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Endothelium in Severe Sepsis

This study has been completed.
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Nathan Shapiro, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier:
NCT00793442
First received: November 18, 2008
Last updated: April 25, 2017
Last verified: April 2017
  Purpose
The overall hypotheses of this project is that severe sepsis is associated with endothelial dysfunction; that endothelial dysfunction, in turn, is predictive of subsequent organ failure and death; and that protocolized resuscitation attenuates endothelial cell (EC) dysfunction and improves patient survival.

Condition Intervention
Sepsis Severe Sepsis Septic Shock Diagnostic Test: Blood Collection and Assays

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Endothelial Cell Signaling and Microcirculatory Flow in Severe Sepsis

Resource links provided by NLM:


Further study details as provided by Nathan Shapiro, Beth Israel Deaconess Medical Center:

Primary Outcome Measures:
  • Mortality [ Time Frame: hospital mortality ]

Secondary Outcome Measures:
  • Organ Dysfunction assessed by Sepsis-related Organ Failure Assessment (SOFA) Score [ Time Frame: first 72 hours ]

Enrollment: 910
Actual Study Start Date: March 2008
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Novel Endothelial Markers Derivation

Our study participants will come from the Protocolized Care for Early Severe Sepsis (ProCESS) trial will be eligible participants.

From the ProCESS subjects, the researchers will include those who were: 1) recruited by participating centers who participated in other components of this ancillary study or 2) who were sequentially enrolled from periods derived from the beginning, middle, and end of the ProCESS study.

Diagnostic Test: Blood Collection and Assays
The researchers will sample blood upon enrollment, at 6 and 24 hours after the baseline sampling. The researchers will measure 6 different endothelial related biomarkers compromising different components of endothelial permeability and hemostasis.
Novel Endothelial Marker Validation
Our study participants will come from the Protocolized Care for Early Severe Sepsis (ProCESS) trial will be eligible participants; the researchers will recruit a sequential 300 patient validation set.
Diagnostic Test: Blood Collection and Assays
The researchers will sample blood upon enrollment, at 6 and 24 hours after the baseline sampling. The researchers will measure 6 different endothelial related biomarkers compromising different components of endothelial permeability and hemostasis.

Detailed Description:

The endothelial response is emerging as a critical element of sepsis pathophysiology. Preclinical data and small human studies suggest that endothelial cells are responsible for increased leukocyte adhesion, inflammation, activation of coagulation, and respond to increased levels of the endothelial cell mediator Vascular Endothelial Cell Growth Factor (VEGF). Furthermore, the endothelium plays an active role in microcirculatory homeostasis and the preservation of microvascular flow.

The researchers propose to study the endothelium by performing a comprehensive endothelial cell "read-out" through the measurement of circulating levels of endothelial cell biomarkers as well as direct visualization of microcirculatory flow with in-vivo videomicroscopy. Accordingly, the broad, long-term objective of this project is to study the role of the endothelium in sepsis in a large, heterogeneous group of patients. To accomplish this, the researchers will investigate two specific aims: 1) to study biomarkers of endothelial cell activation in sepsis; and, 2) to study microcirculatory flow in sepsis.

The overall hypotheses of this project is that severe sepsis is associated with endothelial dysfunction; that endothelial dysfunction, in turn, is predictive of subsequent organ failure and death; and that protocolized resuscitation attenuates endothelial cell (EC) dysfunction and improves patient survival. To test these hypotheses the researchers will utilize ancillary measurements (notably in-vivo assessment of microcirculatory flow), and additional samples and assays from the ProCESS clinical trial. ProCESS is a large, multicenter, randomized, controlled clinical trial testing the efficacy and mechanisms behind protocolized goal-directed resuscitation.

To conduct this line of investigation directed at the endothelium and microcirculation that was not addressed in the original trial, the researchers will select 8 ProCESS study sites for participation in this ancillary study. The researchers will directly visualize and quantify the presence of disturbances in sublingual microcirculatory flow utilizing the novel bedside technique of orthogonal polarization microscopy. Furthermore, the researchers will develop a multi-marker panel that assesses degree of endothelial cell dysfunction and subsequent mortality risk.

The researchers will also capitalize on the randomly assigned interventions in the ProCESS clinical trial to observe differences in endothelial response across the alternative resuscitation strategies. Improved understanding of these mechanisms may lead to strategies to predict outcome, to select patients for tailored (endothelium-directed) therapies, to follow treatment response, and to develop novel therapies for endothelial dysfunction in sepsis.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Emergency department patients with severe sepsis
Criteria

Inclusion Criteria:

  • Enrolled as a participant in the ProCESS Trial (clinicaltrial.gov identifier NCT00510835)
  • At least 18 years of age
  • Suspected infection
  • Two or more systemic inflammatory response syndrome (SIRS) criteria

    • Temperature </= 36˚ C or >/= 38˚C
    • Heart rate >/= 90 beats per minute
    • Mechanical ventilation for acute respiratory process or respiratory rate >/= 20 breaths per minute or PaC02 < 32 mmHg
    • WBC >/= 12,000/mm³ OR </= 4,000/mm³ OR > 10% bands
  • Refractory hypotension (a systolic blood pressure < 90 mm Hg despite an IV fluid challenge of at least 20 ml/kg over a 30 minute period) or evidence of hypoperfusion (a blood lactate concentration >/= 4 mmol/L)

Exclusion Criteria:

  • Known pregnancy
  • Primary diagnosis of acute cerebral vascular event, acute coronary syndrome, -- acute pulmonary edema, status asthmaticus, major cardiac arrhythmia, active
  • gastrointestinal hemorrhage, seizure, drug overdose, burn or trauma
  • Requirement for immediate surgery
  • ANC < 500/mm³
  • CD4 < 50/mm³
  • Do-not-resuscitate status
  • Advanced directives restricting implementation of the protocol
  • Contraindication to central venous catheterization
  • Contradiction to blood transfusion (e.g., Jehovah's Witness)
  • Treating physician deems aggressive care unsuitable
  • Participation in another interventional study
  • Transferred from another in-hospital setting
  • inability to tolerate microscan procedure (eg oxygen requirement via face mack that can not be discontinue for the procedure)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00793442

Locations
United States, Alabama
Universtiy of Alabama
Birmingham, Alabama, United States, 35249
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
United States, New York
North Shore University Hospital
Manhasset, New York, United States, 11030
United States, Pennsylvania
Temple University Hospital
Philadelphia, Pennsylvania, United States, 19140
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15261
United States, Utah
University of Utah Health Sciences Center
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Nathan I Shapiro, MD, MPH Beth Israel Deaconess Medical Center
  More Information

Publications:
Responsible Party: Nathan Shapiro, Associate Professor of Emergency Medicine, Beth Israel Deaconess Medical Center
ClinicalTrials.gov Identifier: NCT00793442     History of Changes
Other Study ID Numbers: 2008P000089
1R01HL091757-01A1 ( U.S. NIH Grant/Contract )
Study First Received: November 18, 2008
Last Updated: April 25, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Nathan Shapiro, Beth Israel Deaconess Medical Center:
sepsis
severe sepsis
septic shock
endothelium
microcirculation
biomarkers

Additional relevant MeSH terms:
Sepsis
Toxemia
Shock, Septic
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Shock

ClinicalTrials.gov processed this record on August 22, 2017