A Phase 2 Study of Inhaled CO for the Treatment of ARDS
Abstract
Acute respiratory distress syndrome (ARDS) is the syndrome defined by the Fiscal Year 2017 (FY17) Peer Reviewed Medical Research Program (PRMRP) Topic Area of Acute Lung Injury, an acute and severe respiratory failure marked by impairment of the lung’s critical ability to move oxygen into the bloodstream. Lung damage in ARDS is so severe that advanced life support in the form of invasive mechanical ventilation is required to prevent respiratory arrest. Despite advances in critical care, ARDS morbidity and mortality remain unacceptably high, with mortality of 27% in even “mild” cases and up to 45% in the most severe ARDS. In a recent global study of prevalence, ARDS was found to represent approximately 10% of admissions to intensive care units (ICUs). In military populations, development of ARDS complicating combat injuries is an independent risk factor for death. ARDS can occur from either a direct injury to the lung or indirectly from trauma or inflammation occurring elsewhere in the body. Direct injuries to the lung include pneumonia, exposure to high concentrations of oxygen, and inhalation of toxic substances like chemicals or gastric contents during loss of consciousness. Examples of injury or illness that indirectly cause ARDS are hemorrhagic shock requiring massive blood product transfusions, trauma or burn injuries, and sepsis from infections outside of the lung. Sepsis is the most common cause of ARDS in civilian and Veteran populations and trauma is of particular relevance to the military, although sepsis also complicates the course of many critically ill patients hospitalized for other reasons, such as trauma or burns. This proposal addresses the specific FY17 PRMRP Area of Encouragement of therapeutics to reduce the severity of ARDS and/or other lung injury secondary to trauma, transfusion, burns, hemorrhagic shock, inhalation, and/or oxygen exposure. Current treatment for patients with ARDS is designed to minimize further complications from critical illness, while allowing time for the underlying lung injury to heal on its own. There are no treatments for ARDS itself, however, either targeting the existing lung damage or promoting healing. The objectives of this proposal are to determine whether one of the body’s own mechanisms for resolving injury can be exploited to treat ARDS. Carbon monoxide (CO) is best known for toxicity in high exposure situations, but it is also a gas produced by our own cells to limit inflammatory responses and protect cells from injury, stimulating resolution of damage and healing. We have shown in healthy human volunteers that short duration, low dose exposures to inhaled CO turns on these same protective biologic programs. Early studies in patients with lung diseases have shown no adverse effects from short, low dose exposures, and three Data and Safety Monitoring Board reviews of our own in-progress Phase I safety trial have also not shown adverse effects related to breathing CO in ARDS patients. The critical questions to be answered in this Phase II trial of inhaled CO (iCO) for treatment of ARDS are: (1) Is iCO effective in reducing the severity of lung injury and other organ failures frequently present in patients with ARDS? (2) Is iCO safe and well-tolerated in this larger Phase II group? (3) Can our dosing algorithm predict safe and effective target drug levels during iCO therapy? (4) Does iCO treatment in ARDS decrease the abnormalities underlying inflammatory injury to cells, promoting resolution of injury? The latter will also assess new ways to clinically measure the biologic processes of injury and resolution of injury through biomarker measurements in order to best guide future application of this new treatment. To achieve these objectives, we will recruit and enroll ARDS patients from medical, surgical, cardiac, and burn ICUs at five medical centers (Weill Cornell, Brigham and Women’s, Massachusetts General, Duke, and the Durham Veterans Administra
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810667
Entities
People
- Augustine M K Choi
Organizations
- United States Army
- Weill Cornell Medicine