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

NCT03993002 | Terminated

• 2 other identifiers: 2016P000144PR151953
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Respiratory Failure

Keywords

Mechanical Ventilation; Alevolar stretch; Hyperoxia; Normoxia; Hypercarbia; Normocarbia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Neutrophil activation

  Change over hours 24, 48 and 72

• Purine metabolism

  Change over hours 24, 48 and 72

Study Arms (4)

Normoxia with Normocarbia

ACTIVE COMPARATOR

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

Normoxia with Hypercarbia

ACTIVE COMPARATOR

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

Hyperoxia with Normocarbia

ACTIVE COMPARATOR

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

Hyperoxia with Hypercarbia

ACTIVE COMPARATOR

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

Interventions

Normoxia with Normocarbia OTHER

PaO2 \< 100 (FiO2 \>= 21%) PaCO2 of 30-40

Normoxia with Normocarbia

Normoxia with Hypercarbia OTHER

PaO2 \< 100 (FiO2 \>= 21%) PaCO2 of 50-60

Normoxia with Hypercarbia

Hyperoxia with Normocarbia OTHER

PaO2 \> 250 (FiO2 \>= 70%) PaCO2 of 30-40

Hyperoxia with Normocarbia

Hyperoxia with Hypercarbia OTHER

PaO2 \> 250 (FiO2 \>= 70%) PaCO2 of 50-60

Hyperoxia with Hypercarbia

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Expected to be on Control Mode Ventilation (CMV) for at least 48 hours from the time of screening

You may not qualify if:

• 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

Sponsors & Collaborators

• Beth Israel Deaconess Medical Center: lead
• United States Department of Defense: collaborator

Study Sites (1)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Related Publications (2)

• 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.

  PMID: 25390327 BACKGROUND

• 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.

  PMID: 20203610 BACKGROUND

MeSH Terms

Conditions

Respiratory Insufficiency; Hyperoxia; Hypercapnia

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Daniel Talmor, MD MPH

  Beth Israel Deaconess Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 26, 2018
• First Posted: June 20, 2019
• Study Start: November 15, 2019
• Primary Completion: March 15, 2020
• Study Completion: October 1, 2021
• Last Updated: March 18, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share
• 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.

Locations

US (1)