View Clinical Trial (Medical Research Study)
Endothelial Cell Signaling and Microcirculatory Flow in Severe Sepsis
| City: |
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Pittsburgh |
| State: |
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Pennsylvania |
| Zip Code: |
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15261 |
| Conditions: |
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Sepsis - Severe Sepsis - Septic Shock |
| Purpose: |
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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.
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| Study Summary: |
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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.
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| Criteria: |
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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)
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| NCT ID: |
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NCT00793442 |
| Primary Contact: |
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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
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| Backup Contact: |
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N/A |
| Location Contact: |
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Pittsburgh, Pennsylvania 15261
United States
Brian Suffoletto, MD
Phone: 412-647-5300
Email: Suffbp@upmc.edu
Site Status: Recruiting |
| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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May 24, 2013 |
| Modifications to this listing: |
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