Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: a prospective observational study

Abstract

IntroductionDespite recent advances in the management of septic shock, mortality rates are still unacceptably high. Early identification of the high-mortality risk group for early intervention remains an issue under exploration. Vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR1) and urokinase plasminogen activator (uPA) have diverse effects in the pathogenesis of sepsis, which involve pro-inflammation, anti-inflammation, endothelial cell repair, and vascular permeability change. Their roles in predicting mortality and organ dysfunction remain to be clarified.MethodsPneumonia-related septic shock patients from medical intensive care units were enrolled for this prospective observational study. We also included 20 patients with pneumonia without organ dysfunction for comparison. Plasma levels of VEGF and sVEGFR1 and uPA activity within 24 hours of shock onset were measured. We compared plasma levels of these biomarkers with APACHE II scores between subgroups of patients, and evaluated their predictive value for 28-day mortality and organ dysfunction.ResultsA total of 101 patients, including 81 with pneumonia-related septic shock and 20 with pneumonia without organ dysfunction, were enrolled. Non-survivors of septic shock had significantly higher plasma sVEGFR1 levels (659.3 ± 1022.8 vs. 221.1 ± 268.9 pg/mL, respectively, P < 0.001) and uPA activity (47.2 ± 40.6 vs. 27.6 ± 17.2 units, respectively, P = 0.001) when compared with those of the survivors. Kaplan-Meier survival analysis demonstrated significantly higher mortality in patients with higher levels of sVEGFR1 (P < 0.001) and uPA activity (P = 0.031). In Cox regression analysis, plasma sVEGFR1 level was independently associated with, and best predicted, the 28-day mortality of septic shock (HR: 1.55, 95% CI: 1.05-2.30). Plasma sVEGFR1 level and uPA activity had good correlation with renal dysfunction, metabolic acidosis, and hematologic dysfunction; their levels significantly increased when the number of organ dysfunctions increased. In multivariate analysis, plasma sVEGFR1 level (HR: 2.82, 95% CI: 1.17-6.81) and uPA activity (HR: 2.75, 95% CI: 1.06-7.13) were independent predictors of the presence of concomitant multi-organ dysfunction. The predictive value of VEGF for mortality and organ dysfunction was limited in pneumonia-related septic shock patients.ConclusionsHigh plasma sVEGFR1 level in the early stage of pneumonia-related septic shock independently predicted 28-day mortality and multi-organ dysfunction.

Biomarkers of endothelial activation/dysfunction in infectious diseases

“…However, this difference did not remain significant in a multivariate analysis. sFlt-1 has been studied in 81 adult patients with septic shock due to pneumonia, and found to be predictive of 28-d mortality 94 . Plasma levels of sFlt-1, but not VEGF, were significantly higher in non-survivors than survivors.…”

Biomarkers of endothelial dysfunction: can they help us deciphering systemic inflammation and sepsis?

“…uPA activity was also considered as an independent marker of renal and hematologic dysfunction as well as metabolic acidosis. With increase of the number of failing organs, the uPA activity also increased (Yang et al 2011).…”

“…At the same time, the physiologic counter-regulation via VEGF scavenging by soluble Flt-1 is induced. Therefore, Flt-1 represents an interesting biomarker candidate, recently demonstrated in 101 patients (Yang et al 2011). High plasma sFlt-1 levels significantly correlated with pneumonia-related septic shock and negative 28-day survival with median values of 659 pg/mL.…”

“…They are described to be involved in the inflammatory process and endothelial cell migration. Moreover, uPA seems to play a critical role in the VEGF-induced vascular permeability change (Yang et al 2011). Under physiological conditions, PAI-1 is released into the circulation and the extracellular space by liver cells, smooth muscle cells, adipocytes, and platelets.…”

Pharmacological Efficiency of Statins and L-Norvalin at an Endotoxin-Induced Endothelial Dysfunction

“…The vascular endothelial is a place for realization of normal and pathological immune and biochemical reactions proceeding with participation of mediators of inflammatory reaction, nitrogen oxide and its metabolites, active radicals of oxygen, etc. at the endotoxin-induced endothelial dysfunction (EIED) [4,5,6,7,8,9,10].…”