Early Insulin Therapy and Development of ARDS

描述（由申请人提供）：对急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）的预防关注相对较少。最近，强化胰岛素治疗（NT）已被证明可以降低重症监护室（ICU）长期住院的重症患者的发病率和/或死亡率，但NT对预防早期重症疾病事件（如ALI/ARDS）的效用尚不清楚。该提案的主要目的是评估早期IIT预防高危人群ALI/ARDS的潜力。在目标1中，将在基于ARDS分子流行病学的回顾性巢式病例对照研究中检查早期胰岛素治疗与ARDS发生之间的关联，该研究是一项针对有ARDS风险患者的大型前瞻性研究。然而，任何预防ALI/ARDS的干预都必须及早进行，最好是在ICU入院前，因为38%的ARDS患者在ICU入院当天就符合ARDS标准。因此，在目标#2中，在一项随机对照试验中，将检查在急诊科（艾德）开始的早期IIT减少肺损伤和调节与脓毒症相关的ALI/ARDS有关的介质的潜力。倾向评分分析方法和多变量逻辑回归模型将用于解释目标#1中的潜在混杂因素。在目标#2中，将在脓毒症的第一周连续记录通过Murray肺损伤评分（LIS）测量的肺损伤。此外，将在进入艾德时以及研究第1天和第3天从重度脓毒症患者中采集血样，并通过液相色谱法和气相色谱法以及ELISA法测定游离脂肪酸、肿瘤坏死因子-α、白细胞介素-6和血管性血友病因子抗原的血浆水平。将使用协方差分析比较随机分配至艾德接受早期IIT的患者与标准ICU组（ICU入院后48小时接受IIT）患者之间LIS和血浆水平随时间的变化。该提案与NHLBI的使命和公共卫生相关。ALI/ARDS是一种破坏性的肺损伤，具有显著的死亡率、发病率和医疗保健成本。任何能够降低ALI/ARDS发生率的干预措施都将在挽救生命和避免发病方面产生重大的流行病学影响。

DESCRIPTION (provided by applicant): There has been relatively little focus on the prevention of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS). Recently, intensive insulin therapy (NT) have been shown to decrease morbidity and/or mortality in critically ill patients with prolonged intensive care unit (ICU) stays, but the utility of NT to protect against early critical illness events such as ALI/ARDS is unknown. The broad objective of this proposal is to assess the potential of early IIT to prevent ALI/ARDS in at-risk populations. In Aim #1, the association between early insulin therapy and development of ARDS will be examined in a retrospective nested case control study based on the Molecular Epidemiology of ARDS, a large prospective study of patients at risk for ARDS. However, any intervention to prevent ALI/ARDS must occur early, preferably prior to ICU admission, since 38% of ARDS patients fulfill ARDS criteria on the day of ICU admission. Thus in Aim #2, in a randomized control trial, the potential of early IIT initiated in the Emergency Department (ED) to reduce lung injury and modulate mediators implicated in sepsis-related ALI/ARDS will be examined. The method of propensity score analyses and multivariate logistic regression models will be used to account for potential confounders in Aim #1. In Aim #2, lung injury as measured by the Murray Lung Injury Score (LIS) will be recorded serially in the first week of sepsis. In addition, blood samples will be collected from patients with severe sepsis on admission to the ED and on Day 1 and 3 of the study and plasma levels of free fatty acids, tumor necrosis factor-a, interleukin-6 and Von Willebrand Factor antigen will be determined by liquid and gas chromatography and by ELISA. Analyses of covariance will be used to compare the change in LIS and plasma levels over time between patients randomized to receive early IIT in the ED versus the standard ICU group who receive IIT 48 hours after ICU admission. This proposal has significant health relatedness to the NHLBI's mission and relevance to public health. ALI/ARDS is a devastating form of lung injury with significant mortality, morbidity, and health care costs. Any intervention that can decrease the incidence of ALI/ARDS will have a significant epidemiologic impact in lives saved and morbidity averted.