Thrombomodulin is Associated with Increased Mortality and Organ Failure in Mechanically Ventilated Children with Acute Respiratory Failure: A Prospective Observational Study.

Abstract

BACKGROUNDAcute respiratory failure (ARF) can progress to acute respiratory distress syndrome (ARDS) and death. Biomarkers such as soluble thrombomodulin (sTM), implicated in pulmonary vascular injury, may allow for risk stratification and prognostic enrichment in ARF.METHODSThis was a prospective observational study of 432 patients aged 2 weeks - 17 years requiring invasive mechanical ventilation. It was ancillary to the multicenter clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). After consent, patients had up to 3 plasma samples collected at 24-hour intervals within 5 days after intubation. sTM was assayed by ELISA. Hazard ratio (HR) for 90-day mortality was determined by cox regression. Mixed effect models (MEM) were used to test for association with extrapulmonary multiorgan failure (MOF) and oxygenation index (OI). Age, race, sex and PRISM-III scores were used as confounding variables for multivariable analyses.RESULTSsTM values ranged from 16.6 to 670.9 ng/ml within 5 days after intubation. Higher sTM was associated with increased 90-day mortality (n=432, adjusted HR= 1.003, p=0.02) and worse OI in the first 5 days after intubation (n=252, Estimate = 0.02, p<0.01). Both initial and slope of sTM were associated with increased extrapulmonary MOF in unadjusted and adjusted analyses (Intercept, Estimate=0.003, p<0.0001; and slope, Estimate=0.01, p=0.0009, n= 386). CONCLUSIONSPlasma sTM are associated with mortality, severity of ARDS extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in pathogenesis of ARF and provide potential application for targeted therapies. TRIAL REGISTRATIONNCT00814099