The AECC criteria were designed to identify a large group of patients who could be of concern to investigators and clinicians because of ALI or ARDS (1
). Because these criteria are inclusive, the resulting population may be very heterogeneous in disease severity and clinical outcomes. Therefore, most clinical trials exclude many patients who meet the AECC criteria to reduce heterogeneity in the enrolled cohorts. ARDS Network trials did not exclude patients who had received zero or very low level PEEPs at baseline. However, only 1.3% of patients enrolled in ARDS Network trials had baseline PEEP levels less than 5 cm H2
O, and approximately 50% of patients had baseline PEEPs of 10 cm H2
O or more. Baseline PEEP alone predicted mortality, but after controlling for baseline PaO2
, PEEP did not predict mortality (). Moreover, effects of two effective study interventions were similar in quartiles of patients defined by the highest and lowest PaO2
ratios, without knowledge of baseline PEEP. These results suggest that at ARDS Network hospitals, addition of a minimum level of PEEP to the PaO2
ratio would not have improved the ability to identify patients at higher risk of death or patients more or less likely to benefit from a new intervention. However, substantial proportions of patients received PEEPs of less than 5 cm H2
O in some other studies of mechanically ventilated patients. Some of these could have had mild ALI/ARDS with low mortality rates (21
). To avoid enrolling these patients in clinical trials, a minimum PEEP of 5 cm H2
O could be required in the eligibility criteria.
In previous studies of ALI/ARDS, some patients with PaO2
≤ 200 had PaO2
s that were greater than 200 or even 300 after mechanical ventilation with PEEPs of 5-10 cm H2
O or greater (9
). In three of these studies, the mortality rates of the patients with higher PaO2
ratios after ventilation with PEEP were substantially lower than those whose PaO2
ratios remained below 200 (9
). For example, in one of the previous studies, patients were ventilated for 24 hours with PEEP of at least 10 cm H2
O before categorizing by PaO2
. Mortality rates for cohorts with PaO2
< 200, 201-300, and > 300 were 45.5, 20, and 6.3%, respectively (10
). However, some of the patients included in these studies had received PEEPs of less than 5 cm H2
O before the standardized ventilator settings. In contrast, only 1% of patients enrolled in ARDS Network trials had received PEEPs of less than 5 cm H2
O before enrollment. Moreover, patients enrolled in the ARDS Network studies had received mechanical ventilation for at least several hours and frequently for more than 24 hours before the baseline AECC data were recorded. Thus, the baseline ventilator settings and arterial oxygenation of the patients enrolled in ARDS Network trials may have been more similar to those of the patients in the previous studies after
ventilation with standardized PEEP than to the initial measurements recorded in the previous studies before
ventilation with standardized PEEP.
In single variable analyses, baseline PEEP and baseline PaO2/FiO2 both predicted mortality. However, some clinicians had apparently used higher PEEP in conjunction with higher FiO2 (or lower PEEP with lower FiO2), presumably to achieve arterial oxygenation goals (). Therefore, baseline PaO2/FiO2 conferred additional information about baseline PEEP. After controlling for baseline PaO2/FiO2, the addition of baseline PEEP did not predict mortality. Moreover the addition of mPaw to PaO2/FiO2 (in the OI) did not increase the predictive value of PaO2/FiO2. Clinicians’ manipulations of PEEP probably caused similar changes in mPaw .
The ARDS Network trials also did not use FiO2, independent of PaO2/FiO2, to exclude patients at low risk of adverse outcomes. In contrast to the findings with PEEP, FiO2 did predict mortality after controlling for PaO2/FiO2. However, in each of the PaO2/FiO2 tertiles, the range of mortality between the lowest and highest FiO2 ranges was approximately 10%, and the lowest mortality (in the subset with the highest PaO2/FiO2 and lowest FiO2) was still substantial at 21%. A subset with substantially lower mortality (with even lower FiO2s and higher PaO2/FiO2s) could probably be identified, but this subset would be quite small.
Our results and interpretations are from analyses of the cohorts of patients enrolled in the trials, which includes patients with several etiologic causes of ALI. Effects of PEEP may be different in groups of patients with direct versus indirect lung injury (24
). If so, then PEEP could add to the predictive value of PaO2
in one of these subsets but not the other. However, more recent studies did not demonstrate different effects of PEEP in direct versus indirect lung injury (25
In this study, mortality was lower in patients whose PaO2
ratios were greater than 200 than in those whose PaO2
ratios were lower than 200. The difference in mortality was similar to but not as marked as in the previous studies (9
) in which patients received standardized ventilator settings with 5-10 cm H2
O PEEP for up to 24 hours before determination of PaO2
. This difference between our study and the previous studies may be attributable to higher levels of PEEP received by some patients in our study at baseline than in the previous studies before patients received standardized ventilator settings for up to 24 hours. Patients with PaO2
ratios greater than 300 at the time of screening were not eligible for enrollment in ARDS Network trials, and their PaO2
ratios and ventilator settings would not be available in our dataset.
Eligibility criteria for clinical trials are frequently designed to avoid enrollment of patients who are unlikely to benefit from a new study intervention, such as those with very low mortality rates, especially if the intervention carries substantial risk. Mortality was significantly lower in patients with higher PaO2/FiO2 ratios in our cohort (). However, the effects of lower tidal volume and fluid-conservative hemodynamic management were similar among groups of patients with very low and high baseline PaO2/FiO2 ratios. Thus, inclusion of patients with mild hypoxemia at baseline did not diminish the power of the trials. On the other hand, by including patients with higher PaO2/FiO2 ratios, the trial results are applicable to a greater proportion of ALI/ARDS patients. Perhaps we could identify a subset with milder impairment in arterial oxygenation in which mortality was even lower; the effects of useful interventions could be less or absent in this subset. However, this subset would probably be small.
In two previous trials in ARDS patients, new therapeutic interventions appeared to be effective only in subsets of patients with severe disease (27
). However, in the ARDS Network tidal volume and hemodynamic management trials, effects of the interventions were similar across the ranges of severity as defined by PaO2
. Thus, patients with mild and moderate ALI/ARDS, as defined by PaO2
, can benefit from some interventions that reduce mortality or time on mechanical ventilation. It is also possible that there is a level of severity above which outcomes are less modifiable by a new clinical trial intervention.
A strength of this study is the large number of patients with pertinent data and the large number of contributing hospitals and intensive care units. The data were collected during conduct of the ARDS Network trials, when patients were enrolled in clinical trials. Therefore the data are relevant to the concerns raised regarding the lack of a minimum PEEP in the eligibility criteria of these trials. A limitation of this study is that while our conclusions apply to the specific trials conducted and to the ARDS Network hospitals where they were conducted, they may not apply in other circumstances. Clinicians’ practices for setting PEEP and FiO2
are highly variable (22
). It is possible that there is greater variability in how PEEP is used at other hospitals. Some clinicians prefer to use very low PEEP, even when FiO2
has been raised to high levels. In such circumstances, a minimum PEEP criterion for eligibility in a clinical trial could help to avoid enrollment of patients with very mild disease. It is also possible that our analyses could not detect a small predictive value of baseline PEEP when added to baseline PaO2
for predicting mortality because of inadequate sample size. Finally, since many patients with ALI/ARDS were excluded from ARDS Network trials, our analysis may not be applicable to those who were not included.