Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial

Pär I Johansson, Peter Søe-Jensen, Morten H Bestle, Niels E Clausen, Klaus T Kristiansen, Theis Lange, Jakob Stensballe, Anders Perner, Pär I Johansson, Peter Søe-Jensen, Morten H Bestle, Niels E Clausen, Klaus T Kristiansen, Theis Lange, Jakob Stensballe, Anders Perner

Abstract

Rationale: The mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who require mechanical ventilation remains high, and endotheliopathy has been implicated. Objectives: To determine the effect of prostacyclin infusion in mechanically ventilated patients infected with SARS-CoV-2 with severe endotheliopathy. Methods: We conducted a multicenter, randomized clinical trial in adults infected with coronavirus disease (COVID-19) who required mechanical ventilation and had a plasma level of thrombomodulin >4 ng/ml; patients were randomized to 72-hour infusion of prostacyclin 1 ng/kg/min or placebo. Measurements and Main Results: The main outcome was the number of days alive and without mechanical ventilation within 28 days. Key secondary outcomes were 28-day mortality and serious adverse events within 7 days. Eighty patients were randomized (41 prostacyclin and 39 placebo). The median number of days alive without mechanical ventilation at 28 days was 16.0 days (SD, 12) versus 5.0 days (SD, 10) (difference of the medians, 10.96 days; 95% confidence interval [CI], -5 to 21; P = 0.07) in the prostacyclin and the placebo groups, respectively. The 28-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (risk ratio, 0.50; 95% CI, 0.24 to 0.96; P = 0.06). The incidence of serious adverse events within 7 days was 2.4% versus 12.8% (risk ratio, 0.19; 95% CI, 0.001 to 1.11; P = 0.10) in the prostacyclin and the placebo groups, respectively. Conclusions: Prostacyclin was not associated with a significant reduction in the number of days alive and without mechanical ventilation within 28 days. The point estimates, however, favored the prostacyclin group in all analyses, including 28-day mortality, warranting further investigation in larger trials. Clinical trial registered with www.clinicaltrials.gov (NCT04420741); EudraCT Identifier: 2020-001296-33.

Keywords: COVID-19; endotheliopathy; prostacyclin; thrombomodulin.

Figures

Figure 1.
Figure 1.
Trial profile.
Figure 2.
Figure 2.
Kaplan-Meier curve of 28- and 90-day survival probability according to allocation (prostacyclin vs. placebo group).

References

    1. World Health Organization 2021. Oct 11]. Available from: .
    1. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. RECOVERY Collaborative Group Dexamethasone in hospitalized patients with Covid-19. N Engl J Med . 2021;384:693–704.
    1. Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, Arabi YM, et al. REMAP-CAP Investigators Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med . 2021;384:1491–1502.
    1. Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, et al. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA . 2020;324:1330–1341.
    1. Grasselli G, Cattaneo E, Florio G, Ippolito M, Zanella A, Cortegiani A, et al. Mechanical ventilation parameters in critically ill COVID-19 patients: a scoping review. Crit Care . 2021;25:115.
    1. Carsana L, Sonzogni A, Nasr A, Rossi RS, Pellegrinelli A, Zerbi P, et al. Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study Lancet Infect Dis 2020201135–1140..
    1. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med . 2020;383:120–128.
    1. Dorward DA, Russell CD, Um IH, Elshani M, Armstrong SD, Penrice-Randal R, et al. Tissue-specific immunopathology in fatal COVID-19. Am J Respir Crit Care Med . 2021;203:192–201.
    1. Mangalmurti NS, Reilly JP, Cines DB, Meyer NJ, Hunter CA, Vaughan AE. COVID-19-associated acute respiratory distress syndrome clarified: a vascular endotype? Am J Respir Crit Care Med . 2020;202:750–753.
    1. Goshua G, Pine AB, Meizlish ML, Chang CH, Zhang H, Bahel P, et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol . 2020;7:e575–e582.
    1. Batah SS, Fabro AT. Pulmonary pathology of ARDS in COVID-19: a pathological review for clinicians. Respir Med . 2021;176:106239.
    1. Matthay MA, Leligdowicz A, Liu KD. Biological mechanisms of COVID-19 acute respiratory distress syndrome. Am J Respir Crit Care Med . 2020;202:1489–1491.
    1. Johansen ME, Johansson PI, Ostrowski SR, Bestle MH, Hein L, Jensen AL, et al. Profound endothelial damage predicts impending organ failure and death in sepsis. Semin Thromb Hemost . 2015;41:16–25.
    1. Loghmani H, Conway EM. Exploring traditional and nontraditional roles for thrombomodulin. Blood . 2018;132:148–158.
    1. Robbins SL, Kumar V, Cotran RS. Pathologic basis of disease . 8th ed. Philadelphia: Saunders; 2010.
    1. Mitchell JA, Kirkby NS. Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system. Br J Pharmacol . 2019;176:1038–1050.
    1. Bruggeman LA, Pellicoro JA, Horigan EA, Klotman PE. Thromboxane and prostacyclin differentially regulate murine extracellular matrix gene expression. Kidney Int . 1993;43:1219–1225.
    1. Sussmann M, Sarbia M, Meyer-Kirchrath J, Nüsing RM, Schrör K, Fischer JW. Induction of hyaluronic acid synthase 2 (HAS2) in human vascular smooth muscle cells by vasodilatory prostaglandins. Circ Res . 2004;94:592–600.
    1. Birukova AA, Tian Y, Dubrovskyi O, Zebda N, Sarich N, Tian X, et al. VE-cadherin trans-interactions modulate Rac activation and enhancement of lung endothelial barrier by iloprost. J Cell Physiol . 2012;227:3405–3416.
    1. Kawabe J, Yuhki K, Okada M, Kanno T, Yamauchi A, Tashiro N, et al. Prostaglandin I2 promotes recruitment of endothelial progenitor cells and limits vascular remodeling. Arterioscler Thromb Vasc Biol . 2010;30:464–470.
    1. Chen HH, Chen TW, Lin H. Prostacyclin-induced peroxisome proliferator-activated receptor-alpha translocation attenuates NF-kappaB and TNF-alpha activation after renal ischemia-reperfusion injury. Am J Physiol Renal Physiol . 2009;297:F1109–F1118.
    1. Cheng CF, Lian WS, Chen SH, Lai PF, Li HF, Lan YF, et al. Protective effects of adiponectin against renal ischemia-reperfusion injury via prostacyclin-PPARα-heme oxygenase-1 signaling pathway. J Cell Physiol . 2012;227:239–249.
    1. Zardi EM, Zardi DM, Cacciapaglia F, Dobrina A, Amoroso A, Picardi A, et al. Endothelial dysfunction and activation as an expression of disease: role of prostacyclin analogs. Int Immunopharmacol . 2005;5:437–459.
    1. Bärthel E, Rauchfuss F, Hoyer H, Habrecht O, Jandt K, Götz M, et al. Impact of stable PGI2 analog iloprost on early graft viability after liver transplantation: a pilot study. Clin Transplant . 2012;26:E38–E47.
    1. Beirne C, Hynes N, Sultan S. Six years’ experience with prostaglandin I2 infusion in elective open repair of abdominal aortic aneurysm: a parallel group observational study in a tertiary referral vascular center. Ann Vasc Surg . 2008;22:750–755.
    1. Berthelsen RE, Ostrowski SR, Bestle MH, Johansson PI. Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS)-a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy. Crit Care . 2019;23:301.
    1. Johansson PI, Bestle M, Søe-Jensen P, Kristiansen KT, Stensballe J, Clausen NE, et al. The effect of prostacyclin (Iloprost) infusion at a dose of 1 ng/kg/min for 72 hours compared to placebo in mechanically ventilated patients with COVID-19: a structured summary of a study protocol for a randomized controlled trial. Trials . 2020;21:746.
    1. Ranieri VM, Pettilä V, Karvonen MK, Jalkanen J, Nightingale P, Brealey D, et al. INTEREST Study Group Effect of intravenous interferon β-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: a randomized clinical trial. JAMA . 2020;323:725–733.
    1. Moezinia CJ, Ji-Xu A, Azari A, Horlick S, Denton C, Stratton R. Iloprost for COVID-19-related vasculopathy. Lancet Rheumatol . 2020;2:e582–e583.

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