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.
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.
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