DAMP-Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium

Study Overview
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Brief Summary
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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.

Detailed Description
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The purpose of the interventional group is to address Aim 3 of this research study. Aim 3 will be accomplished by randomizing eligible patients to normoxic or hyperoxic conditions with normocarbic or hypercarbic blood concentrations through ventilator adjustments per the factorial design. All four groups are considered within the bounds of standard practice for many mechanically ventilated patients. Investigators will exclude patients in whom these settings could be detrimental. The patient will be on the study settings by hour 60 of mechanical ventilation, and these settings will be held for 48 hours from achieving the target partial pressure of oxygen (PaO2) levels. Upon enrollment, an arterial line will be placed if there is not already one in place, and an arterial blood gas (ABG) will be drawn if no ABG has been drawn in the prior 12 hours to enrollment. Over 1-3 hours following ventilator adjustments, several ABGs will be drawn in order to determine the need for additional ventilator adjustments. Foreseeable adjustments include changes to FiO2, respiratory rate, and tidal volume. Once the desired PaO2 level is achieved (time 0), investigators will obtain an ABG q12 hours throughout the 48 hour interventional period. After maintaining the ventilator settings for 48 hours, ventilator management will revert to the clinical team. Blood and bronchoalveolar lavage (BAL) will be collected from the patient at time of enrollment.

Official Title
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Danger Associated Molecular Patterns (DAMP) Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium

Conditions
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Respiratory Failure

Intervention / Treatment
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* Other: Normoxia with Normocarbia
* Other: Normoxia with Hypercarbia
* Other: Hyperoxia with Normocarbia
* Other: Hyperoxia with Hypercarbia


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Normoxia with Normocarbia<br>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 | Other: Normoxia with Normocarbia<br>* PaO2 < 100 (FiO2 >= 21%) PaCO2 of 30-40<br>|
| Active Comparator: Normoxia with Hypercarbia<br>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 | Other: Normoxia with Hypercarbia<br>* PaO2 < 100 (FiO2 >= 21%) PaCO2 of 50-60<br>|
| Active Comparator: Hyperoxia with Normocarbia<br>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 | Other: Hyperoxia with Normocarbia<br>* PaO2 > 250 (FiO2 >= 70%) PaCO2 of 30-40<br>|
| Active Comparator: Hyperoxia with Hypercarbia<br>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 | Other: Hyperoxia with Hypercarbia<br>* PaO2 > 250 (FiO2 >= 70%) PaCO2 of 50-60<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammatory markers | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mechanical Ventilation, Alevolar stretch, Hyperoxia, Normoxia, Hypercarbia, Normocarbia