Extended Intrapleural Tissue Plasminogen Activator (tPA)-Dornase Alfa (DNase) Therapy Beyond the Standard Multicenter Intrapleural Sepsis Trial 2 (MIST-2) Regimen in a High-Risk Patient With Complex Empyema: A Case Report.

Pleural infection, including complicated parapneumonic effusion and empyema, remains a major management challenge, especially in patients who are poor surgical candidates. The Multicenter Intrapleural Sepsis Trial 2 (MIST-2) supports a six-dose regimen of intrapleural tissue plasminogen activator (tPA) plus dornase alfa (DNase), but the optimal duration of therapy in patients with persistent loculations remains uncertain. We describe a 62-year-old man with morbid obesity, New York Heart Association class III diastolic heart failure, and poorly controlled type 2 diabetes mellitus who presented with a complex, loculated left-sided empyema caused by Gemella sanguinis and Escherichia coli. Because of prohibitive operative risk, he was not considered a candidate for video-assisted thoracoscopic surgery. After incomplete improvement following the standard six-dose regimen, characterized by persistent fever, persistently elevated inflammatory markers, and residual loculations on repeat imaging, intrapleural therapy was extended for an additional six doses, for a total of 12 doses over six days. The patient had marked clinical and radiographic improvement, complete lung re-expansion, and no bleeding complications. This case suggests that, in carefully selected high-risk patients with persistent loculated empyema and no surgical option, extended intrapleural tPA-DNase therapy may be a feasible individualized strategy beyond the fixed MIST-2 protocol.