雾化重组组织型纤溶酶原激活剂（rt-PA）治疗新型冠状病毒肺炎（COVID-19）所致急性呼吸衰竭：一项探索性概念验证试验

Nebulized Recombinant Tissue Plasminogen Activator (rt-PA) for Acute COVID-19-Induced Respiratory Failure: An Exploratory Proof-of-Concept Trial.

作者信息

Chowdary Pratima, Agarwal Banwari, Peralta Maria Rita, Bhagani Sanjay, Lee Simon, Goldring James, Lipman Marc, Waqif Emal, Phillips Mark, Philippou Helen, Foley Jonathan H, Mutch Nicola J, Ariëns Robert A S, Stringer Kathleen A, Ricciardi Federico, Watissée Marie, Hughes Derralynn, Nathwani Amit, Riddell Anne, Patch David, Buckley Jim, De Neef Mark, Dimber Rahul, Diaz-Garcia Cecilia, Patel Honey, Nandani Aarti, Dissanayake Upuli, Chadwick Nick, Alkhatip Ahmed A A M M, Watkinson Peter, Raith Eamon, Singh Suveer, Wolff Tony, Jha Rajeev, Brill Simon E, Bakhai Ameet, Evans Alison, Gilani Farhat, Gomez Keith

机构信息

Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK.

Cancer Institute, University College London, London WC1E 6DD, UK.

出版信息

J Clin Med. 2023 Sep 8;12(18):5848. doi: 10.3390/jcm12185848.

DOI:10.3390/jcm12185848

PMID:37762789

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10531875/

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 <300 mmHg PaO/FiO (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.

摘要

新型冠状病毒肺炎（COVID-19）所致的急性肺损伤会导致弥漫性肺泡损伤，伴有肺泡-毛细血管屏障破坏、凝血激活、肺泡纤维蛋白沉积和肺毛细血管血栓形成。雾化吸入重组组织型纤溶酶原激活剂（rt-PA）有可能促进肺泡腔局部溶栓并改善氧合。在这项概念验证性安全性研究中，2020年4月23日至7月30日以及2021年1月21日至2月19日期间，患有COVID-19所致呼吸衰竭且动脉血氧分压/吸入氧分数值（PaO₂/FiO₂）<300 mmHg、需要有创机械通气（IMV）或无创呼吸支持（NIRS）的成人，在两个队列（C1和C2）中接受了雾化rt-PA治疗，并同时接受标准治疗。C1组使用匹配的历史对照（MHC；n = 18）来探索疗效。安全性共同主要终点为治疗相关出血和纤维蛋白原降低<1.0 - 1.5 g/L。在C1组确定了一种具有临床疗效终点且安全性担忧最小的可变给药策略，用于C2组；患者按通气类型分层，每天接受40 - 60 mg rt-PA治疗，持续≤14天。C1组9例患者（IMV，6/9；NIRS，3/9）和C2组26例患者（IMV，12/26；NIRS，14/26）接受了雾化rt-PA治疗，平均（标准差）分别为6.7（4.6）天和9.1（4.6）天。3例患者出现4次出血（1次严重，3次轻度），被认为与治疗相关。纤维蛋白原无显著降低。与MHC组相比，C1组从基线到研究结束时平均PaO₂/FiO₂比值改善更大（C1组：154至299 vs. MHC组：154至212）。在C2组，NIRS和IMV患者的基线PaO₂/FiO₂比值无差异。然而，NIRS组患者的PaO₂/FiO₂比值改善更大（NIRS组：126至240 vs. IMV组：120至188），且所需治疗天数更少（NIRS组：7.86天 vs. IMV组：10.5天）。雾化rt-PA似乎耐受性良好，有改善氧合的趋势，尤其是在NIRS组。需要进行随机临床试验来证明临床效果的显著性和程度。