In a patient with a loculated pleural empyema not adequately drained by chest‑tube drainage, how do intrapleural dornase alfa (recombinant human DNase) and alteplase (tissue‑type plasminogen activator) work and what regimen should be used?

Mechanism of Action and Treatment Protocol for Intrapleural Dornase and Alteplase in Loculated Empyema

Combination therapy with intrapleural tissue plasminogen activator (alteplase/tPA) and dornase alfa (DNase) should be administered at 10 mg tPA twice daily plus 5 mg DNase twice daily for 3 days when initial chest tube drainage fails to adequately drain a loculated empyema. 1

How These Agents Work

Alteplase (tPA) Mechanism

• Alteplase lyses fibrinous strands and septations that form within the pleural space due to inflammatory changes, breaking down the fibrin matrix that creates loculations and prevents adequate drainage 2, 3
• The drug clears lymphatic pores and restores normal pleural fluid dynamics, allowing effective reabsorption of infected fluid 2
• This fibrinolytic action directly targets the fibrinous "walls" that compartmentalize the empyema into multiple pockets 1

Dornase Alfa (DNase) Mechanism

• DNase breaks down extracellular DNA released from degenerating neutrophils in purulent fluid, which is a major contributor to the high viscosity of empyema 2
• The DNA content of pus determines its viscosity—by degrading this DNA, DNase reduces fluid thickness and improves drainage 1
• This enzymatic action complements tPA by addressing the non-fibrin component that makes empyema difficult to drain 1

Synergistic Effect

• The combination works better than either agent alone because empyema contains both fibrinous septations (targeted by tPA) and viscous DNA-rich pus (targeted by DNase) 1
• Single-agent therapy with either tPA or DNase alone should NOT be used, as controlled trials show inferior outcomes 1

Treatment Regimen

Standard Dosing Protocol

• Administer 10 mg tPA + 5 mg DNase intrapleurally twice daily for 3 days (total of 6 doses) 1
• Each agent is diluted in 30-50 mL normal saline and instilled through the chest tube 3
• Clamp the chest tube immediately after instillation for a 1-hour dwell time to allow the drugs to work within the pleural space 3
• After the dwell period, unclamp and connect to continuous suction at -10 to -20 cm H₂O 3
• Maintain continuous suction between doses 3

Alternative Lower-Dose Regimen

• 5 mg tPA twice daily + 5 mg DNase twice daily for 3 days may be equally effective based on retrospective data and can be used when bleeding risk is a concern 1
• Consider reduced tPA doses in patients on therapeutic anticoagulation that cannot be temporarily stopped 1

Expected Clinical Outcomes

Efficacy Metrics

• Increased pleural fluid drainage occurs in 93-100% of treated patients, with daily drainage volumes rising from a median of 325 mL to 890 mL per 24 hours 2, 3, 4
• Radiographic improvement (>40% reduction in pleural opacity) is seen in 85% of patients versus 35% with placebo 2
• Hospital stay is shortened to a mean of 6.2 days compared to 8.7 days with drainage alone 2, 3
• Surgery is avoided in approximately 88-92% of cases when tPA/DNase is used for failed initial drainage 4, 5

Clinical Response Timeline

• Evaluate treatment effectiveness at 5-8 days after initiating therapy 3
• Key indicators of success include resolution of fever and sepsis, increased daily drainage output, and radiographic improvement 3
• Chest tube removal is typically achieved within 48-72 hours after completing the 3-day course, when drainage falls below 25-60 mL per 24 hours and no air leak is present 3

Safety Profile and Complications

Bleeding Risk

• Pleural bleeding requiring transfusion occurs in 2-8.9% of patients, with 5.4% requiring operative intervention in some series 2, 6
• The bleeding risk is significantly higher (33%) in patients on anticoagulation 2
• Obtain informed consent discussing bleeding risk before administering tPA/DNase 1

Other Adverse Events

• Chest pain occurs in approximately 23.5% of patients 4
• Rare bronchopleural communication can occur, manifesting as coughing and expectoration of the instilled solution 7
• Alteplase is safer than streptokinase, which causes fever and systemic antibody responses due to its bacterial origin 2

Critical Clinical Pitfalls to Avoid

• Never use single-agent tPA or DNase alone—the combination is essential for efficacy 1
• Do not use streptokinase—it is inferior to tPA/DNase combination and causes immunological side effects 1
• Do not delay chest tube drainage when loculation is identified, as loculated effusions are associated with longer hospital stays and worse outcomes 2
• Never clamp a bubbling chest tube (if air leak present), as this can create tension physiology 8
• Ensure a respiratory physician or thoracic surgeon is involved early, as specialist consultation reduces time to drainage and morbidity 2

When to Escalate to Surgery

• Consider Video-Assisted Thoracoscopic Surgery (VATS) if medical management fails after approximately 7 days of optimal therapy including tPA/DNase 1, 2, 8
• VATS is preferred over thoracotomy for surgical access 1
• Early surgical drainage should not be considered over initial chest tube drainage with tPA/DNase 1