Predictors of death in established ALI are important and clinically relevant for two reasons. First, previous studies have reported an average duration of mechanical ventilation in ALI between 5 and 16 days, suggesting that a large proportion of patients with ALI are alive and mechanically ventilated 6 days after the diagnosis of ALI [13–15]. Second, important management decisions to escalate or limit the intensity of care are often made during this time interval. In this prospective cohort study of 93 patients with ALI who survived 6 or more days of mechanical ventilation, we found that a low or decreasing respiratory system compliance on the 6th day of mechanical ventilation was associated with an increased risk of death. This finding is novel because few other studies have identified pulmonary predictors of mortality in ALI patients ventilated with lung-protective ventilation during this stage of disease. In addition, if prospectively validated, these findings may help identify patients who are failing traditional therapy and who might benefit from novel rescue therapies.
Although the cumulative risk of complications associated with mechanical ventilation, including ventilator-associated pneumonia and sepsis, increases with each ventilator day, we were surprised to find that the mortality of patients who were ventilated for 6 or more days was similar to patients enrolled in our previous study  which included patients who died or were extubated during the first 6 days of ALI (35% vs. 42%, p = 0.42). Other studies, including the Kings County Lung Injury Project and the ARDSNet trial of steroids for persistent ARDS, reported surprisingly low mortality rates in patients requiring prolonged ventilation for ALI as well [13, 14, 16, 17]. The low mortality in this study may be because the sickest patients who present with severe shock, catastrophic injury, or refractory hypoxemia die during the first 6 days of ALI and thus were not included in this analysis.
Previous studies of pulmonary predictors of mortality in ALI have focused on early predictors of mortality [18, 4, 19, 20] or on physiologic changes between the onset of ALI and the third day of mechanical ventilation [21, 19, 20] in patients ventilated with traditional tidal volumes. In this study, the OI was the only variable predictive of death on the first day of lung injury in bivariate analysis. The OI was an independent predictor of mortality in the complete cohort of patients , and as previously published, is a clinically practical, early predictor of death in both adult  and pediatric  ALI populations. Contrary to previous reports , measures of pulmonary mechanics, including respiratory system compliance and Pplat, were not predictive of death on the first day of mechanical ventilation. This difference from prior studies may be partially attributable to the use of lung-protective ventilation, which could attenuate alveolar stretch during mechanical ventilation.
On the 2nd and 3rd day of ALI, none of the physiologic variables measured in this study were associated with death. In contrast, previous studies found one or more predictors of death on days 2 and 3 of ALI. Cooke at al  examined predictors of mortality in a cohort of 1,113 patients with ALI and found that the change in PaO2/FiO2 ratio between the day of diagnosis and day 3 of hospitalization was predictive of death. Similarly, Estenssoro et al  examined a cohort of 217 patients in Argentina and found that the PaO2/FiO2 ratio was predictive of death on the third day of mechanical ventilation. Lastly, Gajic et al  retrospectively analyzed multiple physiologic variables on day 3 of mechanical ventilation in a large observational trial and then validated it in two independently collected data sets. Gajic et al found that PaO2/FiO2 ratio, Pplat, mean Paw, PEEP and OI on the third day as well as the change in OI and PEEP between days 1 and 3 were predictive of a composite end point of death or ventilator dependence 15 days after intubation.
Three important distinctions may account for the differences between our study, which did not identify pulmonary predictors of death on days 2 or 3 of ALI and the 3 studies reported above. First, patients in our study were managed with a lung-protective ventilation strategy, which may standardize plateau airway pressure and oxygenation. Second, the cohort size may have limited our ability to find statistical differences between survivors and non-survivors on days 2 and 3 of mechanical ventilation. Lastly, our study included only patients who survived >6 days of ALI, thus eliminating patients who died early due to refractory hypoxemia, catastrophic trauma or fulminant septic shock. Although the subgroup of patients who die of hypoxemia is small (approximately 15%), this difference could have driven the statistical significance of the PaO2/FiO2 ratio on the third day of ALI in prior studies [23, 24].
The major finding of this study was that a low or decreasing respiratory system compliance on the 6th day of mechanical ventilation is an independent predictor of mortality in this cohort of patients. Respiratory system compliance may decrease in non-survivors due to a combination several factors, including volume overload, atelectasis and early pulmonary fibroproliferation. Patients with refractory shock may have required more fluid boluses to maintain adequate blood pressures and this may have lead to worsening pulmonary and chest wall edema. Although our data set had greater than 15% missing data for volume administration, there was no statistical difference in daily or cumulative fluid balance between survivors and non-survivors. A higher level of lung collapse and atelectasis may also contribute to decreased compliance in non-survivors. The amount of recruitable lung identified by CT scanning has been shown by others to be associated with mortality during ALI . In the context of our data, lower respiratory system compliance may be indicative of more atelectasis and thus relative over-distention of healthier lung units despite the use of lung-protective ventilation. Lastly, respiratory system compliance may decrease in non-survivors due to the fibroproliferative phase of ALI which can occur as early as the 6th day of mechanical ventilation in autopsy studies . Biochemical studies have identified procollagen peptide I and III, which are precursors of fibrotic collagen, in BAL fluid at the time of ALI diagnosis and the amount of peptide in this specimens correlates with mortality . Future studies utilizing esophageal manometry to accurately estimate the contribution of chest wall or abdominal pressure to total respiratory system compliance, with more complete records of volume administration and weight changes as well as pathologic studies of patient who die during the later phases of ALI could provide a mechanistic explanation for these physiologic findings.
This study has several limitations. First, the small study size may have limited our ability to detect statistical differences in physiologic variables on days 2 and 3 of mechanical ventilation. Second, this study was conducted at an academic and county hospital; thus these findings might not be generalizable to community hospital populations. Third, post-hoc selection of patients can lead to selection bias; however, we believe that our strict criterion (>6 days of mechanical ventilation) for entry into this study was the best way to answer our study question. Fourth, extensive information on transfusion of blood products, a known risk factor for ALI, were not collected. Lastly, due to a small study size we were unable to divide this population into a derivation and validation cohort. Future replication of these findings in a separate cohort of patients with ALI would substantiate our results.