Biomarker Trajectories of Direct and Indirect Acute Respiratory Distress Syndrome in Children
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Pulmonary, Pediatrics, 2022
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INTRODUCTION:  Acute respiratory distress syndrome (ARDS) can be classified according to direct (pulmonary) or indirect (non-pulmonary) etiology in order to mitigate heterogeneity.  Surfactant protein D (SP-D) and angiopoietin-2 (Ang-2) are proposed indicators of direct and indirect ARDS, respectively, whereas utility of the soluble receptor for advanced glycation end-products (sRAGE) is controversial.  The majority of studies have been conducted in adults, and differences in the biomarker levels between direct and indirect ARDS have not been investigated in children.  Therefore, we aimed to compare the longitudinal biomarker profiles of direct and indirect pediatric ARDS using SP-D, sRAGE, and Ang-2. METHODS:  This was a prospective cohort study of intubated children with ARDS, with biomarker measurements on day 0 (n = 279), day 3 (n = 266), and day 7 (n = 207).  We assessed the relationship between biomarkers and direct/indirect ARDS classification, ARDS severity, non-pulmonary organ failures, and PICU mortality using Fisher’s exact test or Cuzick’s non-parametric test of trend, as appropriate.  Based on values for sRAGE from a prior study, we estimated that 275 subjects would provide 80% power to detect a difference of 1 ng/mL in biomarker levels between direct and indirect ARDS at α = 0.017.  RESULTS:  There were 279 subjects with ARDS, with 64 (22.9%) non-survivors.  SP-D was higher in direct ARDS on day 0 (p < 0.001) and was strongly associated with mortality in direct ARDS, with the highest SP-D levels in subjects who died of refractory hypoxemia.  sRAGE was higher in indirect ARDS on days 3 and 7 (both p < 0.001) and correlated with both ARDS severity and with non-pulmonary organ failures.  Ang-2 was higher in indirect ARDS at all timepoints (all p < 0.001) and correlated with non-pulmonary organ failures.  sRAGE and Ang-2 were associated with mortality in both direct and indirect ARDS.  Conclusions were unchanged in sensitivity analyses using only data from the 207 subjects with measurements at all three timepoints. CONCLUSIONS:  SP-D and Ang-2 performed consistent with their proposed roles as biomarkers of direct and indirect pediatric ARDS, respectively.  sRAGE was higher in indirect ARDS, correlated most strongly with multisystem organ failure, and should not be considered a marker of direct ARDS.
Meta Tag
Content Type Presentation
Knowledge Area Pulmonary
Knowledge Area Pediatrics
Knowledge Level Advanced
Membership Level Select
Tag Acute Respiratory Distress Syndrome ARDS
Tag Pediatrics
Tag Acute Lung Injury
Tag Mortality
Tag Respiratory Failure
Year 2022
biomarker trajectories
pediatric acute respiratory distress syndrome
subtyping ARDS
tissue-specific biomarkers
mortality prediction


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