In this study of patients with ALI who were enrolled in the ARDS Network clinical trials between 1996 and 2005, there was a strong, statistically significant temporal improvement in 60-day mortality when comparing enrollment periods. During the 10-year study period, adjusted mortality appeared to improve for patients with the most common causes of lung injury – sepsis, pneumonia and aspiration. However, these trends did not meet statistical significance, likely because of the smaller number of patients in these subgroups. In sum, it appears that general improvements in ICU care translated into decreased ALI mortality for patients treated at ARDS Network centers over the 10 year study period. These findings support previous studies that have shown that mortality from ALI is declining.5-7
However, these prior studies were limited in that they were performed at single centers, and the data supporting these investigations were primarily from years prior to 1994, predating both the American-European Consensus Conference definition of ALI and the introduction of lower tidal volume ventilation. A recent meta-analysis by Zambon and Vincent that included 72 studies and examined survival among patients with ALI from 1994 through 2006 showed that overall mortality decreased by approximately 1.1% per year during this period.15
This meta-analysis was limited by the heterogeneity of the study populations and the lack of individual-level data. The authors were not able to adjust for differences in study inclusion or exclusion criteria, severity of illness or other important clinical or demographic differences.
The present study uses current multi-center data with a uniform definition of ALI and clearly demonstrates that mortality from ALI has improved over the past decade for patients who were treated at ARDS Network centers. Additional strengths of this study include the large number of patients and the detailed patient-level data including information about comorbid conditions and severity of illness. Importantly, prior studies did not perform multivariable analysis with adjustments for severity of illness or comorbid conditions.5-7 15
Several recent studies have shown that there has been a decline in case fatality from sepsis over the past two decades. 16, 17
In addition, Milberg and colleagues observed a significant decrease in mortality from 1983-1993 among patients with sepsis as their cause of lung injury.6
Given the recent advances in the treatment of severe sepsis, including early goal-directed therapy18
and activated protein C19
, it is reasonable to hypothesize that mortality for patients with sepsis-related ALI has improved over the past decade. While there were not statistically significant temporal improvements in mortality among patients with sepsis-associated ALI enrolled in the ARDS Network trials, our study was underpowered to detect small to moderate differences in mortality among the subgroups of patients with different causes of lung injury. This overall temporal trend in improved mortality for patients with diverse causes of lung injury supports the hypothesis that advancements in the general care of critically ill patients may be responsible for these findings. While our study was not capable of determining what mechanisms accounted for the improvement in mortality, recent changes in critical care including, restrictive transfusion protocols, early antibiotic use and nutritional support and appropriate prophylaxis measures are likely contributing.20
Although mortality varied by cause of lung injury, we do not believe that year-to-year variation in case mix accounted for the observed temporal improvement in mortality, as we adjusted for cause of lung injury in the multivariable analysis.
Our study has some limitations. Because this was a secondary analysis of data from randomized controlled trials, it is possible that enrollment targeted patients who were less severely ill in the later trials. Disputing this possibility is the finding that APACHE III scores and APS increased with each subsequent enrollment period. Exclusion of patients requiring renal replacement therapy from FACTT could also have influenced our temporal mortality estimates. However, when the analysis was restricted to patients who did not need renal replacement therapy, the downward temporal mortality trend persisted. Similarly, the transition to lower tidal volume ventilation in the later trials did not appear to be accounting for our findings, as the results were not substantively altered when the analysis was restricted to patients who received lower tidal volume ventilation. Although we had information about many comorbid conditions, we were not able to make comprehensive adjustments for all comorbid conditions. Also, we did not have information about the severity of patients' comorbid conditions like HIV/AIDS or diabetes. It is possible that patients had fewer and less severe comorbid conditions in the later enrollment periods, although there is no apparent reason why this should be so.
Our study may be limited in its generalizability. Over 90% of screened patients were excluded from the ARDS Network trials. We do not have mortality data about patients who were not enrolled in the trials because of issues related to the protection of privacy. Inclusion and exclusion criteria were similar across all trials, making temporal selection bias unlikely. Excluded patients were more likely to have comorbid conditions (transplant, chronic lung disease) and were more likely to be older - characteristics associated with higher mortality. Alternatively, excluded patients were more likely to have trauma as the cause of lung injury and a higher PaO2
These characteristics are associated with lower mortality. Thus, it is difficult to speculate whether mortality was higher or lower among patients who were not enrolled. Further, we do not have information about patients who died before they could be screened or enrolled in the trials. If more severely ill patients died before they could be screened or enrolled during the later time periods, this would have biased our results towards finding a temporal improvement in mortality. Finally, because all patients were cared for at specialized ARDS Network centers, our findings may reflect an improvement of care only at these centers, rather than broad improvements in care throughout the U.S.
Our findings strongly suggest that other advancements in critical care, aside from lower tidal volume ventilation, resulted in improved mortality for patients with ALI treated at ARDS Network centers from 1996-2005. Although we are unable to identify what exactly is accounting for the improvement in mortality, one possible explanation is the bundling of care for patients with ALI restrictive transfusion protocols, early antibiotic administration and nutritional support and appropriate prophylaxis. Importantly, for clinical trials involving patients with ALI, the decreasing mortality rate poses significant challenges in trial design. Future clinical trials investigating new therapies for ALI will need to enroll larger numbers of patients in order to be adequately powered to detect differences in mortality. Alternatively, future trials may need to choose non-mortality outcomes or target higher risk groups in order to find meaningful differences in mortality.