Clinical trial NCT03993002: DAMP-Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium
Official title: Danger Associated Molecular Patterns (DAMP) Mediated Innate Immune Failure and Pneumonia After Trauma - the Harvard-Longwood (HALO) Campus Area Consortium
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Respiratory Failure
Keywords: Mechanical Ventilation
Alevolar stretch
Hyperoxia
Normoxia
Hypercarbia
Normocarbia
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2019-06-20
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: BASIC_SCIENCE

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.

Eligibility 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

Primary outcomes:
measure: Inflammatory markers
timeFrame: Change over hours 24, 48 and 72
Secondary outcomes:
measure: Neutrophil activation
timeFrame: Change over hours 24, 48 and 72
measure: Purine metabolism
timeFrame: Change over hours 24, 48 and 72
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Daniel Talmor, MD MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.