title: 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.
abstract: 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).
  
  
  METHODS
  Double-blind, placebo-controlled randomized trial.
  
  
  METHODS
  Tertiary-care pediatric intensive care unit (ICU).
  
  
  METHODS
  Mechanically ventilated children (0-18 years) with early ARDS.
  
  
  METHODS
  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, PaCO2 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 PaO2/FiO2 ratios on day 8 (r = 0.93, p = 0.024). O2 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.
  
  
  CONCLUSIONS
  Biomarkers selected from endothelial, epithelial, or intravascular factors can be correlated with clinical endpoints in pediatric ARDS. For example, MPT could reduce neutrophil activation (⇓MMP-8), decrease endothelial injury (⇔sICAM-1), and allow epithelial recovery (⇓sRAGE). Large ARDS clinical trials should develop similar frameworks.
  
  
  BACKGROUND
  https://clinicaltrials.gov, NCT01274260.
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Pediatrics, Le Bonheur Children's Hospital, Memphis, TN, USA; Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, TN, USA.
authors.forename: Dai
authors.initials: D
authors.lastname: Kimura
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Pediatrics, Le Bonheur Children's Hospital, Memphis, TN, USA; Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, TN, USA.
authors.forename: Jordy
authors.initials: J
authors.lastname: Saravia
authors.affiliation: Pain Neurobiology Laboratory, Stanford University , Palo Alto, CA , USA.
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Rovnaghi
authors.affiliation: Department of Internal Medicine, Memphis Veterans Affairs Medical Center, Memphis, TN, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Gianfranco Umberto
authors.initials: GU
authors.lastname: Meduri
authors.affiliation: Department of Pediatrics, University of California Los Angeles , Los Angeles, CA , USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwingshackl
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA; Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, TN, USA; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Stephania A
authors.initials: SA
authors.lastname: Cormier
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Kanwaljeet J
authors.initials: KJ
authors.lastname: Anand
keywords: ARDS; Ang-2; ICAM-1; MMP-8; biomarker; methylprednisolone; pediatric; sRAGE