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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

Background: Factors determining referral for advanced heart failure (HF) evaluation are poorly studied. We studied the influence of socioeconomic aspects on the referral process in Denmark, which has a taxpayer-funded national health care system. Methods: We identified all patients aged 18 to 75 years with a first diagnosis of HF during 2010 to 2018. Hospitalized patients had to be discharged alive and were then followed for the outcome of undergoing a right heart catheterization (RHC) used as a surrogate marker of advanced HF work-up. Results: Of 36 637 newly diagnosed patients with HF, 680 (1.9%) underwent RHC during the follow-up period (median time to RHC of 280 days [interquartile range, 73–914]). Factors associated with a higher likelihood of RHC included the highest versus lowest household income quartile (HR, 1.56 [95% CI, 1.19–2.06]; P =0.001), being diagnosed with HF at a tertiary versus nontertiary hospital (HR, 1.68 [95% CI, 1.37–2.05]; P <0.001) and during a hospitalization versus outpatient visit (HR, 1.67 [95% CI, 1.42–1.95]; P <0.001). Level of education, occupational status, and distance to tertiary hospital were not independently associated with RHC. Older age, cancer, and a psychiatric diagnosis were independently associated with a decreased probability of RHC. Conclusions: Higher household income, HF diagnosis during hospitalization, and first admission at a tertiary hospital were associated with increased likelihood of subsequent referral for RHC independent of other demographic and clinical variables. Greater attention may be required to ensure timely referral for advanced HF therapies in lower income groups.

Baseline levels of endotheliopathy are associated with worse respiratory outcomes and mortality in undifferentiated acute respiratory failure (ARF), but knowledge is lacking on the development of endotheliopathy over time in ARF. We, therefore, aimed to evaluate the prognostic significance of trajectories of endotheliopathy during the first days of ARF. We performed a secondary, exploratory analysis of a single‐center prospective cohort including 459 patients requiring mechanical ventilation. Based on Days 1–3 Syndecan‐1, soluble Thrombomodulin (sTM), and Platelet Endothelial Cell Adhesion Molecule‐1 (PECAM‐1), we divided patients into subgroups using latent class mixed modeling and correlated subgroups with clinical outcomes using Cox regression. Based on Syndecan‐1 and sTM, respectively, we identified two subgroups. Based on PECAM‐1, we identified three subgroups. Subgroups based on Syndecan‐1 and sTM were identifiable from the baseline levels, but subgroups based on PECAM‐1 were not. Patients with persistently high levels of both sTM and PECAM‐1 were liberated from mechanical ventilation more slowly (Group high vs. Group low, sTM: hazard ratio [HR]: 0.66, 95% confidence interval [CI]: 0.50–0.88, p = .01, PECAM‐1: HR: 0.59, 95% CI: 0.37–0.93, p = .02) and had higher 30‐day mortality (sTM: HR: 1.90, 95% CI: 1.20–3.01, p = .01, PECAM‐1: HR: 4.25, 95% CI: 1.99–9.07, p < .01). In ARF requiring mechanical ventilation, patients in subgroups with persistently high levels of sTM and PECAM‐1 had lower rates of liberation from mechanical ventilation and higher 30‐day mortality. However, patients with persistently high levels of sTM were identifiable based on the baseline level, and only the trajectory of PECAM‐1 added information to that of the baseline level.