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The criteria that define acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) include PaO2/FiO2 but not positive end-expiratory pressure (PEEP) or FiO2. PaO2/FiO2s of some patients increase substantially after mechanical ventilation with PEEP of 5-10 cm H2O, and the mortality of these patients may be lower than those whose PaO2/FiO2s remain < 200. Also, PaO2/FiO2 may increase when FiO2 is raised from moderate to high levels, suggesting that patients with similar PaO2/FiO2s but different FiO2s have different risks of mortality. The primary purpose of this study was to assess the value of adding baseline PEEP and FiO2 to PaO2/FiO2 for predicting mortality of ALI/ARDS patients enrolled in ARDS Network clinical trials. We also assessed effects of two study interventions on clinical outcomes in subsets of patients with mild and severe hypoxemia as defined by PaO2/FiO2.
Analysis of baseline physiologic data and outcomes of patients previously enrolled in clinical trials conducted by the National Institutes of Health ARDS Network.
Intensive care units of 40 hospitals in North America.
2312 patients with ALI/ARDS.
Only 1.3% of patients enrolled in ARDS Network trials had baseline PEEP < 5 cm H2O, and 50% had baseline PEEP ≥ 10 cm H2O. Baseline PaO2/FiO2 predicted mortality, but after controlling for PaO2/FiO2, baseline PEEP did not predict mortality. In contrast, after controlling for baseline PaO2/FiO2, baseline FiO2 did predict mortality. Effects of two study interventions (lower tidal volumes and fluid-conservative hemodynamic management) were similar in mild and severe hypoxemia subsets as defined by PaO2/FiO2 ratios.
At ARDS Network hospitals, the addition of baseline PEEP would not have increased the value of PaO2/FiO2 for predicting mortality of ALI/ARDS patients. In contrast, the addition of baseline FiO2 to PaO2/FiO2 could be used to identify subsets of patients with low or high mortality.
The American-European consensus conference (AECC) criteria for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) include the acute onset of: (1) bilateral infiltrates on frontal chest radiograph, (2) PaO2/FiO2 less than or equal to 300 Torr (ALI) or 200 Torr (ARDS), and (3) absence of clinical indicators of left atrial hypertension (1). Many clinical studies of ALI/ARDS have used the AECC criteria to identify potentially eligible patients (2-8).
In some patients with bilateral infiltrates, PaO2/FiO2s were lower than 200 while they received mechanical ventilation with zero or low levels of PEEP, but PaO2/FiO2s then increased to greater than 200 or even 300 when low to moderate levels of PEEP were subsequently applied (9-12). In these patients, atelectasis could have been an important cause of hypoxemia rather than shunt from consolidation and pulmonary edema. In one study the mortality of these patients was considerably lower than those whose PaO2/FiO2s remained below 200 after raising PEEP (10). Moreover, in many patients with bilateral infiltrates, PaO2/FiO2s increased substantially when FiO2s were raised from moderate to high levels (11,13). This suggests that among patients with similar PaO2/FiO2s, oxygenation failure is worse and risk of death is higher in those receiving higher FiO2s. Thus, without standardized or minimum PEEP and FiO2 criteria, the AECC criteria could identify a heterogeneous group of patients, some of whom are at low risk of adverse outcomes such as death. If so, then use of the AECC criteria to identify patients for ALI/ARDS trials, without PEEP and FiO2 criteria, could reduce the power of clinical trials because potential effects of new interventions may be smaller in patients with mild disease. Some investigators have speculated that the results of trials that enrolled ALI/ARDS patients using the AECC criteria without a minimum PEEP level were confounded by imbalances between study groups in patients with mild and severe lung injury that could not be detected without increasing PEEP (10). The National Institutes of Health ARDS Network used the AECC criteria as the inclusion criteria for most of its clinical trials since 1996 (2-5,14,15). Exclusion criteria reduced heterogeneity of the enrolled populations, but patients were not excluded if they were on zero or low PEEPs or low FiO2s. The primary purpose of the present study was to explore the potential value of adding PEEP and FiO2 criteria to the AECC criteria to exclude patients with low risk of mortality. A secondary purpose was to address the concern that in patients with mild disease, potential effects of an intervention may be small or nonexistent. To address this concern we examined effects of two study interventions on subsets of ALI/ARDS patients with mild and severe hypoxemia. Parts of this study were presented previously in abstracts (16,17).
We reviewed existing data from 2,443 patients enrolled in 4 ARDS Network clinical trials from 1996 to 2005 (2-5). Etiologic causes of ALI/ARDS were listed as pneumonia (41%), sepsis (24%), aspiration (15%), trauma (9%), and other causes (11%). Baseline ventilator settings were set by clinicians and were available within 4 hours before the time of randomization. Baseline values usually occurred several or many hours after the criteria for ALI were initially met.
We created a frequency-distribution of baseline PEEP levels. To characterize the relationship between baseline PEEP and FiO2, we divided baseline FiO2 into 10 subsets, each with FiO2 range of 0.10, and then displayed distributions of PEEP within each interval. We calculated a correlation coefficient and corresponding 95% confidence interval to assess the relationship between baseline PEEP and FiO2.
We created tertiles of PaO2/FiO2, each containing approximately 770 patients. We used Cochrane-Armitage trend tests to determine if PaO2/FiO2 tertiles predicted mortality. We created three groups of baseline PEEP (≤ 5, 6-10, and ≥ 11 cm H2O) and baseline FiO2 (≤ 0.50, 0.50 – 0.69, and ≥ 0.70) within each PaO2/FiO2 tertile. We used Cochrane-Armitage trend tests to determine if differences in PEEP and FiO2 within each PaO2/FiO2 tertile were associated with differences in mortality.
Oxygenation index (OI) combines mean airway pressure (mPaw) with PaO2/FiO2: OI = mPaw × 100 × FiO2/PaO2. Many studies suggest that OI is useful to assess severity of oxygenation failure and risk of death in individual ALI patients (18-20). To compare the value of PaO2/FiO2 and OI for predicting mortality, we calculated areas under the curve for receiver operating characteristics for both PaO2/FiO2 and OI.
In previous studies, mechanical ventilation with lower tidal volumes reduced mortality (2), and a fluid-conservative hemodynamic strategy was associated with greater ventilator-free days (4). To test the hypothesis that the effects of these interventions were greater in patients with more severe illness, we compared the effects of the interventions in patients with mild and severe baseline hypoxemia. First, we ranked patients in the tidal volume hemodynamic strategy trials according to baseline PaO2/FiO2. We then divided the patients in each trial into baseline PaO2/FiO2 quartiles. Patients with mild and severe hypoxemia were defined as those in the highest and lowest PaO2/FiO2 quartiles, respectively. We compared the effects of study interventions in the highest and lowest PaO2/FiO2 quartiles.
In the ARDS Network trial of higher versus lower PEEP (3), patients in the higher PEEP study group received PEEPs of at least 12 cm H2O after randomization. To assess effects of approximately 12-18 hours of mechanical ventilation with these higher PEEP levels, we compared frequency distributions of PaO2/FiO2 at baseline and on day 1 after randomization. We calculated mortality rates for patients with PaO2/FiO2 ratios < 200, 201-300, and > 300 on the day after randomization. Patients or their surrogates gave informed consent for the original clinical trials. The institutional review board of Johns Hopkins Medicine approved this study of existing data with a waiver of the requirement for informed consent.
Complete physiologic and outcomes data were available on 2312 patients enrolled in the 4 clinical trials. Of these, 77% had PaO2/FiO2 ≤ 200; mortality in this group was 31.4%. Of the remaining 23% with P/F > 200, mortality was 21.9% (P < 0.0001 for the comparison of mortalities).
The distribution of baseline PEEPs for all subjects is shown in Figure 1. The most frequently used baseline PEEPs were 5 and 10 cm H2O. Very few patients (1.3%) had baseline PEEPs less than 5 cm H2O. Approximately 50% of all patients had baseline PEEPs of 10 cm H2O or greater.
The relationship between the clinician-set baseline PEEP and FiO2 levels is shown in Figure 2. Most clinicians selected PEEPs of 5, 8 or 10 cm H2O. When FiO2 was 50% or less, most clinicians selected either 5 or 8 cm H2O. When FiO2 was above 50%, most clinicians selected 10 cm H2O. There was substantial variability in how baseline PEEPs and FiO2s were combined. However, there were relatively few patients with high baseline PEEP combined with low baseline FiO2. Levels of baseline PEEP and FiO2 were positively and significantly correlated (rho = 0.47, 95% CI 0.42 to 0.51; P < 0.001). Thus, although individual approaches varied, clinicians as a whole had apparently adjusted PEEP and FiO2 in concert.
In univariate analyses, lower baseline PaO2/FiO2 predicted 60 day mortality (Table 2). Higher baseline PEEP levels also predicted higher 60 day mortality. Within each PEEP range (≤ 5, 6-10, > 10 cm H2O) mortality increased with decreasing PaO2/FiO2 (Table 2). However, within each PaO2/FiO2 tertile mortality did not increase significantly with increasing PEEP. Like higher PEEP, higher FiO2 also predicted higher 60 day mortality (Table 3). However, unlike higher PEEP, within each PaO2/FiO2 tertile mortality increased significantly with increasing FiO2.
The AUCs of the receiver operating characteristics for OI and PaO2/FiO2 were 0.58 and 0.57, respectively. Thus, the addition of mean airway pressure to PaO2/FiO2 did not improve mortality prediction.
We next compared the effects of the lower tidal volume and fluid-conservative hemodynamic management strategies on patients in the mildest and most severe quartiles of baseline hypoxemia as defined by PaO2/FiO2. Effects of tidal-volume reduction on mortality were similar in the mild and severe hypoxemia quartiles of the tidal volume trial (Figure 3). The interaction between study group and hypoxemia quartile was not significant (P = 0.814). Also, the interaction between study group and FiO2 quartiles was not significant (P = 0.259). The effect of fluid-conservative management on ventilator-free days was similar in the mild and severe hypoxemia quartiles of the hemodynamic management trial (Figure 4). The interaction between study group and hypoxemia subset was not significant (P = 0.106).
Frequency distributions of PaO2/FiO2 at baseline and on the first day after enrollment in the higher PEEP and lower PEEP study groups of the ARDS Network PEEP trial are shown in Figure 5. The proportions of patients in the higher PEEP group with baseline PaO2/FiO2 < 200, 201-300, and > 300 were 79%, 17%, and 4%, respectively. After approximately 12-18 hours of ventilation with PEEPs of at least 12 cm H2O in the higher PEEP group, these proportions shifted to 50%, 36%, and 14%, respectively. The mortality rates of these groups, categorized according to PaO2/FiO2 after 12-18 hours of mechanical ventilation with higher PEEP, were 31, 28, and 13.5%, respectively.
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 H2O, and approximately 50% of patients had baseline PEEPs of 10 cm H2O or more. Baseline PEEP alone predicted mortality, but after controlling for baseline PaO2/FiO2, PEEP did not predict mortality (Table 2). Moreover, effects of two effective study interventions were similar in quartiles of patients defined by the highest and lowest PaO2/FiO2 ratios, without knowledge of baseline PEEP. These results suggest that at ARDS Network hospitals, addition of a minimum level of PEEP to the PaO2/FiO2 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 H2O in some other studies of mechanically ventilated patients. Some of these could have had mild ALI/ARDS with low mortality rates (21-23). To avoid enrolling these patients in clinical trials, a minimum PEEP of 5 cm H2O could be required in the eligibility criteria.
In previous studies of ALI/ARDS, some patients with PaO2/FiO2 ≤ 200 had PaO2/FiO2s that were greater than 200 or even 300 after mechanical ventilation with PEEPs of 5-10 cm H2O or greater (9-12). In three of these studies, the mortality rates of the patients with higher PaO2/FiO2 ratios after ventilation with PEEP were substantially lower than those whose PaO2/FiO2 ratios remained below 200 (9-11). For example, in one of the previous studies, patients were ventilated for 24 hours with PEEP of at least 10 cm H2O before categorizing by PaO2/FiO2. Mortality rates for cohorts with PaO2/FiO2 < 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 H2O before the standardized ventilator settings. In contrast, only 1% of patients enrolled in ARDS Network trials had received PEEPs of less than 5 cm H2O 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 (Figure 2). 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/FiO2 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 (25,26).
In this study, mortality was lower in patients whose PaO2/FiO2 ratios were greater than 200 than in those whose PaO2/FiO2 ratios were lower than 200. The difference in mortality was similar to but not as marked as in the previous studies (9-11) in which patients received standardized ventilator settings with 5-10 cm H2O PEEP for up to 24 hours before determination of PaO2/FiO2. 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/FiO2 ratios greater than 300 at the time of screening were not eligible for enrollment in ARDS Network trials, and their PaO2/FiO2 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 (Table 2). 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 (27,28). 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/FiO2. Thus, patients with mild and moderate ALI/ARDS, as defined by PaO2/FiO2, 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 (22,29,30). 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/FiO2 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.
The addition of PEEP to the AECC criteria would have made little or no difference in the mortality of the patients enrolled in ARDS Network trials. In contrast, the addition of FiO2 to the AECC criteria could be used to identify subsets of patients with relatively low or high mortality. However, our analyses do not support the concern that the effectiveness of interventions varies with the severity of oxygenation failure in subsets of ALI/ARDS patients.
The authors thank Laurent Brochard for providing very useful comments to improve the manuscript.
Supported by NHLBI Contracts NO1-HR-46054-46064 and NO1-HR-56165-56179
This study was funded, in part, by NHLBI Contracts NO1-HR-46054-46064 and NO1-HR-56165-56179.
The authors have not disclosed any potential conflicts of interest.
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