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出境医 / 临床实验 / DAMP-Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium (HALO)

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

Study Description
Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Respiratory Failure Other: Normoxia with Normocarbia Other: Normoxia with Hypercarbia Other: Hyperoxia with Normocarbia Other: Hyperoxia with Hypercarbia Not Applicable

Detailed Description:
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.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Danger Associated Molecular Patterns (DAMP) Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium
Actual Study Start Date : November 15, 2019
Estimated Primary Completion Date : November 1, 2022
Estimated Study Completion Date : November 1, 2024
Arms and Interventions
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

 Other: Normoxia with Normocarbia
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

 Other: Normoxia with Hypercarbia
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

 Other: Hyperoxia with Normocarbia
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

 Other: Hyperoxia with Hypercarbia
PaO2 > 250 (FiO2 >= 70%) PaCO2 of 50-60
Outcome Measures
Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations

Locations
Layout table for location information
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
United States Department of Defense
Investigators
Layout table for investigator information
Principal Investigator: Daniel Talmor, MD MPH Beth Israel Deaconess Medical Center
Tracking Information
First Submitted Date  ICMJE October 26, 2018
First Posted Date  ICMJE June 20, 2019
Last Update Posted Date April 28, 2020
Actual Study Start Date  ICMJE November 15, 2019
Estimated Primary Completion Date November 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 18, 2019) 		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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 18, 2019)
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE DAMP-Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium
Official Title  ICMJE Danger Associated Molecular Patterns (DAMP) Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium
Brief Summary

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 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Respiratory Failure
Intervention  ICMJE
  • Other: Normoxia with Normocarbia
    PaO2 < 100 (FiO2 >= 21%) PaCO2 of 30-40
  • Other: Normoxia with Hypercarbia
    PaO2 < 100 (FiO2 >= 21%) PaCO2 of 50-60
  • Other: Hyperoxia with Normocarbia
    PaO2 > 250 (FiO2 >= 70%) PaCO2 of 30-40
  • Other: Hyperoxia with Hypercarbia
    PaO2 > 250 (FiO2 >= 70%) PaCO2 of 50-60
Study Arms  ICMJE
  • 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

    Intervention: Other: Normoxia with Normocarbia
  • 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

    Intervention: Other: Normoxia with Hypercarbia
  • 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

    Intervention: Other: Hyperoxia with Normocarbia
  • 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

    Intervention: Other: Hyperoxia with Hypercarbia
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. Review.
  • 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: June 18, 2019) 		50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 1, 2024
Estimated Primary Completion Date November 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03993002
Other Study ID Numbers  ICMJE 2016P000144
PR151953 ( Other Grant/Funding Number: Department of Defense )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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.
Time Frame: beginning 12 months after and ending 36 months after primary study publication.
Access Criteria: Proposals should be directed to dtalmor@bidmc.harvard.edu. To gain access, data requestors will need to sign a data access agreement and have any necessary ethics board approvals in place.
Responsible Party Beth Israel Deaconess Medical Center
Study Sponsor  ICMJE Beth Israel Deaconess Medical Center
Collaborators  ICMJE United States Department of Defense
Investigators  ICMJE
Principal Investigator: Daniel Talmor, MD MPH Beth Israel Deaconess Medical Center
PRS Account Beth Israel Deaconess Medical Center
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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