This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Acute lung injury (ALI) is a common and devastating syndrome seen in critically ill patients with over 200,000 cases per year in the US alone. It is associated with high mortality (40% of patients with ALI die) and morbidity, and the financial cost to society is tremendous. Sepsis is the most common risk factor for ALI, accounting for 79% of cases. Only one treatment, using low breath volumes on the mechanical ventilator, has ever been shown to modestly improve survival from ALI, and there are no available therapies known to prevent ALI. New therapies aimed at preventing the development of ALI in patients at risk for the syndrome are desperately needed. Eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), the two omega-3 fatty acids found in fish oil, have multiple anti-inflammatory properties and are a promising new treatment for patients with existing ALI that we and others are studying. There is also exciting plausible biologic rationale for EPA and DHA as a preventative treatment for ALI: 1) in healthy volunteers, EPA and DHA decrease the same types of inflammation that lead to ALI, and 2) EPA and DHA ameliorate the development of ALI in animal models. Work investigating EPA and DHA as a preventative therapy for ALI in humans has not been performed before and, if effective, would represent a monumental leap forward in the care of patients at risk for ALI. However, there are substantial gaps in knowledge of this agent that must be filled before we can proceed with large human trials. For instance, we currently do not know the pharmacokinetics of EPA and DHA in critically ill patients;thus it is unclear how to properly dose the agent. Furthermore, we only have limited understanding of how fish oil might affect the function of circulating immune cells in patients with sepsis who are at risk for, but have not yet developed, ALI. This study defines the pharmacokinetics of EPA and DHA in sepsis patients at risk for ALI compared to healthy controls and investigates the hypothesis that EPA and DHA likely have different kinetics in critically ill patients than in healthy patients. We will also investigate whether administration of EPA and DHA modulates the responses of inflammatory cells in the blood in both patients with sepsis at risk for ALI and in healthy volunteers. All critically ill patients in this study have sepsis but have not yet developed ALI. They are over 18 years old and cared for in an intensive care unit. Once patients are enrolled, they will undergo baseline blood sampling. They receive enteral liquid fish oil in a specified dosing regimen for 7 days, during which time they undergo serial blood draws for pharmacokinetic measurements. They then undergo a 7-day period of """"""""washout"""""""" during which no fish oil is given but pharmacokinetic measurement continue. Healthy controls are also over 18 years old and are recruited from the community. They receive the same oral fish oil dosing regimen (except in capsular form) as the critically ill patients and will have their blood draws according to the same protocol. This research is the first to investigate fish oil as a therapy to prevent acute lung injury in patients at risk and sets the foundation for larger studies. It rigorously defines the pharmacology of EPA and DHA in critically ill patients while investigating the mechanism of action using obtained blood samples.
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