key: cord-1024732-xjtzm2rj authors: Serbanescu-Kele Apor de Zalán, Christiaan M.C.; Foudraine, Norbert A.; Le Noble, Jos L.M.L. title: Inhaled iloprost can improve oxygenation and shunt fraction in severe COVID-19 date: 2022-02-22 journal: Acute Crit Care DOI: 10.4266/acc.2021.01263 sha: e702ba1083848816ca3cfba874e2930031680584 doc_id: 1024732 cord_uid: xjtzm2rj nan Data are provided as median and interquartile range (IQR) or mean and standard deviation, and were compared using a paired t-test or Wilcoxon's test, as appropriate (significance threshold, P<0.05). In total, eight patients met the inclusion criteria. Their median age was 72.5 years (IQR, 67.3-73.8 years); six patients were male. The median positive end-expiratory pressure was 12 cm H 2 O (IQR, 10−16 cm H 2 O); the median OI was 17.8 (IQR, 14.9−20.7), and the median PaO 2 to FiO 2 (P/F) ratio was 75.8 (IQR, 69.6-97.0). Iloprost was started at a median of 23 days (IQR, 14-29.5 days) after onset of symptoms and 12 days (IQR, 9−20 days) after intubation. Up to three measurement sets were performed per patient, resulting in a total of 18 (Table 1) . When only the first set of measurements were considered for each patient (n = 8), the median P/F ratio increased from 75.8 to 96.0 mm Hg (IQR, 69.6-97.0 vs. 78.4-144.4; P=0.012), the mean OI decreased from 17.3 to 14.4 (P=0.007; absolute and relative changes are shown in Figure 1A ), and the mean Qs/Qt decreased from 43.6% to 37.5% (P=0.025) ( Figure 1B ). Considering all sets of measurements, the median P/F ratio increased from 93.5 to 105.0 mm Hg (IQR, 69.9-118.5 vs. 78.9-148.8; P<0.001), the mean OI decreased from 16.3 to 13.8 (P<0.001) (Supplementary Figure 1A) , and the Qs/Qt decreased from 44.2% to 36.9% (P=0.001) (Supplementary Figure 1B) . The relationships between changes in Qs/Qt and OI are shown in Figure 2 . Two patients developed transient hemodynamic side effects: one patient had a drop in systemic vascular resistance, while the other experienced a decrease in left ventricular preload, evidenced by decreased capillary wedge pressure. Our findings provide proof-of-concept that inhaled iloprost can improve oxygenation by decreasing the shunt fraction in mechanically ventilated patients with severe COVID-19 ARDS. To our knowledge, the effects of inhaled iloprost on shunt fraction in severe COVID-19 have not been previously described. These effects of iloprost on oxygenation reflect those described by Sonti et al. [4] after administration of inhaled epoprostenol. However, shunt fraction was not reported, and Tsareva's study [5] included measurements at widely varying intervals. Tsareva et al. [5] found improved oxygenation after 5 days of treatment with iloprost, suggesting a possible disease-modifying effect. However, their patients were not critically ill, and shunt fraction was not described. Interestingly, right-to-left shunt fraction at baseline varied widely (19%-70%), possibly reflecting different disease phenotypes in COVID-19. Furthermore, although most patients showed improved oxygenation after administration of iloprost, some had only a relatively shortlived response, advocatingthe use of more frequent or continuous nebulization. We used inhaled iloprost exclusively as a rescue therapy in patients in whom other interventions failed, which might have led us to include only the sickest patients. In such patients, consolidative and even fibrotic changes might have shown predominance over the vasculopathy that is thought to dominate hypoxemia in early COVID-19 (i.e., our patients might have already been in the H-stage, as proposed by Gattinoni et al. [1] , wherein progressive parenchymal damage results in low compliance and a lesser role of vasoplegia). From a pathophysiologic point of view, inhaled pulmonary vasodilators should have maximum effect during the L-stage, in which hypoxemia is thought to result primarily from ventilation/perfusion mismatch. Iloprost might have disease-modifying effects, by mediating platelet activation, endothelial damage, and pulmonary inflammation. The retrospective nature of our study, its relatively small sample size, and the heterogenous patient population that Future studies should aim to determine the category of COVID-19 patients that responds best to inhaled pulmonary vasodilators. In addition, measuring pulmonary hemodynamic parameters might contribute to further understanding of COVID-19 pathophysiology. In conclusion, we found that inhaled iloprost can improve oxygenation in severe COVID-19 by decreasing shunt fraction. No potential conflict of interest relevant to this article was reported. AUTHOR CONTRIBUTIONS Conceptualization: all authors. Data curation: CMCSAZ. Formal analysis: CMCSAZ. Methodology: all authors. Project administration: JLMLLN, CMCSAZ. Visualization: CMCSAZ. Writing-original draft: CMCSAZ, JlN. Writing-review COVID-19 Does not lead to a "typical" acute respiratory distress syndrome Iloprost inhib-its neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers Thrombocytopathy and endotheliopathy: crucial contributors to COVID-19 thromboinflammation Responsiveness of inhaled epoprostenol in respiratory failure due to COVID-19 Inhaled iloprost improves gas exchange in patients with COVID-19 and acute respiratory distress syndrome We are grateful to our intensive care unit nurses, physicians and other staff. Without their help and expertise, the present study would not have been possible. We are specifically grateful for the contributions of Dr. O. Thomas in drafting the treatment protocol.