The use of systemic tPA in preclinical and human models of ARDS demonstrates improved oxygenation, and a case report of tPA use in severe COVID-19 showed an initial improvement in oxygenation during tPA infusion, but this effect was lost after tPA therapy ceased.156–158 However, the benefits of tPA may be offset by the considerable risk of major bleeding seen in nonstroke clinical trials,159 which has led to the consideration of nebulized therapy to increase local concentrations and reduce systemic coagulation effects.