In an adult with a loculated parapneumonic pleural effusion or empyema inadequately drained by chest tube, what is the recommended intrapleural tissue‑type plasminogen activator (tPA) and dornase alfa regimen, including dosing, administration protocol, contraindications, and criteria for surgical referral?

Intrapleural tPA and Dornase for Loculated Parapneumonic Effusion/Empyema

For adults with loculated parapneumonic effusion or empyema inadequately drained by chest tube, administer combination intrapleural tissue plasminogen activator (tPA) 10 mg twice daily plus dornase alfa (DNase) 5 mg twice daily for 3 days through the existing chest tube. 1

Standard Dosing Protocol

The evidence-based regimen is:

• tPA 10 mg twice daily (every 12 hours) PLUS DNase 5 mg twice daily for 3 consecutive days 1, 2
• Administer through the existing chest tube after initial drainage has slowed or ceased but residual pleural collection remains 1, 2
• Each dose dwells in the pleural space for 1-2 hours with the chest tube clamped, then the tube is reopened to suction 1

Alternative Lower-Dose Regimen

• tPA 5 mg twice daily plus DNase 5 mg twice daily for 3 days may be equally effective based on retrospective data and can be used if deemed necessary 1
• This lower tPA dose may reduce bleeding risk while maintaining efficacy 3

Administration Requirements

Before initiating therapy:

• Obtain informed consent specifically addressing bleeding risk 1, 2, 4
• Ensure small-bore chest tube (≤14F) is already in place 1
• Confirm inadequate drainage from initial chest tube placement alone 1, 2

During administration:

• Instill medications through chest tube, clamp for dwell time (typically 1-2 hours), then place on continuous suction (-10 to -20 cm H₂O) 1
• Monitor for complications, particularly bleeding 5

Contraindications and High-Risk Situations

Reduce tPA dose (consider 5 mg instead of 10 mg) in patients with:

• Active therapeutic anticoagulation that cannot be temporarily stopped 1, 4
• Other conditions conferring higher bleeding risk 1, 4

Absolute contraindications include:

• Active uncontrolled bleeding
• Recent neurosurgery or stroke
• Known hypersensitivity to tPA or DNase

Critical Evidence-Based Principles

Never use single-agent therapy:

• Single-agent tPA or DNase alone do NOT improve clinical outcomes and should not be used 1, 2
• The combination works synergistically: tPA breaks down fibrin deposits while DNase degrades extracellular DNA contributing to fluid viscosity 2

Do not use streptokinase:

• Streptokinase increases post-treatment complications without improving outcomes and should not be used 1, 2, 4

Expected Outcomes

Clinical benefits of tPA/DNase combination:

• Reduces length of hospital stay compared to placebo 1, 2
• Decreases likelihood of persistent fevers 1, 2
• Increases radiographic improvement with better clearance of pleural opacification 1, 2
• Avoids need for surgical intervention in most cases 6, 3

Criteria for Surgical Referral

Refer for VATS (video-assisted thoracoscopic surgery) if:

• No clinical improvement after 2-3 days of tPA/DNase therapy with persistent moderate-to-large effusion and ongoing respiratory compromise 1
• No improvement after 5-7 days of appropriate antibiotics and drainage 4
• Patient develops complications requiring surgical intervention 5

VATS is preferred over thoracotomy when surgery is required, resulting in shorter hospital stays (2.3 days shorter), less postoperative pain, fewer complications, and slightly lower mortality 1, 4

Alternative When tPA/DNase Unavailable

Saline irrigation (250 mL three times daily) can be considered when intrapleural tPA/DNase therapy or surgery is not suitable, though evidence for benefit is limited 1, 2

Common Pitfalls to Avoid

• Do not delay chest tube placement in patients with moderate-to-large effusions or respiratory distress, as delayed drainage increases morbidity and hospital stay 4
• Do not use tPA/DNase as initial therapy—it is reserved for inadequate drainage after chest tube placement 1, 2
• Do not contaminate pleural fluid pH samples with local anesthetic or heparin, as this alters pH measurement 1
• Do not proceed to early VATS or thoracotomy as initial treatment over chest tube drainage unless there are specific indications 1, 4

Monitoring During Treatment

• Assess fever resolution, inflammatory markers, and symptoms regularly 4
• Monitor chest tube output (can remove when drainage <1 mL/kg/24 hours and no air leak) 1
• Watch for hemorrhagic complications (occurs in approximately 5-9% of patients) 5
• Perform follow-up imaging to assess pleural clearance 4