Abstract
IntroductionPrevious reports suggest that endothelial activation is an important process in sepsis pathogenesis. We investigated the association between biomarkers of endothelial cell activation and sepsis severity, organ dysfunction sequential organ failure assessment (SOFA) score, and death.MethodsThis is a prospective, observational study including adult patients (age 18 years or older) presenting with clinical suspicion of infection to the emergency department (ED) of an urban, academic medical center between February 2005 and November 2008. Blood was sampled during the ED visit and biomarkers of endothelial cell activation, namely soluble fms-like tyrosine kinase-1 (sFlt-1), plasminogen activator inhibitors -1 (PAI-1), sE-selectin, soluble intercellular adhesion molecule (sICAM-1), and soluble vascular cell adhesion molecule (sVCAM-1), were assayed. The association between biomarkers and the outcomes of sepsis severity, organ dysfunction, and in-hospital mortality were analyzed.ResultsA total of 221 patients were included: sepsis without organ dysfunction was present in 32%, severe sepsis without shock in 30%, septic shock in 32%, and 6% were non-infected control ED patients. There was a relationship between all target biomarkers (sFlt-1, PAI-1, sE-selectin, sICAM-1, and sVCAM-1) and sepsis severity, P < 0.05. We found a significant inter-correlation between all biomarkers, including the strongest correlations between sFlt-1 and sE-selectin (r = 0.55, P < 0.001), and between sFlt-1 and PAI-1 (0.56, P < 0.001). Among the endothelial cell activation biomarkers, sFlt-1 had the strongest association with SOFA score (r = 0.66, P < 0.001), the highest area under the receiver operator characteristic curve for severe sepsis of 0.82, and for mortality of 0.91.ConclusionsMarkers of endothelial cell activation are associated with sepsis severity, organ dysfunction and mortality. An improved understanding of endothelial response and associated biomarkers may lead to strategies to more accurately predict outcome and develop novel endothelium-directed therapies in sepsis.
Highlights
Previous reports suggest that endothelial activation is an important process in sepsis pathogenesis
Endothelial cell activation and sepsis severity We found an association between biomarker levels and sepsis severity for soluble fms-like tyrosine kinase-1 (sFlt-1) (P < 0.001 for trend across groups), plasminogen activator inhibitors -1 (PAI-1) (P < 0.001), sE-selectin (P < 0.001), sICAM-1 (P < 0.05), and sVCAM-1 (P < 0.04) (Figure 2)
Using a linear mixed-effects model, adjusting for age, gender, and co-morbid burden, we found the following estimated mean differences in biomarker levels over time comparing the non-survivors to survivors: sFlt-1 366 PAI-1 (ng/mL) sFlt-1 (pg/mL); PAI-1 63.2 ng/ml (38.5 to 87.8, P < 0.01); sE-selectin 24.1 ng/mL (5.5 to 42.7, P < 0.01); sICAM-1 135 ng/mL (67 to 202, P < 0.01); and, sVCAM-1 683 ng/mL (320 to 1,046, P < 0.01)
Summary
Previous reports suggest that endothelial activation is an important process in sepsis pathogenesis. The activation state is manifested by enhanced permeability, increased leukocyte adhesion, a shift in the hemostatic balance towards a procoagulant phenotype, and altered regulation of vasomotor tone These changes likely evolved as an adaptive host response to extravascular pathogens, allowing for increased blood flow to the area of insult, local efflux of plasma proteins and leukocytes, and sequestering of the infection. This activated state may be considered dysfunctional when an overactive endothelium disturbs the homeostatic state instead of restoring it, representing a net liability to the host. Endothelial activation and dysfunction are critical determinants of the host response and, represent a unifying explanation for the complex sepsis pathophysiology, as well as an attractive target for systemic therapy
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