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

Martin Schønemann-Lund,Johan E Larsson,Pär I Johansson,Birgitte Lindegaard,Theis S Itenov,Morten H Bestle

doi:10.1186/s13054-021-03877-y

Abstract

BackgroundEndotheliopathy 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.MethodsWe 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.ResultsPatients 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.ConclusionIn 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

Highlights

Endotheliopathy is suggested as pivotal pathophysiology of sepsis and trauma-associated organ fail‐ ure, but its role in acute respiratory failure is not yet determined
All patients were critically ill with a median simplified acute physiology score 3 (SAPS 3) of 65 (IQR 56–75). 95% of patients presented with failure of more than one organ as defined by a Sequential Organ Failure Assessment (SOFA) subscore of ≥ 2 in > 1 of the respiratory, circulatory, central nervous system, kidney, or liver sub-scores (Table 1). 30.7% received NIV and 69.3 received invasive ventilation at baseline
When analyzing the endotheliopathy biomarkers as continuous variables, we found that patients with higher levels of Syndecan-1 (HR 0.84 for an increase from the 25th to the 75th percentile [95% 95% confidence interval (CI) 0.72–0.99, p = 0.03]), Soluble Thrombomodulin (sTM) (HR 0.57 for an increase from the 25th to the 75th percentile [95% confidence intervals (95% CI) 0.46–0.72, p < 0.01]) and Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) (HR 0.8 for an increase from the 25th to the 75th percentile [95% CI 0.69–0.93, p < 0.01]) had lower rates of liberation from mechanical ventilation (MV) before adjustment

Summary

Introduction

Endotheliopathy is suggested as pivotal pathophysiology of sepsis and trauma-associated organ fail‐ ure, 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. Endotheliopathy may be unifying pathophysiology in acute, critical illness, linking different primary pathologies with the common outcome of multiple organ failure [8,9,10]. Endothelial cells and their luminal coating—the glycocalyx—are crucial for maintaining vascular membrane integrity [11], and one of the defining features of Acute Respiratory Distress Syndrome (ARDS) is fluid leak from the alveolar capillaries [12]. Syndecan-1, a proteoglycan part of the endothelial glycocalyx [11, 13], is one of the most studied biomarkers of glycocalyx shedding [11], and levels in blood are increased in multiple disease states [13]

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