Plasma biomarker analysis in pediatric ARDS: Generating future framework from a pilot randomized control trial of methylprednisolone: A framework for identifying plasma biomarkers related to clinical outcomes in pediatric ARDS
© 2016 Kimura, Saravia, Rovnaghi, Meduri, Schwingshackl, Cormier and Anand. Objective: Lung injury activates multiple pro-inflammatory pathways, including neutrophils, epithelial, and endothelial injury, and coagulation factors leading to acute respiratory distress syndrome (ARDS). Low-dose methylprednisolone therapy (MPT) improved oxygenation and ventilation in early pediatric ARDS without altering duration of mechanical ventilation or mortality. We evaluated the effects of MPT on biomarkers of endothelial [Ang-2 and soluble intercellular adhesion molecule-1 (sICAM-1)] or epithelial [soluble receptor for activated glycation end products (sRAGE)] injury, neutrophil activation [matrix metalloproteinase-8 (MMP-8)], and coagulation (plasminogen activator inhibitor-1). Design: Double-blind, placebo-controlled randomized trial. Setting: Tertiary-care pediatric intensive care unit (ICU). Patients: Mechanically ventilated children (0-18 years) with early ARDS. Interventions: Blood samples were collected on days 0 (before MPT), 7, and 14 during low-dose MPT (n = 17) vs. placebo (n = 18) therapy. The MPT group received a 2-mg/kg loading dose followed by 1 mg/kg/day continuous infusions from days 1 to 7, tapered off over 7 days; placebo group received equivalent amounts of 0.9% saline. We analyzed plasma samples using a multiplex assay for five biomarkers of ARDS. Multiple regression models were constructed to predict associations between changes in biomarkers and the clinical outcomes reported earlier, including P/F ratio on days 8 and 9, plateau pressure on days 1 and 2, PaCO 2 on days 2 and 3, racemic epinephrine following extubation, and supplemental oxygen at ICU discharge. Results: No differences occurred in biomarker concentrations between the groups on day 0. On day 7, reduction in MMP-8 levels (p = 0.0016) occurred in the MPT group, whereas increases in sICAM-1 levels (p = 0.0005) occurred in the placebo group (no increases in sICAM-1 in the MPT group). sRAGE levels decreased in both MPT and placebo groups (p < 0.0001) from day 0 to day 7. On day 7, sRAGE levels were positively correlated with MPT group PaO 2 /FiO 2 ratios on day 8 (r = 0.93, p = 0.024). O 2 requirements at ICU transfer positively correlated with day 7 MMP-8 (r = 0.85, p = 0.016) and Ang-2 levels (r = 0.79, p = 0.036) in the placebo group and inversely correlated with day 7 sICAM-1 levels (r = -0.91, p = 0.005) in the MPT group. Conclusion: Biomarkers selected from endothelial, epithelial, or intravascular factors can be correlated with clinical endpoints in pediatric ARDS. For example, MPT could reduce neutrophil activation ([downwards double arrow]MMP-8), decrease endothelial injury (⇔sICAM-1), and allow epithelial recovery ([downwards double arrow]sRAGE). Large ARDS clinical trials should develop similar frameworks.
Publication Source (Journal or Book title)
Frontiers in Pediatrics
Kimura, D., Saravia, J., Rovnaghi, C., Meduri, G., Schwingshackl, A., Cormier, S., & Anand, K. (2016). Plasma biomarker analysis in pediatric ARDS: Generating future framework from a pilot randomized control trial of methylprednisolone: A framework for identifying plasma biomarkers related to clinical outcomes in pediatric ARDS. Frontiers in Pediatrics, 4 (MAR) https://doi.org/10.3389/fped.2016.00031