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）预防的关注相对较少。最近，强化胰岛素治疗（NT）已被证明可以降低重症监护病房（ICU）重症患者的发病率和/或死亡率，但NT在预防早期重症事件（如ALI/ARDS）中的效用尚不清楚。本建议的主要目的是评估早期IIT在高危人群中预防ALI/ARDS的潜力。在目标1中，基于ARDS分子流行病学的回顾性巢式病例对照研究将检查早期胰岛素治疗与ARDS发展之间的关系，这是一项针对ARDS风险患者的大型前瞻性研究。然而，任何预防ALI/ARDS的干预措施都必须尽早进行，最好是在ICU入院之前，因为38%的ARDS患者在ICU入院当天符合ARDS标准。因此，在Aim #2中，在一项随机对照试验中，将研究在急诊科（ED）早期启动IIT以减少肺损伤和调节与败血症相关的ALI/ARDS相关的介质的潜力。在Aim #1中，将使用倾向评分分析和多变量逻辑回归模型的方法来解释潜在的混杂因素。在目标2中，在脓毒症的第一周，将按顺序记录Murray肺损伤评分（LIS）测量的肺损伤。此外，重症脓毒症患者将在入院时和研究的第1天和第3天采集血液样本，并通过液相和气相色谱法和ELISA法测定血浆游离脂肪酸、肿瘤坏死因子-a、白细胞介素-6和血管性血友病因子抗原的水平。协方差分析将用于比较在ED中随机接受早期IIT的患者与在ICU入院后48小时接受IIT的标准ICU组之间LIS和血浆水平随时间的变化。这一建议与国家卫生和社会保障机构的使命和公共卫生具有重大的卫生相关性。急性呼吸窘迫综合征（ALI/ARDS）是一种毁灭性的肺损伤，具有很高的死亡率、发病率和医疗费用。任何能够降低急性呼吸窘迫综合征/急性呼吸窘迫综合征发病率的干预措施都将在挽救生命和避免发病率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.