If dyspnea caused by malignant pleural effusion is relieved by thoracentesis but fluid and dyspnea redevelop, chronic (intermittent) drainage or pleurodesis is indicated. Asymptomatic effusions and effusions causing dyspnea unrelieved by thoracentesis do not require additional procedures.

Indwelling catheter drainage is the preferred approach for ambulatory patients because hospitalization is not necessary for catheter insertion and the pleural fluid can be drained intermittently into vacuum bottles. Pleurodesis is done by instilling a sclerosing agent into the pleural space to fuse the visceral and parietal pleura and eliminate the space. The most effective and commonly used sclerosing agents are talc, doxycycline, and bleomycin delivered via chest tube or thoracoscopy. Pleurodesis is contraindicated if the mediastinum has shifted toward the side of the effusion or if the lung does not expand after a chest tube is inserted.

Shunting of pleural fluid to the peritoneum (pleuroperitoneal shunt) is useful for patients with malignant effusion in whom pleurodesis is unsuccessful and in patients who have trapped lung.

Key Points

  • Transudative effusions are caused by some combination of increased hydrostatic pressure and decreased plasma oncotic pressure.

  • Exudative effusions result from increased capillary permeability, leading to leakage of protein, cells, and other serum constituents.

  • The most common causes of transudative effusions are heart failure, cirrhosis with ascites, and hypoalbuminemia (usually due to the nephrotic syndrome).

  • The most common causes of exudative effusions are pneumonia, cancer, pulmonary embolism, and TB.

  • Evaluation requires imaging (usually chest x-ray) to confirm presence of fluid and pleural fluid analysis to help determine cause.

  • Lateral decubitus x-rays, chest CT, or ultrasonography should be done if it is unclear whether an x-ray density represents fluid or parenchymal infiltrates or whether suspected fluid is loculated or free-flowing.

  • Effusions that are chronic or recurrent and causing symptoms can be treated with pleurodesis or by intermittent drainage with an indwelling catheter.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • FURADANTIN, MACROBID, MACRODANTIN
  • CLOMID
  • PARLODEL
  • DANTRIUM
  • ADENOCARD
  • PERIOSTAT, VIBRAMYCIN
  • No US brand name

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