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Original Research |

Endothelial Permeability and Hemostasis in Septic Shock: Results from the ProCESS Trial

Peter Hou, MD; Michael Filbin, MD; Henry Wang, MD; Long Ngo, PhD; David T. Huang, MD; William C. Aird, MD; Donald M. Yealy, MD; Derek C. Angus, MD MPH; John A. Kellum, MD; Nathan I. Shapiro, MD MPH
Author and Funding Information

Trial registration: This ProceSS parent trial was registered under clinicaltrial.gov identifier [NCT00510835] which was submitted July 18, 2007 and patient recruitment began the study started March 2008. This ancillary investigation was registered with clinicaltrials.gov under the identifier [NCT00793442] on November 18, 2008.

1Departments Emergency Medicine , Brigham and Women’s Hospital, Boston, MA

2Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA

3Department of Emergency Medicine, University of Alabama, Birmingham, AL

4Division of General Medicine in the Department of Medicine, Boston, MA

5Department of Critical Care Medicine, University of Pittsburgh School of Medicine

6Division of Molecular Medicine in the Department of Medicine and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA

7Department of Emergency Medicine, University of Pittsburgh School of Medicine

8Department of Emergency Medicine and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA

Corresponding author Nathan I. Shapiro, MD, MPH Vice Chair of Emergency Medicine Research Beth Israel Deaconess Medical Center 1 Deaconess Road, CC2-W Boston, MA 02215 USA.


Copyright 2017, American College of Chest Physicians. All Rights Reserved.


Chest. 2017. doi:10.1016/j.chest.2017.01.010
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Abstract

Background  We studied patients from the Protocolized Care in Early Septic Shock (ProCESS) trial to determine: the effects of alternative resuscitation strategies on circulating markers of endothelial cell permeability and hemostasis, and; the association between biomarkers and mortality.

Methods  Prospective study of biomarkers of endothelial cell permeability (vegf, sflt-1, ang-2) and hemostasis (vwf, thrombomodulin, tpa) in 605 of the 1341 ProCESS participants in a derivation cohort and 305 in validation. Analyses assess: 1) impact of varying resuscitation strategies on biomarker profiles; and, 2) association of endothelial biomarkers with 60-day in-hospital mortality. The study was conducted in 31 United States EDs in adult septic shock patients. Patients were randomly assigned to one of three resuscitation strategies. Blood samples were collected at enrollment, 6, and 24 hours.

Results  There were 116 (19.2%) and 52 (17.0%) deaths in the derivation and validation cohorts. There was no significant association between treatment strategy and any biomarker levels. Permeability (Ang-2 and SFLT-1) and hemostasis (vwf, thrombomodulin, tpa) biomarkers were higher and VEGF levels were lower in non-survivors (P<0.05 for all). At baseline, sFLT-1 had the highest point estimate for mortality discrimination (derivation AUC=0.74; validation=0.70), similar to lactate (AUC=0.74) and SOFA score (AUC=0.73). In an analysis including all time points and adjusted for age, cancer, and Charlson, sFLT-1 adjusted AUC was 0.80.

Conclusions  We found no relationship between different resuscitation strategies and biomarker profiles in sepsis, but we did identify that elevated levels of Endothelial Cell biomarkers of permeability and hemostasis were associated with increased mortality.


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