Is it important to have two P/F thresholds?
At baseline, no; after 24 h, yes. At baseline, the moderate category was not statistically different from the mild category in terms of mortality (Fig. 1). A simplified version of the Berlin definition created by merging the categories mild and moderate performed as well as the Berlin definition (P = 0.33). This finding suggests that most of the predictive power of the Berlin definition resides on the knowledge of whether or not the patient belongs to the severe category.
In contrast, after 24 h, both the moderate (P = 0.02) and the severe (P < 0.001) categories were significantly different from the mild category in terms of chance of death (Fig. 2). In this scenario, with both using P/F ratios at 24 h, the Berlin definition performed significantly better than the simplified version (P = 0.02).
What about the ancillary variables?
We reassessed the value of compliance and PEEP from the four originally proposed ancillary variables. We did not have data on the corrected minute ventilation or the radiographic score. In addition to the variables proposed, we tested the addition of FiO2 divided into three categories with cutoff values of 0.5 and 0.7, as recently suggested [14▪▪].
We used the compliance adjusted to ideal body weight (IBW) to take into account the differences in lungs sizes – the same procedure that is now the standard practice for the tidal volumes. Instead of using an arbitrary cutoff value of compliance, we chose the median compliance of the severe oxygenation category to optimize the number of patients in each subcategory. The cutoff obtained was 0.4 ml/cm H2O/kg IBW, corresponding to a compliance of 28 ml/cm H2O for a 70-kg patient. We found that compliance was a strong predictor of mortality (P < 0.0001), along with the P/F ratio (P = 0.0047). Classifying patients according to compliance as shown in Table 4 improved the risk stratification within each stratum of P/F ratio.
Adding PEEP did not improve prediction (P = 0.08), even after taking into account the possible nonlinear relationships between PEEP and mortality. Of note, all but six patients had PEEP values equal or greater than 5 cm H2O. Therefore, we cannot exclude that patients with PEEP values below 5 cm H2O would have a different mortality.
Conversely, the addition of FiO2 improved the prediction confirming the findings of Britos et al.[14▪▪]. One possible reason why FiO2 could add predictive power to a model already containing the P/F categories is that, at higher FiO2, PaO2 correlates better with the mass of collapsed lung tissue [22▪▪].
What happens after multivariate adjustment (inclusion of age, APACHE, and pH)?
In the Berlin definition, the authors did ‘not explore other variables that might improve predictive validity, such as age and severity of nonpulmonary organ failure, because they were not specific to the definition of ARDS’. In doing so, however, they failed to adjust for the effect of confounders, an essential step in outcomes research. For example, sicker patients die more often and also tend to have lower P/F ratios. Therefore, it is possible that the mortality differences across the P/F categories be related to nonpulmonary organ failures and not to the severity of the lung disease.
We included the relevant variables, age and APACHE, as suggested by others [19,23▪], as well as baseline pH, a variable strong and independently related to death in our sample. After adjustment for these baseline characteristics, the odds ratio for death of the moderate and severe categories decreased (Figs. 1 and 2), but not enough to change the original message of the Berlin definition.
Additionally, adjustment made it clearer that P/F ratio and compliance were independent risk factors for death and improved the ability to predict death (Fig. 3). Conversely, once P/F ratio and compliance were already considered, FiO2 and PEEP were not informative.
Stratification based on compliance was part of the 1988 Murray definition, and indeed, the Berlin panel acknowledged that a threshold of 20 ml/cm H2O might be an interesting cutoff. In this review, we emphasize that compliance is as important as the P/F ratio in risk stratification and should not be disregarded from the definition of ARDS.
There are some limitations associated with the definitional changes we are proposing. First, the use of the P/F ratio after 24 h would postpone the risk stratification and therefore delay, for example, the inclusion in clinical trials. We believe that the improvement in risk stratification justifies such delay. For example, in one study , 66% of patients meeting ARDS criteria at baseline did not meet ARDS criteria after 24 h of standard ventilatory settings. For clinical purposes, the delay would be less important, because patients could be diagnosed with ARDS using the baseline P/F ratio, and the risk stratification could be updated 24 h later. Second, measurement of compliance requires absence of muscle effort implying either neuromuscular blockade or heavy sedation. Indeed, such respiratory muscle rest is welcome in the early phase of ARDS  and helps ensure the use of protective low tidal volume ventilation.
The Berlin definition brought improvement and simplification over the previous definitions. We believe that the Berlin definition could be further improved by using the data over the first 24 h to reclassify the severity of the disease and by using compliance with optimized cutoffs to stratify each oxygenation category.
The authors thank the National Institutes of Health Acute Respiratory Distress Syndrome Network; the staff working at the respiratory-ICU, Hospital das Clínicas, University of São Paulo; the Canadian Pressure and Volume-Limited Ventilation Group; the centers who participated in the 1994–1996 Multicenter Trial Group on Tidal Volume Reduction in ARDS; and the Baltimore Clinical Research Group.
Conflicts of interest
This study was partially supported by FAPESP (Fundação de Amparo e Pesquisa do Estado de São Paulo), CNPQ (Conselho Nacional de Pesquisa e Desenvolvimento), and FINEP (Fundo de Financiamento de Estudos de Projetos e Programas).
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 68).
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
acute respiratory distress syndrome; definition; disease severity