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Thrombomodulin is associated with increased mortality and organ failure in mechanically ventilated children with
Ana Carolina Costa Monteiro1, Heidi Flori2, Mary K Dahmer2
1Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCLA Ronald Reagan Hospital, University of California, Los Angeles, 757 Westwood Plaza, Los Angeles, CA, 90095, USA. acostamonteiro@mednet.ucla.edu.
Insights
Soluble thrombomodulin (sTM) in children with acute respiratory failure is linked to higher mortality and worse outcomes. This biomarker may indicate vascular injury
Area of Science:
- Critical Care Medicine
- Pediatric Pulmonology
- Vascular Biology
Background:
- Acute respiratory failure (ARF) is a critical condition that can lead to acute respiratory distress syndrome and death.
- Biomarkers are crucial for risk stratification and prognostic assessment in ARF.
- Soluble thrombomodulin (sTM), a marker of endothelial dysfunction, correlates with inflammation and organ damage.
Purpose of the Study:
- To investigate the association between plasma sTM levels and clinical outcomes in pediatric patients with ARF.
- To determine if sTM can serve as a prognostic biomarker for mortality and organ failure in this population.
Main Methods:
- A prospective observational study of 432 pediatric patients (2 weeks-17 years) requiring mechanical ventilation.
- Plasma sTM levels were measured using ELISA within 5 days of intubation.
- Cox regression and mixed-effects models were used to analyze associations with 90-day mortality, multiorgan failure (MOF), and oxygenation index (OI), adjusting for confounders.
Main Results:
- Higher sTM levels were significantly associated with increased 90-day mortality (adjusted HR=1.003, p=0.02).
- sTM levels correlated with a worse oxygenation index (OI) (Estimate=0.02, p<0.01).
- Both initial and changing sTM levels were linked to increased extrapulmonary MOF (p<0.0001 for intercept, p=0.0009 for slope).
Conclusions:
- Plasma sTM is a significant biomarker associated with mortality, respiratory failure severity, and MOF in pediatric ARF.
- These findings suggest a role for vascular injury in ARF pathogenesis.
- sTM may have potential applications in guiding targeted therapies for pediatric ARF.
Background:
Acute respiratory failure (ARF) can progress to acute respiratory distress syndrome and death. Biomarkers may allow for risk stratification and prognostic enrichment in ARF. Thrombomodulin (TM) is a transmembrane antithrombotic mediator expressed in endothelial cells. It is cleaved into its soluble form (sTM) during inflammation and vascular injury. Levels of sTM correlate with inflammation and end organ dysfunction.
Methods:
This 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-h intervals within 5 days after intubation. sTM was assayed by ELISA. The 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.
Results:
sTM 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).
Conclusions:
Plasma sTM is associated with mortality, severity of hypoxic respiratory failure and worsening extrapulmonary MOF in children with ARF. This suggests a role of vascular injury in the pathogenesis of ARF and provides potential applicability towards targeted therapies.
Trial Registration:
https://clinicaltrials.gov/ct2/show/NCT00814099 . In healthy lung endothelium, thrombomodulin (TM) recruits thrombin to activate Protein-C (PC/APC), that inhibits plasminogen activator-1 (PAI-1) and thrombosis. In inflamed and damaged endothelium, TM is cleaved into its soluble form (sTM), precluding its usual regulation of thrombosis. In this study, we measured plasma sTM levels in pediatric patients with respiratory failure and found that sTM correlated with mortality and other clinical markers of poor outcomes.
