Philadelphia, Pennsylvania 19140


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)


NCT ID:

NCT00793442


Primary Contact:

Principal Investigator
Nathan I Shapiro, MD, MPH
Beth Israel Deaconess Medical Center

Nathan I Shapiro, MD, MPH
Phone: 617-754-2343
Email: Nshapiro@bidmc.harvard.edu


Backup Contact:

N/A


Location Contact:

Philadelphia, Pennsylvania 19140
United States

Jacob Ufberg, MD
Phone: 215-707-7550
Email: ufbergjw@tuhs.temple.edu

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

Modifications to this listing: Only selected fields are shown, please use the link below to view all information about this clinical trial.


Click to view Full Listing

If you would like to be contacted by the clinical trial representative please fill out the form below.