Abstract Rationale Pleural infection, including complicated parapneumonic effusions and empyema, continues to cause substantial morbidity and mortality. Standard treatment involves chest tube drainage and antibiotics, yet incomplete evacuation often prompts use of intrapleural enzyme therapy with tissue plasminogen activator (tPA) and dornase alfa (DNase). Although the combination improves drainage and outcomes, its safety - particularly with respect to pleural bleeding, along with its relation to dosage and methods of administration - has not been clearly defined. We conducted a systematic review and meta-analysis to evaluate the safety of intrapleural tPA/DNase in adults with pleural infection. Methods PubMed, Scopus, and Embase were searched in accordance with PRISMA guidelines. Randomized as well as observational studies reporting on adults treated with ≥1 dose of intrapleural tPA + DNase were eligible. The primary endpoint was treatment-related adverse events (AEs): chest pain, pleural bleeding, systemic bleeding, and hemoptysis. Secondary analyses examined AEs by tPA dose and by administration strategy (sequential vs concurrent). Two reviewers independently extracted data and assessed study quality using ROBINS-I and RoB-2. Pooled event rates were calculated with random-effects models (Stata 18). Results Twenty-one studies (2790 patients) met the inclusion criteria. The mean age was 59.6 years, of which 65.3% were men. The most common dose regimen used was tPA 10 mg + DNase 5 mg (86%), and 13% received ≤ 5 mg tPA. The average number of doses was 4.2 (mean cumulative tPA = 38 mg). Sequential administration was used in 34% and concurrent in 66%. AEs were uncommon and mostly mild. Chest pain was most common, occurring in 16.8% (12.2-21.9) of patients. Pleural bleeding occurred in 3.9% (2.4-5.6). Systemic bleeding and hemoptysis were rare (1%). No treatment-related deaths were reported, and 86.7% (70.5-94.6) bleeding events were managed conservatively. Rates of pleural bleeding were similar with full-dose and reduced dose regimens - 5.0% (3.5-9.2) vs 3.9% (1.7-11.2); OR 1.22 (0.5-2.9, p = 0.66). Meta-regression found no dose-dependent relationship between cumulative tPA exposure and bleeding (β=-0.00016; p = 0.92). Sequential and concurrent administration showed comparable risk of pleural bleeding (4.1% vs 5.8%; OR 1.26 0.8-2.0; p = 0.32). Conclusion Intrapleural tPA/DNase is generally safe, with very low rates of clinically significant pleural bleeding and no treatment-related mortality. Chest pain is the most frequent adverse event, while systemic bleeding and hemoptysis are exceedingly rare. Risk of pleural bleeding does not vary by tPA dosage or by sequential versus concurrent administration, supporting the overall safety of current IET practice. This abstract is funded by: none
Gandhi et al. (Fri,) studied this question.