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

Abstract 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.