Nebulized Heparin in Severe Acute Respiratory Syndrome COVID-19

Summary

To evaluate the safety and efficacy of the use of inhalational heparin in patients with pulmonary compromise / pneumonia / SARS associated with COVID-19, laboratory with marked inflammation parameters, and prothrombotic state secondary to it (Fibrinogen, Ferritin and / or elevated D-Dimer) , from admission to hospitalization. The combination of inhalation heparin combined with prophylactic doses of LMWH could reduce the progression to severe forms of the disease, and consequently the need for intensive care units and mechanical ventilation.

Timeline

Start

2020-06-01

Primary completion

2020-10-30

Completion

2021-06-01

Publications

• Background Zhou Y, Zhang Z, Tian J, Xiong S. Risk factors associated with disease progression in a cohort of patients infected with the 2019 novel coronavirus. Ann Palliat Med. 2020 Mar;9(2):428-436. doi: 10.21037/apm.2020.03.26. Epub 2020 Mar 17.
• Background Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Jul 1;180(7):934-943. doi: 10.1001/jamainternmed.2020.0994.
• Background Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11.
• Background Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, Chen H, Ding X, Zhao H, Zhang H, Wang C, Zhao J, Sun X, Tian R, Wu W, Wu D, Ma J, Chen Y, Zhang D, Xie J, Yan X, Zhou X, Liu Z, Wang J, Du B, Qin Y, Gao P, Qin X, Xu Y, Zhang W, Li T, Zhang F, Zhao Y, Li Y, Zhang S. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020 Apr 23;382(17):e38. doi: 10.1056/NEJMc2007575. Epub 2020 Apr 8.
• Background Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020 May;18(5):1094-1099. doi: 10.1111/jth.14817. Epub 2020 Apr 27.
• Background Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 Apr;18(4):844-847. doi: 10.1111/jth.14768. Epub 2020 Mar 13.
• Background Monagle K, Ryan A, Hepponstall M, Mertyn E, Monagle P, Ignjatovic V, Newall F. Inhalational use of antithrombotics in humans: Review of the literature. Thromb Res. 2015 Dec;136(6):1059-66. doi: 10.1016/j.thromres.2015.10.011. Epub 2015 Oct 9.
• Background Page C. Heparin and related drugs: beyond anticoagulant activity. ISRN Pharmacol. 2013 Jul 30;2013:910743. doi: 10.1155/2013/910743. eCollection 2013.
• Background Scazziota A. Pons S. Heparin effects beyond antithrombotic activity. Hematología Volumen 21 Nº Extraordinario: 166175 XXIII Congreso Argentino de Hematología Noviembre 2017
• Background Shastri MD, Peterson GM, Stewart N, Sohal SS, Patel RP. Non-anticoagulant derivatives of heparin for the management of asthma: distant dream or close reality? Expert Opin Investig Drugs. 2014 Mar;23(3):357-73. doi: 10.1517/13543784.2014.866092. Epub 2014 Jan 3.
• Background Trybala E, Liljeqvist JA, Svennerholm B, Bergstrom T. Herpes simplex virus types 1 and 2 differ in their interaction with heparan sulfate. J Virol. 2000 Oct;74(19):9106-14. doi: 10.1128/jvi.74.19.9106-9114.2000.
• Background Courtney Mycroft-West, Dunhao Su, Stefano Elli , Scott Guimond,Gavin Miller, Jeremy Turnbull , Edwin Yates , Marco Guerrini , David Fernig , Marcelo Lima and Mark Skidmore. The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding. bioRxiv preprint doi: https://doi.org/10.1101/2020.02.29.971093.This version posted March 2, 2020.
• Background Scheuch G, Brand P, Meyer T, Herpich C, Mullinger B, Brom J, Weidinger G, Kohlhaufl M, Haussinger K, Spannagl M, Schramm W, Siekmeier R. Anticoagulative effects of the inhaled low molecular weight heparin certoparin in healthy subjects. J Physiol Pharmacol. 2007 Nov;58 Suppl 5(Pt 2):603-14.
• Background Yildiz-Pekoz A, Ozsoy Y. Inhaled Heparin: Therapeutic Efficacy and Recent Formulations. J Aerosol Med Pulm Drug Deliv. 2017 Jun;30(3):143-156. doi: 10.1089/jamp.2015.1273. Epub 2017 Apr 18.
• Background Bendstrup KE, Gram J, Jensen JI. Effect of inhaled heparin on lung function and coagulation in healthy volunteers. Eur Respir J. 2002 Apr;19(4):606-10. doi: 10.1183/09031936.02.00105202.
• Background Harenberg J, Malsch R, Angelescu M, Lange C, Michaelis HC, Wolf H, Heene DL. Anticoagulant effects and tissue factor pathway inhibitor after intrapulmonary low-molecular-weight heparin. Blood Coagul Fibrinolysis. 1996 Jun;7(4):477-83. doi: 10.1097/00001721-199606000-00008.
• Background Ghiasi F, Sadeghian M, Emami M, Kiaie BA, Mousavi S. A Pilot Study of Nebulized Heparin for Prevention of Ventilator Induced Lung Injury: Comparative Effects with an Inhaled Corticosteroid. Indian J Crit Care Med. 2017 Oct;21(10):634-639. doi: 10.4103/ijccm.IJCCM_183_17.
• Background Abdelaal Ahmed Mahmoud A, Mahmoud HE, Mahran MA, Khaled M. Streptokinase Versus Unfractionated Heparin Nebulization in Patients With Severe Acute Respiratory Distress Syndrome (ARDS): A Randomized Controlled Trial With Observational Controls. J Cardiothorac Vasc Anesth. 2020 Feb;34(2):436-443. doi: 10.1053/j.jvca.2019.05.035. Epub 2019 May 27.
• Background Dixon B, Schultz MJ, Smith R, Fink JB, Santamaria JD, Campbell DJ. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial. Crit Care. 2010;14(5):R180. doi: 10.1186/cc9286. Epub 2010 Oct 11.
• Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19: a rapid review. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.

Drugs

Indications