Boston, Massachusetts 02114

  • Septic Shock

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 early effective protocol-directed resuscitation attenuates endothelial dysfunction leading to improved survival.


Study summary:

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. We 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, we 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 early effective protocol-directed resuscitation attenuates endothelial dysfunction leading to improved survival. To test this hypothesis, we will utilize patients, 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, we will select 8 ProCESS study sites for participation in this ancillary study. We will directly visualize and quantify the presence of disturbances in sublingual microcirculatory flow utilizing the novel bedside technique of orthogonal polarization microscopy. Furthermore, we will develop a multi-marker panel that assesses degree of endothelial cell dysfunction and subsequent mortality risk. We 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.


Criteria:

Inclusion Criteria: - Enrolled as a participant in the ProCESS Trial - 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)


Study is Available At:


Original ID:

2008P000089 1R01HL091757-


NCT ID:

NCT00793442


Secondary ID:

1R01HL091757-01A1


Study Acronym:


Brief Title:

Endothelium in Severe Sepsis


Official Title:

Endothelial Cell Signaling and Microcirculatory Flow in Severe Sepsis


Overall Status:

Recruiting


Study Phase:

N/A


Genders:

Both


Minimum Age:

18 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Beth Israel Deaconess Medical Center


Oversight Authority:

United States: Institutional Review Board


Reasons Why Stopped:


Study Type:

Observational


Study Design:

Observational Model: Cohort, Time Perspective: Pro


Number of Arms:

0


Number of Groups:

1


Total Enrollment:

600


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Nathan I Shapiro, MD, MPH
Principal Investigator
Beth Israel Deaconess Medical Center
Primary Contact:Nathan I Shapiro, MD, MPH
617-754-2343
Nshapiro@bidmc.harvard.edu

Study Dates

Start Date:June 2008
Completion Date:January 2017
Completion Type:Anticipated
Primary Completion Date:January 2017
Primary Completion Type:Anticipated
Verification Date:November 2015
Last Changed Date:November 13, 2015
First Received Date:November 18, 2008

Study Outcomes

Outcome Type:Secondary Outcome
Measure:Organ Dysfunction assessed by Sepsis-related Organ Failure Assessment (SOFA) Score
Time Frame:first 72 hours
Safety Issues:True
Outcome Type:Primary Outcome
Measure:Mortality
Time Frame:hospital mortality
Safety Issues:False

Study Interventions

There are no available Study Interventions

Study Arms

Study Arm Type:Other
Arm Name:Severe Sepsis and Septic Shock
Description:Adult patients with severe sepsis who are enrolled in the Protocolized Care for Early Severe Sepsis (ProCESS) trial will be eligible participants.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Beth Israel Deaconess Medical Center
Agency Class:NIH
Agency Type:Collaborator
Agency Name:National Heart, Lung, and Blood Institute (NHLBI)

Samples and Retentions

Study Population: Emergency department patients with severe sepsis
Sample Method:Non-Probability Sample

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: March 30, 2020

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