Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), the severest form of ALI, are acute and life-threatening forms of injury to the lung, together affecting 30,000 to 150,000 people each year in the U.S. ALI is the clinical manifestation of injury to the lung via a 'final common pathway'of oxidant stress, inflammation and capillary permeability. There is no defined medical therapy for ALI and mortality rates range from 35% to 50%. Caring for patients with ALI requires prolonged mechanical ventilation and supportive intensive care, resulting in reduced quality of life and contributing substantially to healthcare costs. It is now well established that fluid overload, weight gain, and reductions in oncotic pressure are deleterious factors in ALI. In critically ill hypoproteinemic patients, the risk for developing ALI is doubled compared to patients with normal serum total protein. Hypoproteinemic ALI patients require significantly longer mechanical ventilation and are three times more likely to die. In the applicant's two prior randomized controlled trials, the treatment combination of albumin with furosemide produced the greatest improvements in arterial oxygenation and systemic hemodynamics compared to treatment with dual placebos or furosemide alone. The mechanisms for benefits in oxygenation are unclear, and the applicant believes that they relate to both the antioxidant capacity of albumin to manipulate redox balance and capillary barrier function, and the colligative nature of albumin to influence extravascular lung water (EVLW). Improvements in oxygenation, antioxidant balance and EVLW are each independently relevant for ALI and may contribute to improved clinical outcomes. This award supports the conduct of a translational clinical trial to demonstrate the efficacy of colloid and diuretic therapy in hypoproteinemic ALI patients and establish the responsible mechanisms. The applicant hypothesizes that changes in oxygenation related to albumin and furosemide therapy in ALI result from biochemical properties of albumin that improve pulmonary glutathione homeostasis to alter NF(B activation and thereby improve alveolar capillary barrier function, combined with colligative properties that affect EVLW. Improvements in oxygenation and EVLW are relevant to ALI patients, both contributing to prolonged mechanical ventilation, decreased survival and reduced quality of life. It is additionally important to elucidate the mechanisms underlying the clinical benefits in order to optimize colloid and diuretic therapy in this condition, to be examined by comparison of albumin with a similarly oncotic synthetic colloid lacking antioxidant capacities. The stated hypotheses and trial design will test clinically relevant outcomes and will provide essential data of monitored comparative colloid-based therapy for new drug development and expanded FDA indications for both drug therapies and physiological monitoring equipment. This trial will also provide requisite data for any subsequent clinical trials targeted at other clinically relevant outcomes, such as mortality, the duration of mechanical ventilation, or health-related quality of life.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
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Special Emphasis Panel (ZFD1-OPD-L (01))
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Kempker, Jordan A; Martin, Greg S (2016) Does Sepsis Case Mix Heterogeneity Prevent Outcome Comparisons? Crit Care Med 44:2288-2289
Kempker, Jordan A; Martin, Greg S (2016) Sepsis to the Fore: Taking the Lead in Critical Care Admissions. Crit Care Med 44:1435-6
Cochi, Shea E; Kempker, Jordan A; Annangi, Srinadh et al. (2016) Mortality Trends of Acute Respiratory Distress Syndrome in the United States from 1999 to 2013. Ann Am Thorac Soc 13:1742-1751
Ogbu, Ogbonna C; Murphy, David J; Martin, Greg S (2015) How to avoid fluid overload. Curr Opin Crit Care 21:315-21
Kempker, Jordan A; West, Kathryn G; Kempker, Russell R et al. (2015) Vitamin D status and the risk for hospital-acquired infections in critically ill adults: a prospective cohort study. PLoS One 10:e0122136
Sevransky, Jonathan E; Checkley, William; Herrera, Phabiola et al. (2015) Protocols and Hospital Mortality in Critically Ill Patients: The United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. Crit Care Med 43:2076-84
Cribbs, Sushma K; Tse, Caroline; Andrews, Joel et al. (2015) Characteristics and Outcomes of HIV-Infected Patients With Severe Sepsis: Continued Risk in the Post-Highly Active Antiretroviral Therapy Era. Crit Care Med 43:1638-45
Nirappil, Freny J; Maheshwari, Ana; Andrews, Joel et al. (2015) Characteristics and outcomes of HIV-1-infected patients with acute respiratory distress syndrome. J Crit Care 30:60-4
Checkley, William; Martin, Greg S; Brown, Samuel M et al. (2014) Structure, process, and annual ICU mortality across 69 centers: United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. Crit Care Med 42:344-56
Prebil, Sarah E W; Andrews, Joel; Cribbs, Sushma K et al. (2014) Safety of research bronchoscopy in critically ill patients. J Crit Care 29:961-4

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