Anne Buercky ¹ Jessica Roos ^1,2 Anja Urbschat ³ Ulrike Heinicke ¹ Carlo Angioni ⁴ Dieter Steinhilber ⁵ Matthias Piesche ⁶ Nerea Ferreirós ⁴ Robert Gurke ⁴ Gerd Geisslinger ⁴ Edith Utech ¹ Kai Zacharowski ¹ Patrick Meybohm ⁷ Patrick Paulus ⁸ Schmitt Elke ^1,9 Thorsten J. Maier ^1,2*

• ¹ Clinic for Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt, Hesse, Germany
• ² Paul-Ehrlich-Institut (PEI), Langen, Germany
• ³ Aarhus University, Aarhus, Central Denmark Region, Denmark
• ⁴ Institute of Clinical Pharmacology Goethe-University Frankfurt, Frankfurt, Germany
• ⁵ Institute of Pharmaceutical Chemistry, Faculty of Biochemistry, Chemistry and Pharmacy, Goethe University Frankfurt, Frankfurt am Main, Hesse, Germany
• ⁶ Biomedical Research Laboratories, Medicine Faculty, Universidad Católica del Maule, Talca, Chile
• ⁷ Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine University Hospital Wuerzburg, Würzburg, Germany
• ⁸ Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Styria, Austria
• ⁹ Institute for Biostatistics and Mathematical Modeling, University Hospital Frankfurt, Frankfurt, Hesse, Germany

Critically ill patients suffer from a wide variety of clinical events, most of them leading to pro-inflammatory states such as sepsis or simply as consequence of major surgery. Many of these patients develop forms of acute kidney injury, heart or acute liver failure during intensive care. Lipid signaling is critically involved in triggering systemic inflammation processes, pain and vascular tone. We therefore hypothesized that fatty-acid-derived lipid mediators might be regulated during inflammatory stages and other clinical events in critically ill patients and might serve as potential biomarker candidates. : Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we determined the levels of 53 lipid mediators in plasma from nine patients. These patients were hospitalized at Frankfurt University Hospital’s intensive care unit (ICU) after cardiac surgery. Inflammatory stages were illustrated over time using clinically established biomarkers such as interleukin-6 (IL-6) and leukocyte count. Normal range values of the lipids were otained from healthy volunteers. Plasma levels clearly outside the normal range were observed for 22 of 53 lipid mediators, of which 13 were increased (including ceramides Cer (d18:0/18:0), Cer (d18:1/16:0), Cer (d18:1/18:1), glucosyl-ceramide GluCer (d18:1/24:1), lactosylceramide LacCer (d18:1), and LacCer (d18:3/24:1), 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), 11,12- and 14,15-DHET and 1- and 2-arachidonoyl glycerol (1-AG and 2-AG), Sphingosine SPH (d18:1) and 20-HETE. Furthermore, nine lipids were decreased (Cer (d18:1/24:0), LacCer (d18:1/16:0), LacCer (d18:1/24:0), sphingosine-1-phosphate S1P (d18:1), S1P (d18:0), the lysophosphatidic acids LPA (16:0), LPA (18:0), LPA (18:1) and 9-HODE. Among increased lipids, the remarkable changes in 1-AG, 2-AG, and to a lower extent of 6-keto-PGF1-alpha plasma levels showed a certain agreement with inflammatory phases. Furthermore, 6-keto-PGF1alpha had its peak shortly before initiation of continuous veno-venous hemodialysis (at least in 5 of the observed patients), 2-AG was elevated in all our nine patients during (right) heart failure in the context of either re-opening patient’s chest, implementation of veno-arterial ECMO or at least while significantly increasing the amount of catecholamines. In this pilot trial we identified several evaluated lipids in critically ill patients representing either potentially (patho-) physiologically relevant mediators of the pro-inflammatory processes and during heart failure or possible markers preceding veno-venous hemodialysis.