title: Elevated soluble thrombomodulin is associated with organ failure and mortality in children with acute respiratory distress syndrome (ARDS): a prospective observational cohort study.
abstract: BACKGROUND
  The significance of endothelial injury in children with the acute respiratory distress syndrome (ARDS) has not been well studied. Plasma levels of soluble thrombomodulin (sTM), an endothelial surface protein involved in coagulation, have been associated with endothelial injury. We hypothesized that elevated plasma sTM would correlate with mortality and organ failure in children with ARDS.
  
  
  METHODS
  We conducted a multicenter prospective observational study of pediatric patients with ARDS between 2008 and 2014. sTM was measured in plasma collected less than 24 hours from ARDS diagnosis. Outcomes were intensive care unit mortality and organ dysfunction by pediatric logistic organ dysfunction scores. Logistic regression was used to adjust for clinically relevant covariates.
  
  
  RESULTS
  Plasma sTM was higher in patients with indirect lung injury compared to direct lung injury (100 ng/mL vs. 86 ng/mL, p = 0.02). Increased sTM levels were correlated with more organ dysfunction in the entire study population (Spearman's rho = 0.37, p < 0.01). Overall mortality was 16%. sTM levels were associated with increased mortality in patients with indirect lung injury (OR 2.7 per log(sTM), p = 0.02). These relationships were independent of age, oxygenation defect, or presence of acute kidney injury.
  
  
  CONCLUSIONS
  Elevated plasma sTM levels are associated with organ dysfunction in children with ARDS and with higher mortality in children with indirect lung injury. These findings highlight the importance of endothelial injury in children with ARDS and may guide the development of future therapies targeted toward endothelial stabilization, repair, or functional replacement in this population.
authors.affiliation: Department of Pediatrics, Division of Critical Care, University of California, San Francisco Benioff Children's Hospital, 550 16th St, Box 0106, San Francisco, CA, 94143, USA. orwoll@ucsf.edu.|Division of Pediatric Critical Care, University of California, San Francisco Benioff Children's Hospital, 747 52nd St., Oakland, 94609, CA, USA. orwoll@ucsf.edu.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Orwoll
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, 55 Fruit St., Boston, 02114, MA, USA. aspicer@partners.org.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Spicer
authors.affiliation: Department of Pediatrics, Division of Critical Care, University of California, San Francisco Benioff Children's Hospital, 550 16th St, Box 0106, San Francisco, CA, 94143, USA. Matt.Zinter@ucsf.edu.|Division of Pediatric Critical Care, University of California, San Francisco Benioff Children's Hospital, 747 52nd St., Oakland, 94609, CA, USA. Matt.Zinter@ucsf.edu.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Zinter
authors.affiliation: Department of Pediatrics, Division of Critical Care, University of California, San Francisco Benioff Children's Hospital, 550 16th St, Box 0106, San Francisco, CA, 94143, USA. Mustafa.Alkhouli@ucsf.edu.
authors.forename: Mustafa F
authors.initials: MF
authors.lastname: Alkhouli
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Children's Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, 90027, CA, USA. RKhemani@chla.usc.edu.
authors.forename: Robinder G
authors.initials: RG
authors.lastname: Khemani
authors.affiliation: Division of Pediatric Critical Care, University of California, San Francisco Benioff Children's Hospital, 747 52nd St., Oakland, 94609, CA, USA. hflori@mail.cho.org.
authors.forename: Heidi R
authors.initials: HR
authors.lastname: Flori
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, 550 16th St., San Francisco, 94158, CA, USA. John.Neuhaus@ucsf.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Neuhaus
authors.affiliation: Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Blvd. South, San Francisco, 94158, CA, USA. Carolyn.Calfee@ucsf.edu.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.affiliation: Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, 555 Mission Bay Blvd. South, San Francisco, 94158, CA, USA. MatthayM@anesthesia.ucsf.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Department of Pediatrics, Division of Critical Care, University of California, San Francisco Benioff Children's Hospital, 550 16th St, Box 0106, San Francisco, CA, 94143, USA. Anil.Sapru@ucsf.edu.
authors.forename: Anil
authors.initials: A
authors.lastname: Sapru
mesh_terms: D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D055370:Lung Injury / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology* / Q000401:mortality / Q000503:physiopathology; D011379:Prognosis; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000209:etiology / Q000401:mortality* / Q000503:physiopathology; D018180:Thrombomodulin / Q000032:analysis / Q000097:blood* / Q000378:metabolism
chemical_list: C546931:THBD protein, human; D018180:Thrombomodulin