Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: Results from a double-blind, placebo-controlled randomized pilot trial

Abstract

Objective A double-blind, randomized controlled trial showed that low-dose glucocorticoid therapy in pediatric ARDS patients is feasible and may improve both ventilation and oxygenation indices in these patients. However, the molecular mechanisms underlying potential changes in outcomes remain unclear. Based on these clinical findings, this study was designed to examine the effects of intravenous methylprednisolone on circulating inflammatory biomarkers in pediatric ARDS patients. Design Double-blind, placebo-controlled randomized trial with blood collection on study entry and day 7. Setting Tertiary care children’s hospital. Patients Children (0–18 years) with ARDS undergoing mechanical ventilation. Interventions 35 children were randomized within 72 hours of mechanical ventilation. The glucocorticoid group received methylprednisolone 2 mg/kg loading dose followed by 1 mg/kg/day continuous infusion from days 1–7. Both groups were ventilated following the ARDSnet recommendations. WBC and differential cell counts, plasma cytokines and CRP levels, and coagulation parameters were analyzed on days 0 and 7. Results At study entry, the placebo group had higher IL-15 and basophil levels. On day 7, in comparison to study entry, the placebo group had lower IL-1α, IFN-γ and IL-10 levels. The glucocorticoid group had lower INF-α, IL-6, IL-10, MCP-1, G-CSF and GM-CSF levels, and higher IL-17α levels on day 7 in comparison to study entry. Total and differential cell counts remained unchanged within the placebo group between days 0 and 7, whereas in the glucocorticoid group total WBC and platelets counts were increased on day 7. Pearson’s correlation studies within the placebo and glucocorticoid groups revealed positive and negative correlations between cytokine levels, cell counts, coagulation parameters and relevant clinical parameters of disease severity identified in our previous study. Multiple regression models identified several cytokines as predictors for alterations in clinical parameters of disease severity. Conclusion This pilot study shows the feasibility of simultaneously measuring multiple inflammatory cytokines, cell counts and coagulation parameters in pediatric ARDS patients. We report statistical models that may be useful for future, larger trials to predict ARDS severity and outcomes.

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

“…In adult ARDS, the same MPT protocol was associated with decreases in plasma IL-6 and proadrenomedullin levels and increases in protein C levels, compared to the placebo ( 39 ). As previously reported, MPT decreased IL-6 in pediatric ARDS as well ( 8 ). Considering the biomarker changes in this study, we propose that corticosteroids may attenuate inflammation, promote early recovery from the epithelial injury, and prevent sustained endothelial damage, leading to earlier improvement in pulmonary edema and oxygenation seen as clinical outcomes.…”

“…MPT therapy did not alter ventilator-free days or mortality but appeared to alter oxygenation and ventilation ( 6 ). We also examined different regulatory patterns of pro- and anti-inflammatory plasma cytokines in the MPT and placebo groups to identify several cytokines as potential predictors for alterations in clinical parameters of disease severity ( 8 ). Larger randomized controlled studies are warranted for investigating corticosteroid use in early pediatric ARDS.…”

Biomarkers in Pediatric ARDS: Future Directions

“…IL-10 is a major anti-inflammatory cytokine, and elevations in plasma and BAL fluid have been associated with the development of ARDS as well as with ARDS mortality in adults ( 80 , 82 , 83 ). It appears that an early rise in IL-10 at the onset of ARDS is followed by normalization of levels over the first 21 days of illness ( 74 ), and this pattern was also seen in children with ARDS, both with and without steroid therapy ( 16 , 20 ). IL-10 is elevated in newborns with RDS ( 22 ), independent of gestational age, and has also been associated with increased development of ARDS and increased mortality among pediatric burn patients with inhalation injury ( 17 ).…”

“…IL-1 and IL-6 levels in BAL fluid were also both found to be elevated in premature babies with RDS and were correlated with the development of chronic lung disease (CLD) ( 56 , 58 , 59 ). As a biomarker of response to therapy, IL-6 was recently found to decrease in response to glucocorticoid (GC) therapy in a randomized trial of GC therapy in children ( 20 ). The relationship of the inflammatory cytokine response to ventilation strategies was also demonstrated in the landmark ARDSNet trial of low-tidal-volume ventilation, where IL-6 and IL-8 levels were observed to decrease in the low-tidal-volume group compared with the controls ( 79 , 80 ).…”

“…IL-10 is elevated in newborns with RDS ( 22 ), independent of gestational age, and has also been associated with increased development of ARDS and increased mortality among pediatric burn patients with inhalation injury ( 17 ). Several other cytokines of the IL family, including IL-4, IL-7, and IL-13 (each in pediatric burn patients) ( 17 ), IL-12 (RDS) ( 22 ), and IL-17 (pARDS) ( 20 ), have been associated with the outcomes from lung injury in individual studies. Comparing non-survivors to survivors from the previously mentioned cohort of severe influenza patients, the investigators also found significant elevations in granulocyte–macrophage colony-stimulating factor, interferon-inducible protein 10, monocyte chemotactic protein 1, and macrophage inflammatory protein 1α ( 14 ), though these findings have yet to be reproduced in other pediatric cohorts.…”