Towards changing the definition of the acute respiratory distress syndrome: one step forward.

Having a common and reliable definition for the acute respiratory distress syndrome (ARDS) or acute lung injury is very important for the management of this severe respiratory complication. At a full stage, this syndrome corresponds to diffuse alveolar damage, but lung pathology is usually not available except at autopsy (1). There is no validated biomarker, even in bronchoalveolar lavage fluid, which could improve our ability for an early recognition of increased lung permeability. An accurate definition is required for clinical trials or epidemiologic studies, with sufficient specificity to reduce the noise-to-signal ratio and good sensitivity to avoid missing patients. An accurate definition can also greatly help clinicians to define which patients may benefit from precise ventilatory strategies, diagnostic procedures, or drug therapy. Our current definition, coming from a consensus (2), has been extremely useful, especially for clinical trials. It combines simple parameters that are available at the bedside and a clinical assessment of the patient. The cornerstone of this definition is the PaO2/FIO2 ratio. This ratio has become the most popular way to quantify oxygenation defects. Several factors greatly influence the value of the PaO2/FIO2 ratio, independently from lung pathology, but are often ignored at the bedside. Mixed venous oxygenation is a crucial one and is influenced by cardiac output. For a given lung status, varying cardiac output and arterial-to-venous difference in oxygen content heavily influences the PaO2/FIO2 ratio (3). For this reason, it was advocated in the 1980s to calculate shunt using the Berggren equation instead of relying on PaO2 and FIO2 alone (4). The decline in the use of the pulmonary artery catheter, necessary to get mixed venous blood, is one of the reasons why this approach is not used anymore. A second determinant is the pressure delivered by the ventilator. For this reason, pediatricians have introduced mean airway pressure in their assessment of oxygenation and calculation of the oxygenation index. Although this approach makes good sense, a clear clinical advantage over the PaO2/FIO2 ratio alone has not been clearly demonstrated. Along the same line, several investigators have argued that the level of positive endexpiratory pressure (PEEP), a major determinant of oxygenation, needed to be taken into account, either by introducing the PEEP level into an oxygenation equation or by imposing a fixed level of PEEP to make calculations (5, 6). It is possible, however, that the vast majority of patients in whom the PaO2/FIO2 ratio is calculated are already on a “moderate,” average level of PEEP. How frequently adding a requirement for a given PEEP level would change the definition has not been clearly evaluated. This was the first question addressed in the work done by Britos and colleagues (7) in this issue of Critical Care Medicine, who explored the influence of the initial PEEP level on mortality across different ranges of PaO2/ FIO2. They used the data collected during conduct of the ARDS Network trials, when patients were enrolled in clinical trials, making a total of 2,312 patients with acute lung injury/ARDS available. They tested if, for a given range of PaO2/ FIO2 values, mortality was different according to the PEEP level, which would suggest that patients with very different disease severity were enrolled under the same oxygenation criterion. It is remarkable, however, to see in the results of Britos et al, how consistent the mortality is between a PEEP at 5 cm H2O or below and a PEEP at 11 cm H2O or above. This suggests that adding PEEP to the definition would not help in better characterizing the disease severity of the patients. Several reasons may explain this. First, when clinicians increase PEEP they probably also often increase FIO2, which by itself decreases the PaO2/FIO2 ratio. Second, clinicians may vary the PEEP settings over a relatively narrow range. Indeed, in the ARDS Network hospitals, very few patients (1.3%) were ventilated with PEEP levels below 5 cm H2O. At the opposite, only 11% of patients had PEEP at 15 cm H2O or higher before enrollment in the trials. Therefore, their results may not apply to ICUs where the PEEP level is frequently under 5 cm H2O or above 14 cm H2O to calculate the initial PaO2/FIO2 ratio. A last issue is the effect of the FIO2 level on the PaO2/FIO2 ratio itself. This is often ignored because it sounds as counterintuitive. Clinicians may think that normalizing PaO2 to FIO2 is possible because a linear relationship exists between the two. This is not the case, however, and several experimental or clinical studies have clearly shown that there is a nonlinear relationship between PaO2 and FIO2, and consequently between PaO2 and PaO2/FIO2 (8–10). The shape of the oxyhemoglobin dissociation curve describing the relationship of the percentage of hemoglobin saturation to the blood PO2 and the equation for human blood oxygen dissociation explains this relationship (11). This relationship is difficult to predict because it depends on the cardiac output, the arterial-to-venous difference in oxygen content, and the shunt fraction (8). In patients with a relatively high shunt, the curve will often display a U shape, with an increase in the PaO2/FIO2 ratio when FIO2 is raised from around 50% or 60% up to 100%. This means that a given PaO2/FIO2 value measured in a patient at FIO2 1.0 will reflect a more severe impairment of oxygenation than in another patient with the same PaO2/FIO2 ratio at a FIO2 of only 50%. It also means that for a given patient, changing FIO2 modifies the *See also p. 2025.