Elsevier

Cytokine

Volume 69, Issue 2, October 2014, Pages 240-247
Cytokine

Elevated biomarkers of endothelial dysfunction/activation at ICU admission are associated with sepsis development

https://doi.org/10.1016/j.cyto.2014.06.010Get rights and content

Highlights

  • The role of endothelial biomarkers in the timely diagnosis of sepsis was evaluated.

  • Circulating E- and P-selectin at ICU admission are related to sepsis development.

  • We sought means to detect sepsis before it is clinically manifested.

Abstract

Widespread endothelial activation and dysfunction often precede clinical sepsis. Several endothelium-related molecules have been investigated as potential biomarkers for early diagnosis and/or prognosis of sepsis, providing different results depending on study designs. Such factors include endothelial adhesion molecules like E- and P-selectin, and the intercellular adhesion molecule-1, vascular endothelial cadherin, growth factors such as Angiopoietin-1 and -2 and vascular endothelial growth factor, as well as von Willebrand factor antigen. We sought to investigate whether circulating biomarkers of endothelial activation/dysfunction measured at ICU admission are associated with subsequent sepsis development.

Eighty-nine critically-ill patients admitted to a general ICU who met no sepsis criteria were studied. Plasma or serum levels of the above-mentioned endothelium-derived molecules were measured during the first 24 h post ICU; acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores, age, sex, diagnostic category, and circulating procalcitonin (PCT) and C-reactive protein (CRP) levels were additionally measured or recorded.

Forty-five patients subsequently became septic and 44 did not. Soluble (s) E- and P-selectin levels, circulating PCT, SOFA score and diagnostic category were significantly different between the two groups. Multiple logistic regression analysis associated elevated sE- and sP-selectin levels and SOFA with an increased risk of developing sepsis, while multiple Cox regression analysis identified sE- and sP-selectin levels as the only parameters related to sepsis appearance with time [RR = 1.026, 95%CI = 1.008–1.045, p = 0.005; RR = 1.005 (by 10 units), 95%CI = 1.000–1.010, p = 0.034, respectively]. When trauma patients were independently analyzed, multiple Cox regression analysis revealed sE-selectin to be the only molecule associated with sepsis development with time (RR = 1.041, 95%CI: 1.019–1.065; p < 0.001).

In conclusion, in our cohort of initially non-septic critically-ill patients, high levels of the circulating endothelial adhesion molecules E- and P-selectin, measured at ICU admission, appear to be associated with sepsis development in time.

Introduction

The vascular endothelium is composed of a single layer of squamous cells that cover the inner surface of blood vessels. While in the past it was believed to be nothing more than an inert divider, in the last decades it has been found that the endothelium is a separate, highly metabolically active organ that plays an important role in organogenesis, tissue homeostasis and immune response [1], [2], [3].

Excessive and sustained activation of the endothelium resulting in increased vascular permeability is a crucial process during sepsis [4], [5]. The septic syndrome is characterized by a systemic inflammatory response in the effort of the organism to eliminate/control infections [6]. A common element of severe infections is the very acute, potent and generalized activation of the immune and hemostatic system [3], [7]. This may result in extensive inflammation and vascular thrombosis, a microcirculatory disorder that has as a consequence the disruption of smooth blood flow and hence oxygen toward the cells [3], [5], [7].

Despite the significant progress of the last decades in the investigation of sepsis mechanisms, mortality due to severe sepsis remains high. Recent data pinpoint endothelial dysfunction as a very important pathogenetic factor [8]. Endothelial activation often precedes endothelial dysfunction, and a large number of endothelial cell (EC) active molecules have been investigated as potential biomarkers for the early diagnosis and prognostication of sepsis [9]. These biomarkers include regulators of endothelial activation, adhesion molecules, as well as mediators of permeability, vasomotor tone, and coagulation [4]. However, as yet there is no generally acceptable way of either diagnosing endothelial dysfunction at its early phase or associating the latter with the septic process [10].

The aim of this study was to determine the role of endothelial biomarkers in the timely diagnosis of sepsis. We evaluated whether elevated levels of circulating endothelial biomarkers of critically-ill patients upon admission to the Intensive Care Unit (ICU) can predict sepsis before it is clinically manifested, so the appropriate therapeutic handlings can be performed at an early phase in an effort to achieve optimal treatment.

Section snippets

Materials and methods

The study was approved by the Evangelismos Hospital Research Ethics Committee and all procedures carried out on patients were in compliance with the Helsinki Declaration. Informed written consent was obtained from all patients’ next-of-kin prior to any study procedure.

Theory/calculation

The majority of studies have reported higher levels of sE-selectin in sepsis compared to healthy controls or other patient groups without sepsis. Since E-selectin is exclusively expressed on activated endothelial cells and no biomarker of endothelial activation/dysfunction has so far been shown to provide consistent clinical utility as either a diagnostic or prognostic indicator in sepsis, we pursued the early patterns of sE-selectin, sP-selectin and other endothelium-related molecules in

Characteristics of the study population

Among the 89 critically-ill adult patients studied, approximately one third were female. The mean patient age in our sample was 46 years (range 18–89 years). The mean admission acute physiology and chronic health evaluation (APACHE) II score was 12.71 ± 4.97 and the mean admission sequential organ failure assessment (SOFA) score was 5.66 ± 2.61. The overall ICU mortality rate amongst our enrolled patients was 6.74%. About 81% of the patients met SIRS criteria at ICU admission. Sepsis subsequently

Discussion

To the best of our knowledge this is the first study that examines patterns of multiple endothelium-related indices in patients with no criteria for sepsis at ICU entry, in an effort to predict sepsis development. Our results indicate that high levels of soluble E-selectin and P-selectin upon ICU admission are higher in critically-ill patients who are going to develop sepsis compared to the patients who will not.

Since early widespread endothelial dysfunction and/or damage appear to be directly

Conclusion

Studies until now have shown elevated sE-selectin levels in septic patients compared to healthy controls and in non survivors compared to survivors. We have now demonstrated that increased sE- and sP-selectin levels differentiate critically-ill initially non-septic patients at ICU admission who will subsequently become septic, probably reflecting the ongoing endothelial dysfunction prior to the clinical presence of sepsis.

Competing interests

None declared.

Source of Funding

This work was funded by the nonprofit institute “THORAX” Research Center for Intensive and Emergency Thoracic Medicine, Athens, Greece.

Author’s contributions

AGV designed and conducted experiments and drafted the manuscript. ZM collected and processed specimens and recorded patient data. SEO designed and supervised the study and edited the manuscript. EJ collected and processed specimens and recorded patient data. NAM designed the study and drafted the manuscript. AK analyzed data and edited the manuscript. AA edited the manuscript and provided valuable input to study design. AK designed the study, collected specimens, supervised patient enrolment,

Acknowledgements

The authors would like to thank Ms. Christina Sotiropoulou, MSc for conducting the statistical analysis. We would also like to thank the nursing staff of the “Evangelismos” Hospital ICU for their assistance.

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