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.

Dai Kimura,Kanwaljeet J Anand,Andreas Schwingshackl,Jordy Saravia,Stephania A Cormier,Cynthia R Rovnaghi,Gianfranco Umberto Meduri

doi:10.3389/fped.2016.00031

Abstract

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). Double-blind, placebo-controlled randomized trial. Tertiary-care pediatric intensive care unit (ICU). Mechanically ventilated children (0-18 years) with early ARDS. 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. 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. 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. https://clinicaltrials.gov, NCT01274260.

Highlights

The pathogenesis of acute respiratory distress syndrome (ARDS) may result from dysregulated inflammation in the endothelial and epithelial spaces from pulmonary or systemic circulations [1]
There were no significant differences in baseline characteristics including age, weight, gender, race, pediatric risk of mortality (PRISM) III score, pediatric index of mortality-2 score, P/F ratio, PEEP, tidal volume, mean airway pressure, blood gas pH, PaCO2, and the number of lobes affected on chest X-ray
Comparisons showed that matrix metalloproteinase-8 (MMP-8) levels decreased from day 0 to 7 (p = 0.0016) in the methylprednisolone therapy (MPT) group, but not in the placebo group. soluble intercellular adhesion molecule-1 (sICAM-1) levels increased significantly from day 0 to 7 (p = 0.0005) in the placebo group, but not in the MPT group. soluble receptor for activated glycation end products (sRAGE) levels decreased in both MPT and placebo groups (p < 0.0001) from day 0 to day 7 (Table 1)

Summary

Introduction

The pathogenesis of acute respiratory distress syndrome (ARDS) may result from dysregulated inflammation in the endothelial and epithelial spaces from pulmonary or systemic circulations [1]. ARDS is associated with alveolar and interstitial edema, infiltration of inflammatory cells (neutrophils and macrophages) into the alveolar space due to vascular permeability, abnormal coagulation, and endothelial and alveolar epithelial injury [1]. Corticosteroids may suppress this dysregulated inflammation in ARDS and thereby improve clinical outcomes [2]. In adult patients with ARDS, early low-dose corticosteroid treatment showed promising results [3]. The American College of Critical Care Medicine recommends the use of corticosteroids only for adult patients with moderate to severe ARDS resulting from communityacquired pneumonia (grade 2B). This study did not record the indications for corticosteroid administration and neither considered the length of therapy nor the need for tapering steroids to prevent rebound inflammation [5]

Methods

Results

Discussion

Conclusion