H. Pleural Effusion

• Thoracentesis should be performed for new and unexplained pleural effusions when sufficient fluid is present to allow a safe procedure. Observation of pleural effusion(s) is reasonable in the setting of overt congestive heart failure, viral pleurisy, or recent thoracic or abdominal surgery.
• Laboratory testing helps distinguish pleural fluid transudates from exudates; however, certain types of exudative pleural effusions might be suspected simply by observing the quality of the fluid obtained during thoracentesis.
• Frankly purulent fluid indicates an empyema.
• A putrid odor suggests an anaerobic empyema.
• A milky, opalescent fluid suggests a chylothorax, resulting most often from lymphatic obstruction by malignancy or thoracic duct injury by trauma or surgical procedures.
• Grossly bloody fluid indicates the need for a spun hematocrit test of the sample. A pleural fluid hematocrit level of more than 50% of the peripheral hematocrit level defines a hemothorax, which often requires tube thoracostomy.

• 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 have become the criterion standards. The fluid is considered an exudate if any of the following apply:
• Pleural fluid to serum protein ratio more than 0.5
• Pleural fluid to serum lactate dehydrogenase (LDH) ratio more than 0.6
• Pleural fluid LDH more than two thirds of the upper limits of normal serum value
• These criteria require simultaneous measurement of pleural fluid and serum protein and LDH. However, a meta-analysis of 1448 patients suggested that the following pleural fluid measurements alone might have sensitivity and specificity comparable to Light's criteria for distinguishing transudates from exudates (Heffner, 1997).
  • Pleural fluid LDH more than 0.45 of the upper limit of normal serum values
  • Pleural fluid cholesterol more than 45 mg/dL
  • Pleural fluid protein more than 2.9 g/dL

• Pleural effusions in patients on chronic diuretic therapy for congestive heart failure may be incorrectly classified as exudates when using these criteria because of the concentration of protein and LDH within the pleural space due to diuresis.
  • 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.
  • In addition, recent studies suggest that pleural fluid levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are elevated in effusions due to congestive heart failure. Thus, at institutions where this test is available, high pleural levels of NT-proBNP (> 4000 ng/L) may help to confirm heart failure as the cause of a chronic effusion where diuresis has increased pleural fluid protein and LDH levels into the exudative range.
• Pleural fluid LDH levels greater than 1000 IU/L suggest empyema, malignant effusion, rheumatoid effusion, or pleural paragonimiasis.
• In addition to these tests, glucose and pleural fluid pH should be measured during the initial thoracentesis in most situations.
• A low pleural glucose concentration (<30 mg/dL) indicates rheumatoid pleurisy or empyema, and a low pleural glucose concentration (30-50 mg/dL) suggests malignant effusion, tuberculous pleuritis, esophageal rupture, or lupus pleuritis.
• 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 6 hours. However, recent studies have shown that when collected in heparinized syringes, pleural fluid pH does not change significantly even at room temperature over several hours. 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 pH is highly correlated with pleural fluid glucose levels. Pleural fluid pH 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 than is a low pleural fluid glucose level.
• In parapneumonic effusions, pleural fluid pH less than 7.1-7.2 indicates the need for urgent drainage of the effusion, and pleural fluid pH more than 7.3 suggests that the effusion may be managed with systemic antibiotics alone.
• In malignant effusions, pleural fluid pH 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.

• Pleural fluid lymphocytosis, with lymphocytes greater than 85% of the total nucleated cells, suggests tuberculosis (TB), lymphoma, sarcoidosis, chronic rheumatoid pleurisy, yellow nail syndrome, or chylothorax. Pleural lymphocytes of 50-70% of the nucleated cells suggests malignancy.
• Pleural fluid eosinophilia (PFE), with eosinophils 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 caused by pulmonary embolism with infarction, or benign asbestos pleural effusion. PFE may be associated with other nonmalignant diseases, including parasitic disease (especially paragonimiasis), fungal infection, 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 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 more than 5% of total nucleated cells makes a diagnosis of TB unlikely.
• Markedly increased numbers of mesothelial cells, especially in bloody or eosinophilic effusions, suggests pulmonary embolism as the cause.
• Culture of infected pleural fluid yields positive results in approximately 60% of cases, although less often for anaerobic organisms. Diagnostic yields may be increased by directly culturing pleural fluid into anaerobic blood culture bottles.
• 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.
• Heparinize samples (1 mL of 1:1000 heparin per 50 mL of pleural fluid) if bloody, and refrigerate if not processed within 1 hour.
• The reported diagnostic yields of cytology vary from 60-90%, depending on the extent of pleural involvement and the type of primary malignancy.
• The sensitivity of cytology is not related to the volume of pleural fluid tested; sending more than 50 mL of pleural fluid for cytology does not increase the yield.
• Cytology findings are positive in 58% of effusions related to mesothelioma.
• 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 values are normal or only modestly increased.
• Suspect TB pleuritis in patients with a history of exposure or a positive purified protein derivative (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), and pleural fluid cultures grow Mycobacterium 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 to 90%.
• Adenosine deaminase (ADA) activity of more than 43 U/mL in pleural fluid supports the diagnosis of TB pleuritis. However, the test has a sensitivity of only 78%; therefore, pleural ADA values less than 43 U/mL do not exclude the diagnosis of TB pleuritis.
• Interferon-gamma concentrations in pleural fluid greater than 140 pg/mL also support the diagnosis of TB pleuritis, but this test is not routinely available.
• Additional specialized tests are warranted when specific etiologies are suspected.
  • Measure pleural fluid amylase if a pancreatic origin or ruptured esophagus is suspected or if a unilateral left pleural effusion remains undiagnosed after initial testing. An additional assay of amylase isoenzymes can help distinguish a pancreatic source from other etiologies.
  • Measure triglycerides and cholesterol on 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.
• Despite primary evaluation with serial thoracenteses with cytology, 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.
• The 2 diagnostic imperatives in this situation are pulmonary embolism and tuberculous pleuritis. In both cases, the pleural effusion is a harbinger of subsequent morbidity if undiagnosed. In contrast, a short delay in diagnosing metastatic malignancy to the pleural space has less clinical significance.
• Pulmonary embolism should be considered and CT angiography should be ordered if clinical suspicion is high.
• Pleural biopsy should be considered, especially if TB or malignancy are suspected. 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. Closed-needle pleural biopsy is a blind technique but can be performed at the patient's bedside. Medical thoracoscopy has a higher diagnostic yield for malignancy; closed-needle pleural biopsy diagnoses 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 TB and is a useful alternative procedure for this diagnosis where available.

• Among patients with undiagnosed pleural effusions after the primary evaluation, predict a benign course for those who meet all 6 of the following clinical parameters. No further evaluation is necessary.
• Patients are clinically stable.
• Patients do not have weight loss.
• The results of the PPD test are negative and the pleural ADA value is less than 43 U/mL.
• The patient does not have a fever.
• The pleural fluid differential cell count has less than 95% lymphocytes.
• The effusion occupies less than 50% of the hemithorax.
• For other patients with undiagnosed exudative effusions, approximately 20% will have a specific etiology determined, including malignancy. For such patients, weigh the benefits and risks of pursuing a diagnosis using progressively more invasive procedures, given the low likelihood of finding a curable etiology.
• Consider bronchoscopy only if a patient has parenchymal abnormalities or hemoptysis.Surgical approaches to the diagnosis of pleural effusions include thoracoscopy (pleuroscopy) and open thoracotomy, which reveal an etiology in 92% of effusions that remain undiagnosed after a medical evaluation.
• Where available, medical thoracoscopy may be both diagnostic and therapeutic; talc sclerosis can be performed at the time of the procedure.
• 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 diagnosis.

Procedures:

• Perform diagnostic thoracentesis 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.
• 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. Mechanical ventilation with positive end-expiratory pressure does not increase the risk of pneumothorax after thoracentesis, but it increases the likelihood of a tension pneumothorax or persistent bronchopleural fistula if the lung is punctured.
• Complications of diagnostic thoracentesis include pain at the puncture site, cutaneous or internal bleeding, pneumothorax, empyema, and spleen/liver puncture.
• Pneumothorax complicates approximately 12-30% of thoracenteses but requires treatment with a chest tube in less than 5% of cases.
• 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.
• 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 at 1-2 rib interspaces below the level of dullness to percussion determined during the physical examination.
• Once the site is disinfected with chlorhexidine and /or povidone/iodine 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 find the effusion. 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.
• 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 puncture over the eighth rib at the mid-to-posterior auxiliary line.
• Supplemental oxygen is often administered during thoracentesis, both 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 is lower when a more experienced clinician performs the procedure. Consequently, a skilled and experienced clinician should perform thoracentesis in patients who have a higher risk of complications or relative contraindications for thoracentesis or those who cannot sit upright.
• Postprocedure chest radiographs to exclude pneumothorax are not needed in asymptomatic patients after uncomplicated procedures (single needle pass without aspiration of air).

Medical Care: Transudative effusions are usually managed by treating the underlying medical disorder. However, whether transudates or exudates, drain large pleural effusions if they are causing severe respiratory symptoms, even if the cause is understood and disease-specific treatment is available. The management of exudative effusions depends on the underlying etiology of the effusion. Pneumonia, malignancy, or TB causes most exudative pleural effusions, or effusions are deemed idiopathic. Drain complicated parapneumonic effusions and empyemas to avoid fibrosing pleuritis. Malignant effusions are usually drained to palliate symptoms and may require pleurodesis to prevent recurrence.

• Although medications cause only a small proportion of all pleural effusions, they are associated with exudative pleural effusions.
• Implicated drugs include medications that cause drug-induced lupus syndrome (eg, procainamide, hydralazine, quinidine), nitrofurantoin, dantrolene, methysergide, procarbazine, and methotrexate.
• Recognition of these iatrogenic causes of pleural effusion avoids unnecessary additional diagnostic procedures and leads to definitive therapy, which is discontinuation of the medication.
• 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, which 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) pleural fluid pH less than 7.2, (3) loculated effusions, and (4) bacteria on Gram stain or culture.
• Patients with parapneumonic effusions who do not meet criteria for immediate tube drainage should improve clinically within 1 week with appropriate antibiotic treatment.
• Radiographically reassess patients with parapneumonic effusions who do not improve or who deteriorate clinically.

• Malignant pleural effusions usually signify incurable disease with considerable morbidity and a dismal mean survival of less than 1 year.
  • Drainage of large malignant effusions might relieve dyspnea caused by distortion of the diaphragm and chest wall produced by the effusion.
  • Pleural sclerosis also might be necessary to prevent recurrence of symptomatic effusions.

  TB pleuritis typically is self-limited. However, because 65% of patients with primary TB pleuritis reactivate their disease within 5 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 are usually managed by dietary and surgical modalities discussed below. However, recent studies suggest that somatostatin analogues also may help in reducing efflux of chyle into the pleural space.