• Christopher D Barrett, Hunter B Moore, Ernest E Moore, Janice Wang, Negin Hajizadeh, Walter L Biffl, Lawrence Lottenberg, Purvesh R Patel, Michael S Truitt, Robert C McIntyre, Todd M Bull, Lee Anne Ammons, Arsen Ghasabyan, James Chandler, Ivor S Douglas, Eric P Schmidt, Peter K Moore, Franklin L Wright, Ramona Ramdeo, Robert Borrego, Mario Rueda, Achal Dhupa, D Scott McCaul, Tala Dandan, Pralay K Sarkar, Benazir Khan, Coimbatore Sreevidya, Conner McDaniel, Heather M Grossman Verner, Christopher Pearcy, Lorenzo Anez-Bustillos, Elias N Baedorf-Kassis, Rashi Jhunjhunwala, Shahzad Shaefi, Krystal Capers, Valerie Banner-Goodspeed, Daniel S Talmor, Angela Sauaia, and Michael B Yaffe.
• Department of Surgery, Boston University School of Medicine, Boston, MA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Departments of Biological Engineering and Biology, Massachusetts Institute of Technology, Cambridge, MA.
• Chest. 2022 Mar 1; 161 (3): 710-727.

BackgroundPulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients.Research QuestionDoes tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe?Study Design And MethodsAdults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality.ResultsFifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit.InterpretationThe combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality.Trial RegistryClinicalTrials.gov; No.: NCT04357730; URL: www.Clinicaltrialsgov.Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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