title: Profound endothelial damage predicts impending organ failure and death in sepsis.
abstract: Endothelial damage contributes to organ failure and mortality in sepsis, but the extent of the contribution remains poorly quantified. Here, we examine the association between biomarkers of superficial and profound endothelial damage (syndecan-1 and soluble thrombomodulin [sTM], respectively), organ failure, and death in sepsis. The data from a clinical trial, including critically ill patients predominantly suffering sepsis (Clinicaltrials.gov: NCT00271752) were studied. Syndecan-1 and sTM levels at the time of study enrollment were determined. The predictive ability of biomarker levels on death and organ failures during follow-up were assessed in Cox models adjusted for potential confounders including key organ dysfunction measures assessed at enrollment. Of the 1,103 included patients, 418 died. sTM levels at the time of enrollment independently predicted risk of death in adjusted models (hazard ratio [HR] [highest quartile > 14 ng/mL vs. lowest quartile < 7 ng/mL] 2.2 [95% confidence interval [CI]: 1.2-4.0], p = 0.02, respectively). Conversely, syndecan-1 levels failed to predict death (adjusted HR [> 240 vs. < 70 ng/mL] 1.0 [95% CI: 0.6-1.5], p = 0.67). sTM but not syndecan-1 levels at enrollment predicted risk of multiple organ failure during follow-up (HR [> 14 ng/mL vs. < 7 ng/mL] 3.5 [95% CI: 1.5-8.3], p = 0.005 and 2.0 [95% CI: 0.8-5.0], p = 0.1321, respectively). Profound damage to the endothelium independently predicts risk of multiple organ failure and death in septic patients. Our findings also suggest that the detrimental effect of profound endothelial damage on risk of death operates via mechanisms other than causing organ failures per se. Therefore, damage to the endothelium appears centrally involved in the pathogenesis of death in sepsis and could be a target for intervention.
authors.affiliation: CHIP, Department of Infectious Diseases and Rheumatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Johansen
authors.affiliation: Department of Surgery, University of Texas Medical School at Houston, Houston, Texas.
authors.forename: Pär I
authors.initials: PI
authors.lastname: Johansson
authors.affiliation: Section for Transfusion Medicine, Capital Region Blood Bank, Rigshospitalet, Denmark.
authors.forename: Sisse R
authors.initials: SR
authors.lastname: Ostrowski
authors.affiliation: Department of Anesthesia and Intensive Care at Nordsjaellands Hospital, Denmark.
authors.forename: Morten H
authors.initials: MH
authors.lastname: Bestle
authors.affiliation: Department of Anesthesia and Intensive Care at Nordsjaellands Hospital, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Hein
authors.affiliation: Department of Anesthesia and Intensive Care at University Hospital Glostrup, Denmark.
authors.forename: Anne L G
authors.initials: AL
authors.lastname: Jensen
authors.affiliation: Department of Anesthesia and Intensive Care at University Hospital Herlev, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Søe-Jensen
authors.affiliation: Department of Anesthesia and Intensive Care at University Hospital Aarhus, Denmark.
authors.forename: Mads H
authors.initials: MH
authors.lastname: Andersen
authors.affiliation: Department of Anesthesia and Intensive Care at University Hospital Hvidovre, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Steensen
authors.affiliation: Department of Anesthesia and Intensive Care at University Hospital Gentofte, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.affiliation: Department of Anesthesia and Intensive Care at University Hospital Bispebjerg, Denmark.
authors.forename: Katrin
authors.initials: K
authors.lastname: Thormar
authors.affiliation: Centre of Diagnostic Investigations, Rigshospitalet, Denmark.
authors.forename: Bettina
authors.initials: B
authors.lastname: Lundgren
authors.affiliation: CHIP, Department of Infectious Diseases and Rheumatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cozzi-Lepri
authors.affiliation: CHIP, Department of Infectious Diseases and Rheumatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
authors.affiliation: CHIP, Department of Infectious Diseases and Rheumatology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens-Ulrik
authors.initials: JU
authors.lastname: Jensen
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D004730:Endothelium, Vascular / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure / Q000097:blood / Q000473:pathology*; D011237:Predictive Value of Tests; D011379:Prognosis; D018805:Sepsis / Q000097:blood / Q000473:pathology*; D053668:Syndecan-1 / Q000097:blood; D018180:Thrombomodulin / Q000097:blood
chemical_list: D015415:Biomarkers; C508241:SDC1 protein, human; D053668:Syndecan-1; D018180:Thrombomodulin