Chris Barrett COBRE Abstract

Project Summary/Abstract: Barrett Project

Infection of the pleural space, along with retained traumatic hemothorax, are pleural space diseases that generate marked morbidity and mortality, with an annual disease burden in the U.S. of approximately 400,000 patients. The common theme of treating these two entities is drainage of the contents within the pleural space to clear the infection and prevent chronic lung entrapment. However, drainage is complicated by fibrin loculations formed by the body to wall off infection and clot formed by the stagnant blood that renders simple tube thoracostomy inadequate in many cases. Thus, the standard of care for infected and complex intrapleural collections is treatment with intrapleural fibrinolytics (tissue plasminogen activator, tPA) in combination with DNAse to break up these loculations/clots to allow effective drainage, which has also been adopted for retained hemothorax. Unfortunately, while most diseases treated with fibrinolytic therapy resolve with one or two doses of tPA, intrapleural diseases require an average of 6 doses over 3 days that are inordinately large relative to the small pleural space. The reason for needing such large and numerous doses of tPA and DNAse remain largely unexplained, and the failure rate remains 20-25% such that many patients often require surgery and have prolonged hospital stays and high rates of mortality. The prevailing theory for failed intrapleural fibrinolysis is that high levels of the tPA inhibitor plasminogen activator inhibitor-1 (PAI-1) are present in inflammatory environments, however this conceptually challenged by PAI-1’s conformational lability and known susceptibility to inactivating cleavage events by neutrophil elastase that is present in inflamed/infected spaces. Our preliminary data (n=10 patients) supports this, where we have observed.