TY - JOUR
AU - Chowdary, Pratima
AU - Agarwal, Banwari
AU - Peralta, Maria Rita
AU - Bhagani, Sanjay
AU - Lee, Simon
AU - Goldring, James
AU - Lipman, Marc
AU - Waqif, Emal
AU - Phillips, Mark
AU - Philippou, Helen
AU - Foley, Jonathan H
AU - Mutch, Nicola
AU - Ariëns, Robert A S
AU - Stringer, Kathleen A
AU - Ricciardi, Federico
AU - Watissée, Marie
AU - Hughes, Derralynn
AU - Nathwani, Amit
AU - Riddell, Anne
AU - Patch, David
AU - Buckley, Jim
AU - De Neef, Mark
AU - Dimber, Rahul
AU - Diaz-Garcia, Cecilia
AU - Patel, Honey
AU - Nandani, Aarti
AU - Dissanayake, Upuli
AU - Chadwick, Nick
AU - Alkhatip, Ahmed A A M M
AU - Watkinson, Peter
AU - Raith, Eamon
AU - Singh, Suveer
AU - Wolff, Tony
AU - Jha, Rajeev
AU - Brill, Simon
AU - Bakhai, Ameet
AU - Evans, Alison
AU - Gilani, Farhat
AU - Gomez, Keith
PY - 2023
DA - September
TI - Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial
JO - Journal of Clinical Medicine
VL - 12
IS - 18
DO - https://doi.org/10.3390/jcm12185848
AB - Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a &lt;300 mmHg PaO2/FiO2(P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April–30 July 2020 and 21 January–19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and &lt;1.0–1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.
PB - MDPI
UR - https://hdl.handle.net/2164/22042
KW - Coronavirus (COVID-19)
ER