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Objectives Paediatric acute respiratory distress syndrome (PARDS) is a heterogeneous condition and identifying a specific biomarker remains a challenge. We aimed to validate the association of plasma soluble receptor for advanced glycation end-products (sRAGE) and angiopoietin-2 (Ang-2) with PARDS diagnosis, and its prognostic performance.Methods This prospective observational study included children with PARDS and non-PARDS critical illness. Plasma sRAGE and Ang-2 levels were measured using enzyme-linked immunosorbent assays. Comparisons were made between PARDS versus non-PARDS critical illness and survivors versus non-survivors. Multivariable logistic regression was used to determine the association between biomarkers and intensive care unit (ICU) mortality after adjusting for age and the Pediatric Index of Mortality 3 score.Results 93 and 117 patients with PARDS and non-PARDS critical illness, respectively, were included in this study. Plasma sRAGE was higher in PARDS versus non-PARDS critical illness (2981 (1027 to 6198) vs 1575 (864 to 2994) pg/mL; p=0.002) and in non-survivors vs survivors (5323 (1647 to 8261) vs 1601 (864 to 3572); p<0.001). Plasma Ang-2 was elevated in non-survivors versus survivors (3054 (1760 to 6808) vs 1748 (845 to 3868); p=0.002), though there was no difference between PARDS and non-PARDS groups. In the multivariable model, sRAGE demonstrated an independent association with PARDS diagnosis (adjusted OR (aOR) 1.01 95% CI 1.01 to 1.02; p=0.003) and ICU mortality (aOR 1.02 (95% CI 1.01 to 1.03); p<0.001), whereas there was no association observed with Ang-2.Conclusion Within an ICU cohort, only sRAGE demonstrated an association with the diagnosis of PARDS and ICU mortality, which remained after controlling for confounders.