What is the appropriate approach to analyzing pleural fluid, including how to differentiate transudate from exudate and subsequent management?

Analysis of Pleural Fluid

Initial Diagnostic Approach

Perform diagnostic thoracentesis with a 21-gauge needle and send pleural fluid for protein, LDH (with simultaneous serum samples), cytology, pH (if infection suspected), Gram stain, culture in both sterile vials and blood culture bottles, and acid-fast bacilli stain and culture. 1, 2

Visual Inspection First

• Note the appearance and odor of the fluid immediately after aspiration 1
• Serous/clear fluid can be either transudate or exudate and requires biochemical analysis 2
• Turbid/milky fluid should be centrifuged: if the supernatant clears, suspect empyema (cell debris); if it remains turbid, suspect chylothorax or pseudochylothorax (high lipid content) 1
• Bloody fluid requires hematocrit measurement: if pleural fluid hematocrit is >50% of peripheral blood hematocrit, diagnose hemothorax; if <1%, the blood is not clinically significant 1
• An unpleasant odor suggests anaerobic infection 1

Differentiating Transudate from Exudate

Step 1: Measure Pleural Fluid Protein

• If pleural fluid protein <25 g/L → Transudate 2
• If pleural fluid protein >35 g/L → Exudate 2
• If pleural fluid protein 25-35 g/L → Proceed to Light's criteria 1, 2

Step 2: Apply Light's Criteria (When Protein is 25-35 g/L or Borderline)

An effusion is exudative if it meets ANY ONE of the following: 2, 3

• Pleural fluid/serum protein ratio >0.5
• Pleural fluid/serum LDH ratio >0.6
• Pleural fluid LDH >0.67 (or >67%) of the upper limit of normal for serum LDH

Performance: Light's criteria have 98% sensitivity but only 72% specificity for identifying exudates 2, 3

Step 3: Address "Pseudoexudates" (False Positives)

Common pitfall: Light's criteria misclassify 25-30% of transudates from heart failure or cirrhosis as exudates, especially in patients receiving diuretics 2, 3

When to suspect a pseudoexudate: Light's criteria suggest exudate BUT clinical picture strongly suggests heart failure or cirrhosis 2

Use these reclassification tools: 2, 3

• Serum-effusion albumin gradient (SEAG): Calculate serum albumin minus pleural fluid albumin; if >1.2 g/dL → Transudate (97.5% accuracy)
• Albumin ratio: Pleural fluid/serum albumin <0.6 → Transudate
• NT-proBNP: Pleural fluid or serum NT-proBNP >1500 pg/mL confirms heart failure etiology (sensitivity 92-94%, specificity 88-91%)

Alternative When Serum Samples Unavailable

If you cannot obtain simultaneous serum samples, use the "or" rule: 2, 4, 5

• Pleural fluid LDH >67% of upper limit of normal for serum AND
• Pleural fluid cholesterol >55 mg/dL → Exudate

This combination provides discriminative capacity comparable to Light's criteria 5

Management Based on Classification

If Transudate (>80% are heart failure)

• Treat the underlying cause: heart failure, cirrhosis, or hypoalbuminemia 1, 2
• No further invasive testing needed if the effusion responds to diuretic therapy 2
• Avoid bilateral thoracentesis in patients with clear heart failure unless atypical features are present or the effusion fails to respond to diuretics 2

If Exudate

Send comprehensive panel: 1, 6

• Differential white cell count
• Cytology (detects only 60% of malignant effusions) 1
• Bacterial cultures in blood culture bottles (increases diagnostic yield) 1
• Gram stain and acid-fast bacilli stain and culture
• pH (mandatory if infection suspected; pH <7.2 mandates urgent chest tube drainage) 1, 6
• Glucose (very low <60 mg/dL suggests rheumatoid pleuritis or complicated parapneumonic effusion) 6
• Adenosine deaminase (if tuberculosis suspected) 6

Most common causes of exudates: 2, 6, 7

• Pneumonia/parapneumonic effusion (pH <7.2, LDH >200 IU/L, nucleated cells >5,000/µL)
• Malignancy
• Tuberculosis
• Pulmonary embolism (75% have pleuritic pain; effusion usually <1/3 hemithorax; dyspnea disproportionate to size)

If cytology is negative and malignancy suspected: 1

• Obtain contrast-enhanced CT thorax with fluid present (enables better pleural visualization)
• Proceed to pleural biopsy (ultrasound/CT-guided, closed pleural biopsy, or thoracoscopy)

Critical Caveats

• Imaging cannot replace biochemical analysis: CT attenuation and ultrasound echogenicity show significant overlap between transudates and exudates (CT sensitivity 69%, specificity 66%) and are unreliable for classification 2, 3
• Diuretic therapy is the most common cause of misclassification, concentrating pleural fluid and making transudates appear exudative 2, 3
• Different laboratory analyzers can cause up to 18% discordance in classification, particularly affecting LDH measurements 2
• Pleural fluid pH <7.2 in non-purulent effusions mandates urgent chest tube drainage; delayed management increases morbidity 6
• Approximately 40% of needle-track incisions become invaded by tumor in mesothelioma, so consider this risk when performing procedures 6
• Maintain high clinical suspicion for pulmonary embolism when pleuritic pain, small effusion, and disproportionate dyspnea are present, as pleural fluid studies are not diagnostic for PE 6