Pro- and Anti-Inflammatory Responses and Clinical Outcomes in Critically Ill Patients With Endotheliopathy: A Cohort Study

Abstract

Background: Multiple organ dysfunction syndrome (MODS) in critical illness involves dysregulated immune and inflammatory responses, endotheliopathy, and coagulation activation. We investigated how three types of endotheliopathy biomarkers relate to pro- and anti-inflammatory responses and clinical outcomes in intensive care unit (ICU) patients.

Methods: In this secondary, explorative analysis of a prospective single-centre cohort (n = 459), we assessed associations between endotheliopathy biomarkers (syndecan-1, soluble thrombomodulin (sTM), platelet endothelial cell adhesion molecule-1 (PECAM-1)) and inflammatory biomarkers (pro-inflammatory: IFN-ϒ, IL-1β, IL-2, IL-6, IL-8, IL-12p70, TNF-α; anti-inflammatory: IL-4, IL-10, IL-13) at ICU admission using linear regression. Associations with 30-day clinical outcomes were analysed using linear and Cox regression. All models were adjusted for age, sex, septic shock, pre-ICU surgery and chronic disease.

Results: Higher levels of all three endotheliopathy biomarkers were associated with higher levels of inflammatory biomarkers. PECAM-1, however, showed no significant association with IFN-ϒ, IL-1β and IL-12p70. IL-4 was excluded from linear regression due to > 50% imputed values. Higher levels of all three endotheliopathy biomarkers were significantly associated with increased mean and maximum modified Sequential Organ Failure Assessment (mSOFA) scores over 30 days, as well as with renal, hepatic, and coagulation failure, and 30-day all-cause mortality. Only sTM was significantly associated with cardiovascular failure; none were significantly associated with respiratory failure. Higher levels of sTM were associated with the highest levels of inflammatory biomarkers, the largest increases in mean and maximum mSOFA scores, and the highest hazard ratios for organ failure and 30-day all-cause mortality, compared with syndecan-1 and PECAM-1.

Conclusion: In this cohort of critically ill ICU patients, endotheliopathy was associated with (1) higher levels of pro- and anti-inflammatory biomarkers at ICU admission and (2) MODS, single organ failure, and 30-day all-cause mortality. Among the three endotheliopathy biomarkers, sTM demonstrated the most consistent and strongest associations with both inflammatory biomarkers and clinical outcomes. These findings are exploratory and should be interpreted as hypothesis-generating.

Editor's comment: In this analysis of different biomarkers in a critically ill cohort, associations are demonstrated between markers related to endothelial stress, cytokines related to modulation of inflammation, and severity of illness scores.

FIGURE 1

Flowchart of the inclusion‐ and exclusion process. §Missing measurements of the inflammatory biomarkers, resulting from an analytical error in the laboratory. The eight patients are considered missing completely at random (MCAR) due to the nature of the error. §§The study cohort presented here has 80% overlap with the cohort (n = 459) presented in the papers by Schønemann‐Lund et al. [25, 47], but it is not identical.