Journal of Clinical Medicine (Sep 2023)
Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial
- Pratima Chowdary,
- Banwari Agarwal,
- Maria Rita Peralta,
- Sanjay Bhagani,
- Simon Lee,
- James Goldring,
- Marc Lipman,
- Emal Waqif,
- Mark Phillips,
- Helen Philippou,
- Jonathan H. Foley,
- Nicola J. Mutch,
- Robert A. S. Ariëns,
- Kathleen A. Stringer,
- Federico Ricciardi,
- Marie Watissée,
- Derralynn Hughes,
- Amit Nathwani,
- Anne Riddell,
- David Patch,
- Jim Buckley,
- Mark De Neef,
- Rahul Dimber,
- Cecilia Diaz-Garcia,
- Honey Patel,
- Aarti Nandani,
- Upuli Dissanayake,
- Nick Chadwick,
- Ahmed A. A. M. M. Alkhatip,
- Peter Watkinson,
- Eamon Raith,
- Suveer Singh,
- Tony Wolff,
- Rajeev Jha,
- Simon E. Brill,
- Ameet Bakhai,
- Alison Evans,
- Farhat Gilani,
- Keith Gomez
Affiliations
- Pratima Chowdary
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Banwari Agarwal
- Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Maria Rita Peralta
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Sanjay Bhagani
- Department of Infectious Diseases, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Simon Lee
- Department of Infectious Diseases, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- James Goldring
- Respiratory Medicine, Royal Free London NHS Foundation Trust, London NW1 2BU, UK
- Marc Lipman
- Respiratory Medicine, Royal Free London NHS Foundation Trust, London NW1 2BU, UK
- Emal Waqif
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Mark Phillips
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Helen Philippou
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK
- Jonathan H. Foley
- Freeline Therapeutics, London SG1 2BP, UK
- Nicola J. Mutch
- Aberdeen Cardiovascular & Diabetes Centre, School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK
- Robert A. S. Ariëns
- Discovery and Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK
- Kathleen A. Stringer
- Department of Clinical Pharmacy, College of Pharmacy University of Michigan, Ann Arbor, MI 48109, USA
- Federico Ricciardi
- Department of Statistical Science, University College London, London WC1E 6BT, UK
- Marie Watissée
- WStats Limited, Winchester SO23 8GH, UK
- Derralynn Hughes
- Cancer Institute, University College London, London WC1E 6DD, UK
- Amit Nathwani
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Anne Riddell
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- David Patch
- Department of Hepatology, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Jim Buckley
- Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Mark De Neef
- Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Rahul Dimber
- Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Cecilia Diaz-Garcia
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Honey Patel
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Aarti Nandani
- Clinical Trials Pharmacy, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Upuli Dissanayake
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Nick Chadwick
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Ahmed A. A. M. M. Alkhatip
- Department of Anaesthesia, Birmingham Children’s Hospital, Birmingham B4 6NH, UK
- Peter Watkinson
- NIHR Biomedical Research Centre Oxford, Oxford University Hospitals NHS Trust, University of Oxford, Oxford OX3 9DU, UK
- Eamon Raith
- Bloomsbury Institute for Intensive Care Medicine, Department of Experimental and Translational Medicine, University College London, London WC1E 6JF, UK
- Suveer Singh
- Department of Respiratory and Critical Care Medicine, Chelsea & Westminster Hospital, London SW10 9NH, UK
- Tony Wolff
- Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Rajeev Jha
- Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Simon E. Brill
- UCL Respiratory, University College London, London WC1E 6JF, UK
- Ameet Bakhai
- Department of Intensive Care and Anaesthesia, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Alison Evans
- University College London (UCL)/University College London Hospitals NHS Trust (UCLH) Joint Research Office, London WC1E 6BT, UK
- Farhat Gilani
- University College London (UCL)/University College London Hospitals NHS Trust (UCLH) Joint Research Office, London WC1E 6BT, UK
- Keith Gomez
- Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- DOI
- https://doi.org/10.3390/jcm12185848
- Journal volume & issue
-
Vol. 12,
no. 18
p. 5848
Abstract
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 2/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 <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.
Keywords
- acute respiratory illness
- critical care
- recombinant tissue plasminogen activator
- nebulization
- fibrinolytics
- COVID-19 pandemic