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.

Keywords

sepsis - endothelial damage - thrombomodulin - syndecan-1

Note

The members of the PASS study group are as follows: Central Coordinating Centre, J. U. Jensen, B. Lundgren, J. Grarup, M. L. Jakobsen, S. S. Reilev, M. Kofoed-Djursner, J. D. Lundgren; Regional Coordinating Centres, Hvidovre, J. Løken, M. Steensen; Gentofte, T. Mohr, K. Thornberg, K. Thormar; Hillerød, L. Hein, M. Bestle; Glostrup, D. Strange, A. Ø. Lauritsen; Herlev, H. Tousi, P. Søe-Jensen; Roskilde, N. Reiter, N. E. Drenck; Skejby, M. H. Andersen, P. Fjeldborg; Århus, K. M. Larsen; Data Management and Statistical Centre, Z. Fox, J. Kjær, D. Kristensen; Procalcitonin Analysis & Logistics Centre, J. U. Jensen, B. Lundgren, M. B. Rasmussen, C. S. V. Hallas, M. Zacho, J. Iversen, T. Leerbeck, M. Jeppesen, K. S. Hansen, K. B. Jensen; Data and Safety Monitoring Board, H. Masur (Chair), J. Chastre, H. Schønheyder, C. Pedersen; Clinical Microbiology Management, B. Lundgren, J. D. Knudsen, A. Friis-Møller, K. Schønning, A. Lester, H. Westh, G. Lisby, J. K. Møller, B. Bruun, J. J. Christensen, C. Østergaard, M. Arpi, K. Astvad, M. D. Bartels, J. Engberg, H. Fjeldsøe-Nielsen, JU. S. Jensen; PASS Site Clinical Investigators, L. Hein, T. Mohr, D. G. Strange, P. L. Petersen, A. Ø. Lauritsen, S. Hougaard, T. Mantoni, L. Nebrich, A. Bendtsen, L. H. Andersen, F. Bærentzen, A. Eversbusch, B. Bømler, R. Martusevicius, T. Nielsen. P. M. Bådstøløkken, C. Maschmann, U. Grevstad, P. Hallas, A. Lindhardt, T. Galle, K. Graeser, E. Hohwu-Christensen, P. Gregersen, H. C. Boesen, L. M. Pedersen, K. Thiesen, L. C. Hallengreen, I. Rye, J. Cordtz, K. R. Madsen, P. R. C. Kirkegaard, L. Findsen, L. H. Nielsen, D. H. Pedersen, J. H. Andersen, C. Albrechtsen, A. Jacobsen, T. Jansen, A. G. Jensen, H. H. Jørgensen, M. Vazin; L. Lipsius, K. Thornberg, J. Nielsen, K. Thormar, M. Skielboe, B. Thage,C. Thoft, M. Uldbjerg, E. Anderlo, M. Engsig, F. Hani, R. B. Jacobsen. L. Mulla, U. Skram; H. Tousi, P. Søe-Jensen, T. Waldau, T. Faber, B. Andersen, I. Gillesberg, A. Christensen, C. Hartmann, R. Albret, D. S. Dinesen, K. Gani, M. Ibsen; J. Løken, M. Steensen, J. A. Petersen, P. Carl, E. Gade, D. Solevad, C. Heiring, M. Jørgensen, K. Ekelund, A. Afshari, N. Hammer, M. Bitsch, J. S. Hansen, C. Wamberg, T. D. Clausen, R. Winkel, J. Huusom, D. L. Buck, U. Grevstad, E. Aasvang, K. Lenz, P. Mellado, H. Karacan, J. Hidestål, J. Høgagard, J. Højbjerg, J. Højlund, M. Johansen, S. Strande; M. Bestle, S. Hestad, M. Østergaard, N. Wesche, S. A. Nielsen, H. Christensen, H. Blom, C. H. Jensen, K. Nielsen, N. G. Holler, K. A. Jeppesen; M. H. Andersen, P. Fjeldborg, A. Vestergaard, O. Viborg, C. D. Rossau; N. Reiter, M. Glæemose, M. B. Wranér, C. B. Thomsen, B. Rasmussen, C. Lund-Rasmussen, B. Bech, K. Bjerregaard, L. Spliid, L. L. W. Nielsen, N. E. Drenck; K. M. Larsen, M. Goldinger, D. Illum, C. Jessen, A. Christiansen, A. Berg, T. Elkmann, J. A. K. Pedersen, M. Simonsen; H. Joensen, H. Alstrøm, C. Svane, A. Engquist.

Author Contributions

M. E. J., P. I. J., S. R. O., M. H. B., L. H., A. G. J., P. S. J., M. H. A., M. S., T. M., K. T., B. L., A. C. L., J. D. L., and J. U. J. collected the data, planned and designed experiments; M. E. J., P. I. J., S. R. O., M. H. B., A. C. L., J. D. L., and J. U. J. analyzed the data; and M. E. J., P. I. J., S. R. O., M. H. B., L. H., A. G. J., P. S. J., M. H. A., M. S., T. M., K. T., B. L., A. C. L., J. D. L., and J. U. J. contributed to the writing of the article.

Grants

This study was supported by a grant from The Lundbeck Foundation. The Lundbeck Foundation had no influence on the design or conduct of the study; collection, management, analysis, and interpretation of the data or the preparation or approval of the article.

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