- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03993002
DAMP-Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium (HALO)
Danger Associated Molecular Patterns (DAMP) Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium
The mortality burden of trauma in the United States is substantial, and is currently the leading cause of death in warfare and in civilians below age 45. Infection and sepsis are leading causes of morbidity and death in early survivors. Pneumonia (PNA) occurs in 17-36% of ventilated trauma patients; far more than non-trauma patients. The long held dogmatic notion of a mechanical predisposition to development of pneumonia in trauma has lacked robust support. However, there is evidence of the innate immune response to injury plays a major role in increasing susceptibility to infection.
This application is for support of a Focused Program Award addressing the role that "danger signaling" due to "danger associated molecular patterns" (or DAMPs) derived from somatic tissue injuries play in altering innate immune signaling in the lung in ways that predisposes to PNA. This innate immune response plays a pivotal role in the development and progression of lung inflammation. The organization of the Focused Program Award is into six Projects with collaborators from the Departments of Surgery, Medicine and Anesthesiology at Beth Israel Deaconess Medical Center; the Department of Surgery at Brigham and Women's Hospital and the Departments of Biology and Biological Engineering at Massachusetts Institute of Technology.
The human subjects interaction portion of this project is covered in the Human Subjects & Samples Project of the Award, although the information and tissues obtained from this Project will be shared with the other Projects, and the activities planned for those Projects are outlined in this application.
Study Overview
Status
Conditions
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02215
- Beth Israel Deaconess Medical Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Expected to be on Control Mode Ventilation (CMV) for at least 48 hours from the time of screening
Exclusion Criteria:
- Patients presenting with a primary acute neurological disorder
- Patients who are post cardiac arrest
- Known pregnancy
- Concomitant enrollment in HALO as a case (trauma) patient
- Not committed to full ventilator support
- Treating physician refusal
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Factorial Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Normoxia with Normocarbia
Mechanical ventilation will be adjusted based on arterial blood gas results. Patient will remain on study settings for 48 hours from achieving target setting. Blood and BAL will be collected at the time of enrollment, at 24 hours, at 48 hours and at 72 hours. PaO2 < 100 (FiO2 >= 21%) PaCO2 of 30-40 |
PaO2 < 100 (FiO2 >= 21%) PaCO2 of 30-40
|
Active Comparator: Normoxia with Hypercarbia
Mechanical ventilation will be adjusted based on arterial blood gas results. Patient will remain on study settings for 48 hours from achieving target setting. Blood and BAL will be collected at the time of enrollment, at 24 hours, at 48 hours and at 72 hours. PaO2 < 100 (FiO2 >= 21%) PaCO2 of 50-60 |
PaO2 < 100 (FiO2 >= 21%) PaCO2 of 50-60
|
Active Comparator: Hyperoxia with Normocarbia
Mechanical ventilation will be adjusted based on arterial blood gas results. Patient will remain on study settings for 48 hours from achieving target setting. Blood and BAL will be collected at the time of enrollment, at 24 hours, at 48 hours and at 72 hours. PaO2 > 250 (FiO2 >= 70%) PaCO2 of 30-40 |
PaO2 > 250 (FiO2 >= 70%) PaCO2 of 30-40
|
Active Comparator: Hyperoxia with Hypercarbia
Mechanical ventilation will be adjusted based on arterial blood gas results. Patient will remain on study settings for 48 hours from achieving target setting. Blood and BAL will be collected at the time of enrollment, at 24 hours, at 48 hours and at 72 hours. PaO2 > 250 (FiO2 >= 70%) PaCO2 of 50-60 |
PaO2 > 250 (FiO2 >= 70%) PaCO2 of 50-60
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Inflammatory markers
Time Frame: Change over hours 24, 48 and 72
|
ROS production (output is in relative light units per second (RLU/sec)) using luminol-dependent chemiluminescence, measured every 90 sec over the assay time-course of 60 min.
Over thirty surface markers on neutrophil subpopulations, including CD10, CD11b, CD15, CD16, CD45, CD66b, CD45, CD274, CD279, and CD88, at various times after trauma will be analyzed using flow cytometry and CyTOF technology.
Where indicated, activation of p38/MK2 intracellular signaling pathway will be analyzed by western blotting, and RNA expression profiles of individual cells will be attempted using single-cell RNA sequencing technologies.
|
Change over hours 24, 48 and 72
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Neutrophil activation
Time Frame: Change over hours 24, 48 and 72
|
ROS production (output is in relative light units per second (RLU/sec)) using luminol-dependent chemiluminescence, measured every 90 sec over the assay time-course of 60 min.
Over thirty surface markers on neutrophil subpopulations, including CD10, CD11b, CD15, CD16, CD45, CD66b, CD45, CD274, CD279, and CD88, at various times after trauma will be analyzed using flow cytometry and CyTOF technology.
Where indicated, activation of p38/MK2 intracellular signaling pathway will be analyzed by western blotting, and RNA expression profiles of individual cells will be attempted using single-cell RNA sequencing technologies.
|
Change over hours 24, 48 and 72
|
Purine metabolism
Time Frame: Change over hours 24, 48 and 72
|
Conversion of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) into adenosine (ADO) in lymphomononuclear cells obtained from the peripheral blood and BAL of trauma patients and controls.
|
Change over hours 24, 48 and 72
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Daniel Talmor, MD MPH, Beth Israel Deaconess Medical Center
Publications and helpful links
General Publications
- Lord JM, Midwinter MJ, Chen YF, Belli A, Brohi K, Kovacs EJ, Koenderman L, Kubes P, Lilford RJ. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014 Oct 18;384(9952):1455-65. doi: 10.1016/S0140-6736(14)60687-5. Epub 2014 Oct 17.
- Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010 Mar 4;464(7285):104-7. doi: 10.1038/nature08780.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2016P000144
- PR151953 (Other Grant/Funding Number: Department of Defense)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
The PI fully endorses the sharing of final research data to serve important scientific goals, to be done by publication, communications and online data "mixed mode" sets at the respective PI webpage. The PI will aim for the timely release and sharing of final research data from DoDsupported studies that will enable for use by other researchers.
The rights and privacy of individuals who participate in sponsored research must be protected at all times. Data intended for broader use should be free of identifiers that would permit linkages to individual research participants and variables that could lead to deductive disclosure of the identity of individual subjects. Should any intellectual property arise which requires a patent, the PI will ensure that the technology (materials and data) remains widely available to the research community in accordance with the NIH Principles and Guidelines documented in http://grants.nih.gov/grants/policy/data_sharing/data_sharing_brochure.pdf.
IPD Sharing Time Frame
IPD Sharing Access Criteria
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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