The whole is greater than the sum of its parts * I n 1994

I n 1994, the American-European Consensus Conference gave formal definition and structure to the concept of adult respiratory distress syndrome (ARDS), a diagnosis that had many configurations in the preceding decades (1). With that framework established, a more concise body of literature could be written to fill in the gaps of our knowledge and understanding. Mortality of ARDS patients had declined from the early 1980s to 1996, then leveled off (2), particularly in the septic population. Was the intensive care community part of the solution or the problem? We were both. Building on the work of many investigators, the ARDS Network demonstrated in 2000 that ventilation with lower tidal volumes than traditionally used improved outcomes in patients with acute lung injury (ALI) and ARDS (3). The concepts of ventilator-associated lung injury and ventilator-induced lung injury followed. While the ventilator-related diagnoses provided new entities to treat, the clinical picture became more muddled. Dr. Frank and colleagues (4) reported on the use of biological markers in an attempt to identify “ventilator attributable injury. ” A marker profile emerged that differed between patients ventilated with low tidal volume vs. traditional volumes. For example, the level of tumor necrosis factor receptor-1, which is a marker for alveolar epithelial injury, prognosticated morbidity and mortality with ALI, and also was influenced by low tidal volume ventilation (5). Our understanding of the role played by biological markers in the management of ALI/ARDS continues to evolve. The diagnoses of ARDS, ALI, ventilator-associated lung injury, and ventilator-induced lung injury have been applied to a wide swath of patients. The lack of homogeneity of patient population and situation complicates the design of clinical trials. Dr. Wood and colleagues (6) recommended attention to four important factors: prevalence, absolute outcome, attributable outcome, and treatment responsiveness. ALI/ARDS patients often have a significant mortality attributable to their underlying disease; if sample size is not adequate, treatment benefits may not be apparent. Appropriate study group selection also is important in trial design to assure reliability of outcome data and conclusions (7). Ware summarized 64 studies investigating the use of clinical and biological markers for ARDS/ALI prognosis, with the hope that a core group of markers would allow better selection of study groups and identification of those patients requiring more complex ventilatory modalities. She identified that increased levels of interleukin-6, interleukin-8, von Willebrand factor, surfactant protein-D, intercellular adhesion molecule-1, soluble tumor necrosis factor receptor-2, and plasminogen activator inhibitor-1 and decreased levels of protein C were predictive of death. Members of the ARDS network and collaborators have used additional data collected in the network to tease out more specific information and implications than that previously published. Dr. Eisner and colleagues (8) found that nearly all clinical risk groups responded with similar benefit to low tidal volume ventilation, although mortality differed among risk types. Those identified with a traumatic cause of lung failure had statistically lower mortality than those with sepsis, aspiration, pneumonia, and other causes. In this issue of Critical Care Medicine, Dr. Calfee and colleagues (9), in conjunction with the ARDS Network, ask the next questions: Do trauma patients with ALI/ ARDS fare better than patients with other risk factors? Why? Are there levels of biological markers, both endothelialspecific and more general signs of inflammation/coagulation, that are associated with better outcomes? The authors analyzed data collected for the Acute Respiratory Distress Syndrome Network low tidal volume (ARMA) (3) and Assessment of Low Tidal Volume and Increased Endexpiratory Volume to Obviate Lung Injury (ALVEOLI) trials (10) that evaluated the use of low tidal volume ventilation and higher positive end-expiratory pressure levels, respectively, in the outcome of ALI/ARDS. Patients were divided between trauma (n 141) and nontrauma (n 1307) populations. They analyzed clinical factors such as demographics; associated diseases; Acute Physiology, Age, and Chronic Health Evaluation III scores; hemodynamic measurements; and ventilatory parameters. Levels of intercellular adhesion molecule-1, von Willebrand factor, surfactant protein-D, soluble tumor necrosis factor receptor-1, interleukin-6, interleukin-8, protein C, and plasminogen activator inhibitor-1 were evaluated. Rigorous statistical analysis was performed. The primary outcome measure was 90day mortality. Trauma patients had mortality significantly lower than the nontrauma patients. Interestingly, biomarkers more specific for alveolar epithelial injury were decreased in the trauma group, but systemic markers were similar. Did they prove that this marker profile has prognostic and therapeutic implications? Or are the data true but unrelated? Yes, trauma patients do better in this study— because they are younger, healthier, and less severely ill. The machination of statistics necessary to prove that those factors do not matter would do Houdini proud. The data were adjusted for age; gender; ethnicity; low tidal volume strategy; comorbidities; Acute Physiology, Age, and Chronic Health Evaluation III scores; and PaO2/FIO2 ratios. Remaining were leukemia, lymphoma, solid tumors with metastases, liver failure, and cirrhosis. These were not comparable groups. Consideration of the data reveals several other problems. The authors state, “First, this study comprehensively describes the clinical features of traumaassociated ALI in a large cohort . ” The trauma population was only 141 patients, 10% of the study. The mechanism of injury, injury severity score, and presence of a direct chest injury were not collected *See also p. 2243.