Inhaled prostacyclin analogues in COVID-19 associated acute respiratory distress syndrome: scientific rationale

Eka Prasetya Budi Mulia, Kevin Luke, Eka Prasetya Budi Mulia, Kevin Luke

Abstract

Background: COVID-19 associated acute respiratory distress syndrome (CARDS) is a severe form of SARS CoV-2 infection and affects about 15-30% of hospitalized patients with a high mortality rate. Growing research and data suggest several available drugs with appropriate pharmacological effects to treat COVID-19.

Main body: Prostacyclin analogues are regiments for pulmonary artery hypertension. Prostacyclin analogues are expected to be beneficial in treating CARDS based on at least four rationales: (1) inhaled prostacyclin analogues improve oxygenation, V/Q mismatch, and act as an ARDS therapy alternative; (2) it alleviates direct SARS-CoV-2-related coagulopathy; (3) increases nitric oxide production; and (4) possible anti-inflammatory effect. Prostacyclin analogues are available in oral, intravenous, and inhaled forms. The inhaled form has the advantage over other forms, such as parenteral administration risks. Previously, a meta-analysis demonstrated the beneficial effects of inhaled prostaglandins for ARDS treatment, such as improved PaO2/FiO2 and PaO2 along with reduced pulmonary artery pressure. Currently, two ongoing randomized controlled trials are evaluating inhaled epoprostenol (VPCOVID [NCT04452669]) and iloprost (ILOCOVID [NCT04445246]) for severe COVID-19 patients.

Conclusions: Inhaled prostacyclin could be considered in patients with refractory, life-threatening hypoxia despite standard management.

Keywords: ARDS; COVID-19; Epoprostenol; Prostacyclin.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

References

    1. Wu R, Wang L, Kuo HCD, Shannar A, Peter R, Chou PJ, et al. An update on current therapeutic drugs treating COVID-19. Curr Pharmacol Rep. 2020;6:56–70. doi: 10.1007/s40495-020-00216-7.
    1. Van Haren FMP, Page C, Laffey JG, Artigas A, Camprubi-Rimblas M, Nunes Q, et al. Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Crit Care. 2020;24:1–11. doi: 10.1186/s13054-020-03148-2.
    1. Hasan SS, Capstick T, Ahmed R, Kow CS, Mazhar F, Merchant HA, et al. Mortality in COVID-19 patients with acute respiratory distress syndrome and corticosteroids use: a systematic review and meta-analysis. Expert Rev Respir Med. 2020;14:1149–1163. doi: 10.1080/17476348.2020.1804365.
    1. Searcy RJ, Morales JR, Ferreira JA, Johnson DW. The role of inhaled prostacyclin in treating acute respiratory distress syndrome. Ther Adv Respir Dis. 2015;9:302–312. doi: 10.1177/1753465815599345.
    1. Bethesda (2012) Prostacyclin analogs. National Institute of Diabetes and Digestive and Kidney Diseases
    1. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19) Intensive Care Med. 2020;46:854–887. doi: 10.1007/s00134-020-06022-5.
    1. Konstam MA, Kiernan MS, Bernstein D, Bozkurt B, Jacob M, Kapur NK, et al. Evaluation and management of right-sided heart failure: a scientific statement from the American Heart Association. Circulation. 2018;137:e578–622. doi: 10.1161/CIR.0000000000000560.
    1. Attaway AH, Scheraga RG, Bhimraj A, Biehl M, Hatipoğ LU. Severe covid-19 pneumonia: pathogenesis and clinical management. BMJ. 2021 doi: 10.1136/bmj.n436.
    1. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180:934–943. doi: 10.1001/jamainternmed.2020.0994.
    1. Grasselli G, Tonetti T, Protti A, Langer T, Girardis M, Bellani G, et al. Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study. Lancet Respir Med. 2020;8:1201–1208. doi: 10.1016/S2213-2600(20)30370-2.
    1. Park JF, Banerjee S, Umar S. In the eye of the storm: the right ventricle in COVID-19. Pulm Circ. 2020 doi: 10.1177/2045894020936660.
    1. Oktaviono YH, Mulia EPB, Luke K, Nugraha D, Maghfirah I, Subagjo A. Right ventricular dysfunction and pulmonary hypertension in COVID-19: a meta-analysis of prevalence and its association with clinical outcome. Arch Med Sci. 2021 doi: 10.5114/aoms/136342.
    1. Franco V, Bradley EA, Badagliacca R, Sabanayagam A, Rajpal S, Lastinger LT, et al. Pulmonary vasodilators: beyond the bounds of pulmonary arterial hypertension therapy in COVID-19. Pulm Circ. 2020;10:2045894020970369. doi: 10.1177/2045894020970369.
    1. Fuller BM, Mohr NM, Skrupky L, Fowler S, Kollef MH, Carpenter CR. The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta-analysis. Chest. 2015;147:1510–1522. doi: 10.1378/chest.14-3161.
    1. Afshari A, Bastholm Bille A, Allingstrup M. Aerosolized prostacyclins for acute respiratory distress syndrome (ARDS) Cochrane Database Syst Rev. 2017 doi: 10.1002/14651858.CD007733.pub3.
    1. Sakamaki F, Kyotani S, Nagaya N, Sato N, Oya H, Satoh T, et al. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation. 2000;102:2720–2725. doi: 10.1161/01.CIR.102.22.2720.
    1. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-γ: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–189. doi: 10.1189/jlb.0603252.
    1. McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55:1915–1922. doi: 10.1016/j.jacc.2010.01.027.
    1. AbuHalimeh BJ, Parambil JG, Tonelli AR. Different efficacy of inhaled and oral medications in pulmonary hypertension. Hear Lung J Acute Crit Care. 2017;46:334–337. doi: 10.1016/j.hrtlng.2017.04.010.
    1. Mitchell JA, Ahmetaj-Shala B, Kirkby NS, Wright WR, Mackenzie LS, Reed DM, et al. Role of prostacyclin in pulmonary hypertension. Glob Cardiol Sci Pract. 2014;2014:53. doi: 10.5339/gcsp.2014.53.
    1. Kumar P, Thudium E, Laliberte K, Zaccardelli D, Nelsen A. A comprehensive review of treprostinil pharmacokinetics via four routes of administration. Clin Pharmacokinet. 2016;55:1495–1505. doi: 10.1007/s40262-016-0409-0.
    1. Huang CY, Lee JK, Chen ZW, Cheng JF, Chen SY, Lin LY, et al. Inhaled prostacyclin on exercise echocardiographic cardiac function in preserved ejection fraction heart failure. Med Sci Sports Exerc. 2020;52:269–277. doi: 10.1249/MSS.0000000000002145.
    1. De Wet CJ, Affleck DG, Jacobsohn E, Avidan MS, Tymkew H, Hill LL, et al. Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg. 2004;127:1058–1067. doi: 10.1016/j.jtcvs.2003.11.035.
    1. Sawheny E, Ellis AL, Kinasewitz GT. Iloprost improves gas exchange in patients with pulmonary hypertension and ARDS. Chest. 2013;144:55–62. doi: 10.1378/chest.12-2296.
    1. Dunkley KA, Louzon PR, Lee J, Vu S. Efficacy, safety, and medication errors associated with the use of inhaled epoprostenol for adults with acute respiratory distress syndrome: a pilot study. Ann Pharmacother. 2013;47:790–796. doi: 10.1345/aph.1R540.
    1. DeGrado JR, Szumita PM, Schuler BR, Dube KM, Lenox J, Kim EY, et al. Evaluation of the efficacy and safety of inhaled epoprostenol and inhaled nitric oxide for refractory hypoxemia in patients with coronavirus disease 2019. Crit Care Explor. 2020;2:e0259. doi: 10.1097/cce.0000000000000259.
    1. Sonti R, Pike CW, Cobb N. Responsiveness of inhaled epoprostenol in respiratory failure due to COVID-19. J Intensive Care Med. 2021;36:327–333. doi: 10.1177/0885066620976525.
    1. Li J, Fink JB, Augustynovich AE, Mirza S, Kallet RH, Dhand R. Effects of inhaled epoprostenol and prone positioning in intubated coronavirus disease 2019 patients with refractory hypoxemia. Crit Care Explor. 2020;2:e0307. doi: 10.1097/cce.0000000000000307.
    1. Franco V (2020) Venta prost in subjects with COVID-19 requiring mechanical ventilation. ClinicalTrialsGov
    1. Kharma N (2020) Inhaled iloprost for suspected COVID-19 respiratory failure. ClinicalTrialsGov
    1. Filippini A, Bnà C, Bellosta R, Bazzani R, Luzzani L, Pegorer MA, et al. COVID-19 acute respiratory distress syndrome: can iloprost have a role for the treatment? Respir Med Case Rep. 2021 doi: 10.1016/j.rmcr.2021.101358.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe