What are the indications for pleurofibrinolysis (intrapleural administration of fibrinolytic agents such as streptokinase or urokinase)?

Indications for Pleurofibrinolysis

Intrapleural fibrinolytics are indicated for any complicated parapneumonic effusion with thick fluid and loculations, or empyema with overt pus, where they shorten hospital stay and reduce the need for surgical intervention. 1

Primary Indications

Complicated Parapneumonic Effusions

• Use fibrinolytics when chest tube drainage alone fails to adequately drain loculated parapneumonic effusions (defined as <70 mL drainage per 24 hours after initial placement). 2, 3
• Loculations identified on ultrasound or CT imaging that prevent effective pleural fluid clearance are a clear indication for fibrinolytic therapy. 3, 4
• The presence of thick fluid with septations on imaging warrants fibrinolytic administration even before drainage failure becomes apparent. 1

Empyema

• Frank pus in the pleural space (overt empyema) is an absolute indication for fibrinolytic therapy as an adjunct to chest tube drainage and antibiotics. 1
• Fibrinolytics lyse fibrinous strands that form loculations, clear lymphatic pores, and restore normal pleural fluid dynamics. 1

Size-Based Criteria

• Large effusions (>50% hemithorax opacification) that are loculated require drainage with fibrinolytic therapy in approximately 66% of cases. 3
• Moderate effusions associated with respiratory distress should receive fibrinolytic therapy if loculations are present. 3
• Small effusions (<10 mm rim or <25% hemithorax) generally do not require fibrinolytics and can be managed with antibiotics alone. 3

Clinical Algorithm for Decision-Making

Step 1: Initial Assessment (Days 0-1)

• Obtain chest ultrasound to identify septations (81-88% sensitivity, 83-96% specificity for loculations). 3
• Place chest tube with ultrasound guidance at the optimal site. 1
• Initiate appropriate antibiotics. 1

Step 2: Evaluate Drainage Response (Days 1-3)

• If drainage is <70 mL per 24 hours after initial placement, initiate fibrinolytic therapy immediately. 2
• If thick fluid with loculations is present on imaging, start fibrinolytics regardless of initial drainage volume. 1

Step 3: Fibrinolytic Protocol

• Administer tPA 10 mg + DNase 5 mg twice daily for 3 days (6 doses total) as the preferred regimen based on the most recent high-quality evidence showing superior outcomes. 5
• Alternative: Urokinase 100,000 IU once daily for 3 days if tPA/DNase is unavailable. 4
• Clamp chest tube for 1 hour after instillation, then reopen to drainage. 1, 5

Step 4: Reassessment (Days 5-8)

• Evaluate clinical response at 5-8 days: assess fever resolution, sepsis improvement, and drainage adequacy. 1, 4
• If effective drainage has not been achieved by day 5-8, discuss with thoracic surgery for possible VATS or thoracotomy. 1, 4

Evidence Quality and Nuances

The recommendation for fibrinolytics is supported by multiple guidelines, though with important caveats. The BTS pediatric guidelines 1 provide Level B evidence showing shortened hospital stay (7.39 vs 9.49 days with urokinase vs placebo, p=0.027). However, the adult literature shows more mixed results—the large BTS/MRC trial found streptokinase had no beneficial effect in adult empyema 1, while smaller studies showed benefit. This discordance may reflect publication bias or differences in patient populations. 6

The most recent and highest quality evidence strongly favors the tPA/DNase combination over single-agent fibrinolysis, with significant reductions in hospital stay, persistent fevers, and improved radiographic outcomes. 5 This represents a paradigm shift from older guidelines recommending streptokinase or urokinase monotherapy.

Agent Selection

First-Line: tPA + DNase

• tPA 10 mg + DNase 5 mg twice daily for 3 days is the preferred regimen based on American College of Chest Physicians guidelines, showing superior efficacy to either agent alone. 5

Alternative Agents (if tPA/DNase unavailable)

• Urokinase 100,000 IU once daily for 3 days is the second choice, particularly in pediatric patients where it has RCT evidence. 1, 4
• Streptokinase 250,000 IU twice daily for 3 days is no longer recommended due to lack of benefit in the largest trial and higher complication rates. 5, 1

Pediatric Dosing

• Urokinase 40,000 units in 40 mL saline twice daily for children ≥1 year or ≥10 kg. 1
• Urokinase 10,000 units in 10 mL saline twice daily for children <1 year or <10 kg. 1

Critical Pitfalls to Avoid

• Do not use streptokinase as first-line therapy—it showed no benefit in the largest adult trial and carries immunological risks including fever and systemic antibody formation. 1, 5
• Do not delay surgical consultation beyond 5-8 days if drainage remains inadequate despite fibrinolytic therapy. 1, 4
• Always ensure chest tube patency before attributing poor drainage to loculations—flush with 20-50 mL normal saline if blockage is suspected. 4
• Do not attempt pleurodesis in patients with loculated effusions and non-expandable lung—it will fail. 3
• Obtain informed consent before tPA administration due to bleeding risk (2-8.5% rate, higher with alteplase at 20 mg dose). 3, 7
• Give patients receiving streptokinase an exposure card and use urokinase or tPA for any future systemic indications (MI, PE) due to antibody formation. 1, 4

Expected Outcomes

• Complete resolution in 85-90% of cases without surgery. 1, 3
• Increased daily drainage volume (380-420 mL in first 24 hours post-instillation). 2
• Shorter hospital stays (mean 6.2 days with fibrinolytics vs 8.7 days with drainage alone). 3
• Greater radiological improvement (85% showing >40% reduction in pleural opacity). 3
• Reduced surgical referral rate (OR 0.37,95% CI 0.21-0.68). 6