Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19,Chest

当前位置： X-MOL 学术 › Chest › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19
Chest ( IF 9.6 ) Pub Date : 2021-09-27 , DOI: 10.1016/j.chest.2021.09.024
Christopher D Barrett ₁ , Hunter B Moore ₂ , Ernest E Moore ₃ , Janice Wang ₄ , Negin Hajizadeh ₄ , Walter L Biffl ₅ , Lawrence Lottenberg ₆ , Purvesh R Patel ₇ , Michael S Truitt ₈ , Robert C McIntyre ₂ , Todd M Bull ₉ , Lee Anne Ammons ₁₀ , Arsen Ghasabyan ₁₀ , James Chandler ₁₀ , Ivor S Douglas ₁₁ , Eric P Schmidt ₁₁ , Peter K Moore ₉ , Franklin L Wright ₂ , Ramona Ramdeo ₄ , Robert Borrego ₁₂ , Mario Rueda ₁₂ , Achal Dhupa ₅ , D Scott McCaul ₅ , Tala Dandan ₅ , Pralay K Sarkar ₇ , Benazir Khan ₇ , Coimbatore Sreevidya ₇ , Conner McDaniel ₈ , Heather M Grossman Verner ₁₃ , Christopher Pearcy ₈ , Lorenzo Anez-Bustillos ₁₄ , Elias N Baedorf-Kassis ₁₅ , Rashi Jhunjhunwala ₁₄ , Shahzad Shaefi ₁₆ , Krystal Capers ₁₆ , Valerie Banner-Goodspeed ₁₆ , Daniel S Talmor ₁₆ , Angela Sauaia ₁₇ , Michael B Yaffe ₁₈

Affiliation

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.
Department of Surgery, University of Colorado Denver, Aurora, CO.
Department of Surgery, University of Colorado Denver, Aurora, CO; Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO.
Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY.
Division of Trauma/Acute Care Surgery, Department of Surgery, Scripps Memorial Hospital La Jolla, La Jolla, CA.
Department of Surgery, St. Mary's Medical Center, Florida Atlantic University, West Palm Beach, FL.
Department of Medicine, Baylor College of Medicine, Houston, Dallas, TX.
Department of Surgery, Methodist Dallas Medical Center, Dallas, TX.
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, Aurora, CO.
Ernest E. Moore Shock Trauma Center at Denver Health, Department of Surgery, Denver, CO.
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Denver Health Medical Center, Denver, CO.
Division of Pulmonary/Critical Care Medicine, Department of Medicine, Scripps Memorial Hospital La Jolla, La Jolla, CA.
Clinical Research Institute, Methodist Dallas Medical Center, Dallas, TX.
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston.
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.
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.

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 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.

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 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.

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

中文翻译：

阿替普酶治疗 SARS-CoV-2 COVID-19 呼吸衰竭的研究

背景

肺血管微血栓是 COVID-19 呼吸衰竭的一种拟议机制。我们假设早期使用组织型纤溶酶原激活剂 (tPA)，然后使用治疗性肝素会改善这些患者的肺功能。

研究问题

tPA 能否改善严重 COVID-19 呼吸衰竭患者的肺功能，是否安全？

研究设计和方法

从 2020 年 5 月 14 日到 2021 年 3 月 3 日，患有 COVID-19 引起的呼吸衰竭的成年人被随机分为两个阶段。第 1 阶段 (n = 36) 包括对照组（标准护理治疗）与 tPA 推注（50-mg tPA IV 推注，随后 7 天肝素；目标激活部分促凝血酶原激酶时间 [aPTT]，60-80 秒）团体。第 2 阶段 (n = 14) 包括对照组与 tPA 滴注（50-mg tPA IV 推注，随后 tPA 滴注 2mg/h 加肝素 500 单位/小时超过 24 小时，然后肝素维持 60-80 的 aPTT s 7 天）组。如果患者在过去 4.5 小时内未接受神经系统检查或横截面脑成像以排除中风和出血性转化的可能性，则将其排除在入组之外。主要结果是 Pa o ₂至 F io ₂随机化后 48 小时，比基线值有所改善。次要结局包括 Pa o ₂与 F io ₂比值改善 > 50% 或 Pa o ₂与 F io ₂比值在 48 小时时≥ 200（复合结局）、无呼吸机天数 (VFD) 和死亡率。

结果

50 名患者被随机分组：1 期对照组 17 名，tPA 推注组 19 名，对照组 8 名，2 期 tPA 滴注组 6 名。没有发生严重出血事件。在 tPA 推注组中，随机分组后 6 至 168 小时，Pa o ₂与 F io ₂比值显着（P < .017）高于基线；对照组无明显改善。在接受 tPA 推注的患者中，48 小时时 Pa o ₂与 F io ₂比率的百分比变化（16.9% 对照[四分位距 (IQR)，–8.3% 至 36.8%] vs 29.8% tPA 推注 [IQR，4.5% -88.7%]；P = .11)，综合结果（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) 和住院死亡率 (41.2% vs 21.1%; P = .19)与对照组相比，没有达到统计学上的显着差异。接受 tPA 滴注的患者没有获益。