Therapeutic iloprost for the treatment of acute respiratory distress syndrome (ARDS) (the ThIlo trial): a prospective, randomized, multicenter phase II study

Abstract

Background: Acute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS. Methods: The Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO 2 /FiO 2 . Secondary endpoints include 90day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany. Discussion: The results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS.

The Role of Innate Immunity and Bioactive Lipid Mediators in COVID-19 and Influenza

“…For example, while prostaglandin E2 is frequently regarded as pro-inflammatory mediator, several recent studies have underlined its anti-inflammatory and tissue regenerative functions ( FitzGerald, 2015 ; Duffin et al, 2016 ). Along these lines, a recent phase II trial by Haeberle et al is testing the synthetic prostacyclin (PGI2) analog iloprost for the treatment of ARDS ( Haeberle et al, 2020 ). Moreover, just recently, the omega-6 PUFA adrenic acid and its derivatives have been shown to exert anti-inflammatory properties ( Brouwers et al, 2020 ).…”

COVID-19 acute respiratory distress syndrome: can iloprost have a role for the treatment?

“…An application of inhaled iloprost is noted in the guidelines of the Association of the Scientific Medical Societies for the treatment of ARDS, and in inhalation injury-ARDS appears safe and was associated with a statistically significant improvement in oxygenation [ 2 , 3 , 4 , 5 ]. These effects could be due to the enhanced perfusion preferentially to well-ventilated lung regions with reduction of pulmonary pressures in peripheral vessels and interstitial inflammatory edema.…”

“…Moreover, the iloprost antithrombotic effect, endothelial damage repairing and neoangiogenetic activity [ 2 , 3 , 4 , 5 , 11 ] could play a role in the thrombotic events COVID-19 correlated.…”

“…COVID-19 infection is frequently complicated with pulmonary embolism, arterial ischemia and venous thrombosis of limbs and myocarditis or arrhythmia. Some clinical study documented improvement of gas exchange in ARDS with inhaled iloprost [ 2 , 3 , 4 , 5 ].…”

Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome

“…Beneficial effects similar to iNO were reported for inhaled aerosolised PGI 2 , although it was only tested in small cohorts of ARDS [42]. General use of inhaled PGI 2 is currently not recommended; however, the ThIlo study (NCT03111212), a prospective, randomised, multicentre trial, is currently recruiting patients to evaluate the effects of PGI 2 in a larger cohort [154].…”