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Background and objective: Intrapleural tissue plasminogen activator/ deoxyribonuclease (tPA/DNase) therapy is increasingly used in pleural infection. Bleeding risks and costs associated with tPA remain the clinical concerns. Our dose de-escalation series aims to establish the lowest effective dosing regimen for tPA/DNase. This study assesses the intrapleural use of 2.5 mg tPA/5 mg DNase for pleural infection. Methods: Consecutive patients with pleural infection treated with a starting regime of 2.5 mg tPA/5 mg DNase were included from two centres in Australia and UK. Escalation of tPA dose was permitted if clinical response was inadequate. Results: Sixty-nine patients (mean age 61.0 years) received intrapleural 2.5 mg tPA/5 mg DNase. Most (88.4%) were treated successfully and discharged from hospital without surgery by 90 days. Patients received a median of 5 [interquartile range [IQR] = 3-6] doses of tPA/DNase. Total amount of tPA used per patient was 12.5 mg [median, IQR = 7.5-15.0]. Seventeen patients required dose escalation of tPA; most (n = 12) for attempted drainage of distant non-communicating locule(s). Treatment success was corroborated by clearance of pleural opacities on radiographs (from median 27.0% [IQR = 17.1-44.5] to 11.0% [IQR = 6.4-23.3] of hemithorax, p < 0.0001), increased pleural fluid drainage (1.98 L [median, IQR = 1.38-2.68] over 72 h following commencement of tPA/DNase) and reduction of serum C-reactive protein level (by 45.0% [IQR = 39.3-77.0] from baseline at day 5, p < 0.0001). Two patients required surgery. Six patients with significant comorbidities (e.g., advanced cancer) had ongoing infection when palliated and died. Two patients experienced selflimiting pleural bleeding and received blood transfusion. Conclusion: A starting intrapleural regime of 2.5 mg tPA/5 mg DNase, with uptitration if needed, can be effective and deserves further exploration.

<b><i>Background:</i></b> Indwelling pleural catheters (IPC) are increasingly used for management of recurrent (especially malignant) effusions. Pleural infection associated with IPC use remains a concern. Intrapleural therapy with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) significantly reduces surgical referrals in non-IPC pleural infection, but data on its use in IPC-related pleural infection are scarce. <b><i>Objective:</i></b> To assess the safety and efficacy of intrapleural tPA and DNase in IPC-related pleural infection. <b><i>Methods:</i></b> Patients with IPC-related pleural infection who received intrapleural tPA/DNase in five Australian and UK centers were identified from prospective databases. Outcomes on <i>feasibility</i> of intrapleural tPA/DNase delivery, its <i>efficacy</i> and <i>safety</i> were recorded. <b><i>Results:</i></b> Thirty-nine IPC-related pleural infections (predominantly <i>Staphylococcus aureus</i> and gram-negative organisms) were treated in 38 patients; 87% had malignant effusions. In total, 195 doses (median 6 [IQR = 3–6]/patient) of tPA (2.5 mg–10 mg) and DNase (5 mg) were instilled. Most (94%) doses were delivered via IPCs using local protocols for non-IPC pleural infections. The mean volume of pleural fluid drained during the first 72 h of treatment was 3,073 (SD = 1,685) mL. Most (82%) patients were successfully treated and survived to hospital discharge without surgery; 7 required additional chest tubes or therapeutic aspiration. Three patients required thoracoscopic surgery. Pleurodesis developed post-infection in 23/32 of successfully treated patients. No major morbidity/mortality was associated with tPA/DNase. Four patients received blood transfusions; none had systemic or significant pleural bleeding. <b><i>Conclusion:</i></b> Treatment of IPC-related pleural infection with intrapleural tPA/DNase instillations via the IPC appears feasible and safe, usually without additional drainage procedures or surgery. Pleurodesis post-infection is common.

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