Endotheliopathy is associated with slower liberation from mechanical ventilation: a cohort study

Abstract

Background Endotheliopathy is suggested as pivotal pathophysiology of sepsis and trauma-associated organ failure, but its role in acute respiratory failure is not yet determined. We investigated if endotheliopathy biomarkers at ICU admission are associated with illness severity and clinical outcomes in patients with acute respiratory failure requiring mechanical ventilation. Methods We conducted a prospective single-center cohort study including 459 mechanically ventilated adults at ICU admission. Plasma levels of three endotheliopathy biomarkers were measured at ICU admission: Syndecan-1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1). The primary outcome was the rate of liberation from mechanical ventilation, which is presented together with the rate of the competing risk of death while still on mechanical ventilation. Secondary outcomes were PaO2/FiO2-ratios on admission and on last measurement in patients dying within five days, and 30-day all-cause mortality. The primary outcome and 30-day all-cause mortality were analyzed using Cox regression, controlled for gender, age, chronic obstructive pulmonary disease, septic shock, heart failure, PaO2/FiO2-ratio at admission, respiratory infection, acute kidney injury, and bilirubin. PaO2/FiO2-ratios were analyzed using linear regression, controlled for age, chronic obstructive pulmonary disease, respiratory infection, and shock. Results Patients with high sTM were liberated from mechanical ventilation at a lower rate (adjusted hazard ratio (HR) 0.71, for an increase from the 25th to the 75th percentile, 95% confidence interval (CI) 0.54–0.93, p = 0.01). Patients with high PECAM-1 were liberated from mechanical ventilation at a lower rate, but only during the first 5 days (adjusted HR 0.72, for an increase from the 25th to the 75th percentile, 95% CI 0.58–0.9, p < 0.01). High levels of Syndecan-1 and PECAM-1 were associated with a higher rate of death while still on mechanical ventilation. sTM and PECAM-1 were negatively associated with PaO2/FiO2-ratio at ICU admission and no biomarker was associated with last measured PaO2/FiO2-ratio. High levels of all biomarkers were associated with higher 30-day all-cause mortality. Conclusion In acute respiratory failure, endotheliopathy biomarkers are associated with lower rates of liberation from mechanical ventilation, hypoxemia at ICU admission, and 30-day all-cause mortality. Graphic Abstract

Novel subgroups in acute respiratory failure based on the trajectories of three endotheliopathy biomarkers: A cohort study

“…This property cannot be formally tested, but based on the known strong associations between the endotheliopathy biomarkers and illness severity, organ dysfunctions, and all-cause mortality, we suspect that it is met in our data. 16,39,48 This is further backed by the finding that the group with missing samples while still in the ICU seemed to be younger and healthier than the group with complete samples (Appendix S3: Table S6). With missing numbers of this magnitude, we can, however, not exclude the possibility that other unknown factors influence the frequency of missingness (data are "missing not at random").…”

“…10 It is often implicitly assumed that serial measurements of a biomarker carry information beyond that of a baseline value. Inconsistent with that belief, we found that the subgroups based on the trajectories of Syndecan-1 and sTM did not change from ICU Days 1 through 3, and therefore added limited value beyond that of the baseline values measured at ICU Day 1. sTM is a well-validated biomarker at baseline, 16,38,39 but in two randomized trials, the intervention was not associated with a decrease in sTM levels despite showing promise for reducing mortality. 40,41 In the latter study, the intervention was associated with a small decrease in Syndecan-1.…”

“…The present study is a secondary, exploratory analysis of Metabolomics, and the main findings have been reported elsewhere. 16 Metabolomics was a prospective, single-center cohort study conducted between November 2016 and June 2019 in the ICU at Copenhagen University Hospital -North Zealand and recruited patients aged 18 years or more, acutely admitted to the ICU, with an expected stay >24 h, who were subject to active treatment.…”

“…9,15 We have previously reported that endotheliopathy at ICU admission is associated with a higher rate of death while intubated and slower liberation from MV in undifferentiated patients with ARF requiring MV. 16 There is, however, no knowledge of the development of endotheliopathy during the first days of ARF. Evidence suggests that the endothelium can be negatively affected by common treatments in the ICU such as positive-pressure ventilation 17,18 and fluid therapy.…”

Markers of endothelial glycocalyx dysfunction in Clarkson disease

“…This is reflected by increased serum levels of markers of endotheliopathy [ 29 ]. Elevated sCD138 and sTM levels predict morbidity and mortality in mechanically ventilated patients [ 30 ]. However, severe and protracted hemoconcentration and hypoalbuminemia are uncommon in these conditions [ 31 ].…”