Early Acute Lung Injury: Prospective Evaluation Prior to Respiratory Failure

描述(申请人提供)：急性肺损伤(ALI)是一种由于肺和非肺损伤而导致的急性缺氧性呼吸衰竭综合征，是发病率和死亡率的主要原因。尽管NHLBI进行了20年的有针对性的调查，但在ALI进展为需要机械通气的呼吸衰竭之前，人们对ALI知之甚少。因此，这项研究计划的目的是：1)前瞻性地确定发展为需要机械通气的ALI的独立预测因素，并建立早期ALI的临床定义；2)评估炎症和肺损伤的生物标志物的发病作用及其对进展为ALI的风险分层的改进价值；3)测试雾化β-2激动剂在早期ALI患者中的潜在治疗价值。具体而言，AIM 1将通过筛查所有成人急诊科和医疗服务入院的胸部X线片来识别潜在的早期ALI病例。入院的患者在胸部X线片上出现双侧阴影，而不是由于单纯性左房高血压，在住院期间将跟踪观察进展为ALI。入院72小时内将记录临床特征(人口学、诊断、合并症、生命体征和Borg呼吸困难评分)。发展为ALI的独立预测因素将通过多变量Logistic回归确定，并纳入早期ALI的临床定义。在特定的AIM 2中，将在研究登记后0和24小时测量代表导致急性肺损伤的不同途径的生物标志物(IL-8、sTNFR-1、vWF、ICAM-1、SP-D和RAGE)的水平。生物标志物将通过多元回归分析进行分析，以评估其在对进展为ALI的风险患者进行分层方面的价值，并提供对早期ALI发病机制的深入了解。在特定的AIM 3中，我将在早期ALI患者中进行雾化吸入沙丁胺醇与安慰剂的随机临床试验。主要终点将是治疗第4天的Pa02/Fi02。次要结果指标将是ALI的进展率和血浆生物标志物水平的变化。这将是第一次此类试验，以确定早期ALI患者可以被识别出来，并在需要机械通气之前开始治疗。相关性(参见说明书)：遵循严重脓毒症的早期目标导向治疗模式，早期ALI患者并在需要机械通气之前(因此在满足当前研究进入标准之前)开始治疗可能会带来临床益处。建立早期ALI的循证临床定义将有助于为将来的临床试验登记受试者的识别和风险分层。(摘要结束)

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a syndrome of acute hypoxic respiratory failure due to pulmonary and non-pulmonary insults and is a major cause of morbidity and mortality. Despite two decades of targeted investigation by the NHLBI, little is known about ALI prior to progression to respiratory failure requiring mechanical ventilation. Accordingly, the aims of this research plan are to: 1) prospectively identify independent predictors of progression to ALI requiring mechanical ventilation and establish a clinical definition of early ALI; 2) evaluate the pathogenetic role of biologic markers of inflammation and lung injury and their value for refining risk stratification of patients at risk for progression to ALI, and 3) test the potential therapeutic value of an aerosolized beta-2 agonist in patients with early ALI. In SPECIFIC AIM 1 will identify cases of potential early ALI by screening chest radiographs of all adult emergency department and medicine service admissions. Patients admitted to the hospital with bilateral opacities on chest radiograph not due to isolated left atrial hypertension will be followed for progression to ALI during their hospitalization. Clinical characteristics (demographics, diagnoses, comorbidities, vital signs, and Borg dyspnea scores) will be recorded for the first 72 hours of admission. Independent predictors of progression to ALI will be determined by multivariate logistic regression and incorporated into a clinical definition of early ALI. In SPECIFIC AIM 2, plasma levels of biomarkers (IL-8, sTNFr-1, vWF, ICAM-1, SP-D and RAGE) representing distinct pathways contributing to acute lung injury will be measured at time 0 and 24 hours after study enrollment. Biomarkers will be analyzed by multivariate regression analysis to assess their value for stratifying patients at risk for progression to ALI and provide mechanistic insight into the pathogenesis of early ALI. In SPECIFIC AIM 3 I will conduct a randomized clinical trial of aerosoUzed albuterol vs. placebo in patients with early ALI. The primary endpoint will be the Pa02 / Fi02 on day 4 of treatment. Secondary outcome measures will be rate of progression to ALI and change in plasma biologic marker levels. This will be a first-of-its-kind trial to establish that patients with early ALI can be identified and treatment can be initiated prior to need for mechanical ventilation. RELEVANCE (See instructions): Following the paradigm of early goal-directed therapy for severe sepsis, clinical benefit may derive from identifying patients with early ALI and initiating treatment prior to the need for mechanical ventilation (and therefore prior to meeting current study entry criteria). Establishing evidence based clinical definition of early ALI will facilitate identification and risk stratification of subjects for enrollment in future clinical trials. (End of Abstract)