EPA & DHA IN CRITICALLY ILL PATIENTS WITH SEPSIS AND CONTROLS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 急性肺损伤（ALI）是一种常见的、毁灭性的综合征，仅在美国每年就有超过20万例危重患者。 它与高死亡率（40%的ALI患者死亡）和发病率相关，并且社会的经济成本是巨大的。 脓毒症是ALI最常见的危险因素，占病例的79%。 只有一种治疗方法，即在机械呼吸机上使用低呼吸量，已被证明可以适度改善ALI的生存率，并且没有已知的预防ALI的可用疗法。 迫切需要新的治疗方法来预防有综合征风险的患者发生ALI。 二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）是在鱼油中发现的两种omega-3脂肪酸，具有多种抗炎特性，是我们和其他人正在研究的现有ALI患者的有希望的新治疗方法。 EPA和DHA作为ALI的预防性治疗也有令人兴奋的合理生物学原理：1）在健康志愿者中，EPA和DHA减少导致ALI的相同类型的炎症，2）EPA和DHA改善动物模型中ALI的发展。 研究EPA和DHA作为人类ALI预防性治疗的工作以前从未进行过，如果有效，将代表着护理有ALI风险的患者的巨大飞跃。 然而，在我们能够进行大规模人体试验之前，必须填补对这种药物的认识方面的巨大空白。 例如，我们目前不知道EPA和DHA在重症患者中的药代动力学;因此，不清楚如何正确给药。 此外，我们对鱼油如何影响脓毒症患者循环免疫细胞功能的了解有限，这些患者有发生ALI的风险，但尚未发展成ALI。 本研究定义了EPA和DHA在有ALI风险的脓毒症患者中的药代动力学，并与健康对照组进行了比较，并研究了EPA和DHA在危重患者中可能具有与健康患者不同的动力学的假设。 我们还将研究是否EPA和DHA的管理调节炎症细胞在血液中的反应，在脓毒症患者的ALI风险和健康志愿者。 本研究中的所有重症患者均患有脓毒症，但尚未发生ALI。 他们18岁，在重症监护室接受护理。 一旦患者入组，他们将接受基线血样采集。 他们以指定的给药方案接受肠内液体鱼油7天，在此期间，他们进行连续抽血以进行药代动力学测量。 然后，他们经历了7天的“洗脱”期，在此期间没有鱼油，但药代动力学测量继续进行。 健康对照组也是18岁，从社区招募。 他们接受与重症患者相同的口服鱼油给药方案（胶囊形式除外），并将根据相同的方案进行抽血。 这项研究是第一个研究鱼油作为预防高危患者急性肺损伤的疗法，并为更大规模的研究奠定了基础。 它严格定义了EPA和DHA在重症患者中的药理学，同时使用获得的血液样本研究其作用机制。

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 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 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.