Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.

Autor:	Barrett CD; 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., Moore HB; Department of Surgery, University of Colorado Denver, Aurora, CO., Moore EE; Department of Surgery, University of Colorado Denver, Aurora, CO; Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO. Electronic address: ernest.moore@dhha.org., Wang J; Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY., Hajizadeh N; Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY., Biffl WL; Division of Trauma/Acute Care Surgery, Department of Surgery, Scripps Memorial Hospital La Jolla, La Jolla, CA., Lottenberg L; Department of Surgery, St. Mary's Medical Center, Florida Atlantic University, West Palm Beach, FL., Patel PR; Department of Medicine, Baylor College of Medicine, Houston, Dallas, TX., Truitt MS; Department of Surgery, Methodist Dallas Medical Center, Dallas, TX., McIntyre RC Jr; Department of Surgery, University of Colorado Denver, Aurora, CO., Bull TM; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, CO., Ammons LA; Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO., Ghasabyan A; Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO., Chandler J; Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO., Douglas IS; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Denver Health Medical Center, Denver, CO., Schmidt EP; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Denver Health Medical Center, Denver, CO., Moore PK; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, CO., Wright FL; Department of Surgery, University of Colorado Denver, Aurora, CO., Ramdeo R; Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY., Borrego R; Division of Pulmonary/Critical Care Medicine, Department of Medicine, Scripps Memorial Hospital La Jolla, La Jolla, CA., Rueda M; Division of Pulmonary/Critical Care Medicine, Department of Medicine, Scripps Memorial Hospital La Jolla, La Jolla, CA., Dhupa A; Division of Trauma/Acute Care Surgery, Department of Surgery, Scripps Memorial Hospital La Jolla, La Jolla, CA., McCaul DS; Division of Trauma/Acute Care Surgery, Department of Surgery, Scripps Memorial Hospital La Jolla, La Jolla, CA., Dandan T; Division of Trauma/Acute Care Surgery, Department of Surgery, Scripps Memorial Hospital La Jolla, La Jolla, CA., Sarkar PK; Department of Medicine, Baylor College of Medicine, Houston, Dallas, TX., Khan B; Department of Medicine, Baylor College of Medicine, Houston, Dallas, TX., Sreevidya C; Department of Medicine, Baylor College of Medicine, Houston, Dallas, TX., McDaniel C; Department of Surgery, Methodist Dallas Medical Center, Dallas, TX., Grossman Verner HM; Clinical Research Institute, Methodist Dallas Medical Center, Dallas, TX., Pearcy C; Department of Surgery, Methodist Dallas Medical Center, Dallas, TX., Anez-Bustillos L; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA., Baedorf-Kassis EN; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA., Jhunjhunwala R; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA., Shaefi S; Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston., Capers K; Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston., Banner-Goodspeed V; Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston., Talmor DS; Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston., Sauaia A; Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO; Colorado School of Public Health and Department of Surgery, University of Colorado Denver, Denver, CO., Yaffe MB; 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.
Jazyk:	angličtina
Zdroj:	Chest [Chest] 2022 Mar; Vol. 161 (3), pp. 710-727. Date of Electronic Publication: 2021 Sep 27.
DOI:	10.1016/j.chest.2021.09.024
Abstrakt:	Background: Pulmonary 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 Question: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? Study Design and Methods: Adults 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 Pao 2 to Fio 2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao 2 to Fio 2 ratio improvement of > 50% or Pao 2 to Fio 2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality. Results: Fifty 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 Pao 2 to Fio 2 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 Pao 2 to Fio 2 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. Interpretation: The 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 Registry: ClinicalTrials.gov; No.: NCT04357730; URL: www. Clinicaltrials: gov. (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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