Abstract
BackgroundEffective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke‐induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single‐chain urokinase plasminogen activator (scuPA) moderated this adverse effect and supported transient improvement in gas exchange and lung mechanics. However, neither aerosolized plasminogen activator (PA) yielded durable improvements in physiologic responses or reduction in cast burden. Here, we hypothesized that perfluorochemical (PFC) liquids would facilitate PA distribution and sustain improvements in physiologic outcomes in ISALI.MethodsSpontaneously breathing adult sheep (n = 36) received anesthesia and analgesia and were instrumented, exposed to cotton smoke inhalation, and supported by mechanical ventilation for 48 h. Groups (n = 6/group) were studied without supplemental treatment, or, starting 4 h post injury, they received intratracheal low volume (8 mL) PFC liquid alone or a dose range of tPA/PFC or scuPA/PFC suspensions (4 or 8 mg in 8 mL PFC) every 8 h. Outcomes were evaluated by sequential measurements of cardiopulmonary parameters, lung histomorphology, and biochemical analyses of bronchoalveolar lavage fluid.ResultsDose‐response and PA‐type comparisons of outcomes demonstrated sustained superiority with low‐volume PFC suspensions of scuPA over tPA or PFC alone, favoring the highest dose of scuPA/PFC suspension over lower doses, without airway bleeding.ConclusionsWe propose that this improved profile over previously reported aerosolized delivery is likely related to improved dose distribution. Sustained salutary responses to scuPA/PFC suspension delivery in this translational model are encouraging and support the possibility that the observed outcomes could be of clinical importance.
Highlights
Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke-induced acute lung injury (ISALI) is lacking
We found that high-dose nebulized tissue plasminogen activator (tPA) delivery was confounded by airway bleeding complications, while single-chain urokinase plasminogen activator (scuPA) was well tolerated and supported transient improvement in gas exchange and lung mechanics
There were group differences in this finding with none of the animals treated with PFC alone requiring intervention, while 50% of animals treated with tPA/PFC suspension and 40% of animals treated with scuPA/PFC suspension were treated
Summary
Effective clinical management of airway clot and fibrinous cast formation of severe inhalational smoke-induced acute lung injury (ISALI) is lacking. Aerosolized delivery of tissue plasminogen activator (tPA) is confounded by airway bleeding; single-chain urokinase plasminogen activator (scuPA) moderated this adverse effect and supported transient improvement in gas exchange and lung mechanics. We used a wellestablished sheep model of cotton ISALI and investigated aerosolized delivery of tissue plasminogen activator (tPA) or single-chain urokinase plasminogen activator (scuPA) in saline.[7] We found that high-dose nebulized tPA delivery was confounded by airway bleeding complications, while scuPA was well tolerated and supported transient improvement in gas exchange and lung mechanics. The better response to scuPA appeared to relate to its relative resistance to plasminogen activator inhibitor (PAI-1) and ability to form bioactive complexes amenable to low-grade release of uPA for up to 24 h.7,8 neither of the aerosolized interventions achieved durable reduction in cast burden or improvements in physiologic responses in this severe lung injury model.[7]
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