Thrombomodulin is associated with increased mortality and organ failure in mechanically ventilated children with acute respiratory failure: biomarker analysis from a multicenter randomized controlled trial

Ana Carolina Costa Monteiro, Heidi Flori, Mary K Dahmer, Myung Shin Sim, Michael W Quasney, Martha A Q Curley, Michael A Matthay, Anil Sapru, BALI Study Investigators of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, Ana Carolina Costa Monteiro, Heidi Flori, Mary K Dahmer, Myung Shin Sim, Michael W Quasney, Martha A Q Curley, Michael A Matthay, Anil Sapru, Scot T Bateman, M D Berg, Santiago Borasino, G Kris Bysani, Allison S Cowl, Cindy Darnell Bowens, E Vincent S Faustino, Lori D Fineman, A J Godshall, Ellie Hirshberg, Aileen L Kirby, Gwenn E McLaughlin, Shivanand Medar, Phineas P Oren, James B Schneider, Adam J Schwarz, Thomas P Shanley, Lauren R Sorce, Edward J Truemper, Michele A Vander Heyden, Kim Wittmayer, Athena Zuppa, David Wypij, Ana Carolina Costa Monteiro, Heidi Flori, Mary K Dahmer, Myung Shin Sim, Michael W Quasney, Martha A Q Curley, Michael A Matthay, Anil Sapru, BALI Study Investigators of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, Ana Carolina Costa Monteiro, Heidi Flori, Mary K Dahmer, Myung Shin Sim, Michael W Quasney, Martha A Q Curley, Michael A Matthay, Anil Sapru, Scot T Bateman, M D Berg, Santiago Borasino, G Kris Bysani, Allison S Cowl, Cindy Darnell Bowens, E Vincent S Faustino, Lori D Fineman, A J Godshall, Ellie Hirshberg, Aileen L Kirby, Gwenn E McLaughlin, Shivanand Medar, Phineas P Oren, James B Schneider, Adam J Schwarz, Thomas P Shanley, Lauren R Sorce, Edward J Truemper, Michele A Vander Heyden, Kim Wittmayer, Athena Zuppa, David Wypij

Abstract

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://ichgcp.net/clinical-trials-registry/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.

Keywords: Acute respiratory distress syndrome; Acute respiratory failure; Coagulation; Dead space ventilation; Thrombomodulin; Vascular injury.

Conflict of interest statement

The authors have declared that they have no conflict of interest exists.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Box plot representing distribution of daily sTM values collected for each patient. Mean for each day is represented by ‘x’, outliers are represented by an open circle. Number (n) for individual days is as follows: 56 on day 0, 134 on day 1, 167 on day 2, 118 on day 3, 45 on day 4, 4 on day 5
Fig. 2
Fig. 2
Receiver operating curve for the odds ratio of mortality based on sTM measured at day 1. n = 233

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