Soluble Fms-Like Tyrosine Kinase-1 Associates With Risk of Acute Respiratory Distress Syndrome and Mortality in Sepsis

IMPORTANCE: The vascular endothelial growth factor (VEGF) signaling pathway is important in the pathogenesis of acute respiratory distress syndrome (ARDS) with supportive genetic and proteomic evidence. Genetic polymorphisms within FLT1 , which encodes VEGF receptor 1, associate with risk of ARDS in sepsis. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is a secreted splice variant of FLT1 that acts as a potent antagonist to circulating VEGF. OBJECTIVES: To assess the association between early plasma concentrations of sFlt-1 and risk of ARDS and to determine if ARDS mediates the relationship between sFlt-1 and mortality during sepsis. DESIGN, SETTING, AND PARTICIPANTS: In a prospective cohort study, we enrolled 198 critically ill patients with sepsis per Sepsis-2 criteria. ARDS was defined per Berlin criteria. MAIN OUTCOMES AND MEASURES: Levels of sFlt-1 were quantified using electrochemiluminescence on plasma collected in the emergency department upon admission. We tested the association between plasma levels of sFlt-1 with ARDS and mortality using logistic regression adjusting for age, sex, and pulmonary versus nonpulmonary source of sepsis. We applied causal mediation analysis to determine the percentage of the total effect of sFlt-1 on mortality that was mediated by ARDS. RESULTS: We enrolled 198 patients; ARDS developed within 6 days in 29%. Plasma levels of sFlt-1 were significantly associated with risk of ARDS in sepsis (odds ratio [OR], 1.91 per log increase; 95% CI, 1.31–2.76 per log increase; p < 0.01). Plasma sFlt-1 levels were also associated with mortality (OR, 2.19 per log increase; 95% CI, 1.57–3.08 per log increase; p < 0.01). ARDS mediated 20.3% (95% CI, 6.9–98.1%) of the total effect of sFlt-1 on mortality ( p < 0.01). CONCLUSIONS AND RELEVANCE: Higher plasma levels of sFlt-1 were associated with an increased risk of ARDS and ARDS mediated a significant proportion of the sFlt-1-associated mortality observed during sepsis. Our findings further implicate dysregulated VEGF signaling in ARDS and suggest that plasma sFlt-1 merits further investigation as an early endothelial therapeutic target for sepsis-associated ARDS and mortality.