Concurrent Versus Sequential Intrapleural tPA–DNase Administration: Comparative Effectiveness and Safety in Pleural Infection

RATIONALE AND OBJECTIVES: Intrapleural tissue plasminogen activator (tPA) plus deoxyribonuclease (DNase) improves drainage in pleural infection, but the optimal administration sequence is uncertain. We evaluated whether concurrent co-instillation of tPA/DNase is associated with improved effectiveness or altered safety compared with sequential administration in patients with infectious pleural effusions. METHODS: We performed a retrospective cohort study at a tertiary hospital in Southern California including adults who received intrapleural tPA and DNase (August 2017-August 2025). We restricted our analysis to suspected or confirmed infectious pleural effusions. Exposure was concurrent co-instillation (single dwell) versus sequential administration (tPA followed 1 hour later by DNase with separate dwells). Primary outcomes were radiographic resolution on follow-up chest CT as documented in contemporaneous radiology reports, need for surgical intervention (VATS/open decortication), and hospital length of stay. Multivariable logistic regression adjusted for age, sex, body mass index, chest tube size, early therapy initiation (<24 hours from chest tube placement), and chest tube placement method. Safety endpoints included analgesic utilization (from medication administration records) and serial hemoglobin trends and transfusion. MEASUREMENTS AND RESULTS: Among 233 treated patients, 210 met criteria for infectious pleural effusions (sequential n = 149; concurrent n = 61). Radiographic resolution occurred more frequently with concurrent versus sequential therapy (80% vs 52%) and remained independently associated with concurrent administration after adjustment (adjusted OR 4.70, 95% CI 2.18-10.10). Surgical intervention occurred in 25% overall and was less frequent with concurrent therapy (13% vs 30%); concurrent administration was associated with lower adjusted odds of surgery (adjusted OR 0.30, 95% CI 0.13-0.70). Median length of stay was 10 days (IQR 7-15) with concurrent therapy versus 12 days (IQR 9-16) with sequential therapy (P = .059). Analgesic utilization during therapy did not differ meaningfully between strategies. Hemoglobin trajectories and transfusion rates were similar, and transfusion during therapy was rare. CONCLUSIONS: In this single-center cohort of infectious pleural effusions, concurrent intrapleural tPA/DNase administration was associated with higher radiographic resolution and lower surgical referral compared with sequential dosing, without evidence of increased analgesic burden or bleeding-related safety signals. Prospective comparative studies are warranted to confirm causality and identify patients most likely to benefit.