What Are the Limitations of the Current Definition?

The major limitation is that ARDS and its severity can be assessed on a single blood gas measurement without prior standardized ventilator settings. However, PEEP may have a major influence on oxygenation, and in the three RCTs that have compared two levels of PEEP (lower vs. higher), oxygenation was always more satisfactory in the higher-PEEP group than in the lower-PEEP group [14-16]. In a meta-analysis including these three trials, survival was better using high PEEP than using low PEEP in patients with a PaO₂ to FiO₂ ratio <200 mmHg [17], and therefore, the experts have recommended the use of high PEEP levels in patients with moderate or severe ARDS [9]. After optimizing ventilator settings and by increasing the PEEP level, several studies have shown that a high proportion of patients could have their severity modified based on PaO₂/FiO₂ ratio, from severe to moderate/mild or from moderate to mild [18-20]. FiO₂ variations may also be associated with significant changes in PaO₂/FiO₂ ratio [18, 21], and it has been shown that, for the same PaO2/FiO2 ratio, patients ventilated with high FiO2 had higher mortality than those ventilated with lower FiO₂ [22]. To homogenize disease severity, ventilatory settings should be optimized using low tidal volumes around 6 mL/kg of predicted body weight and high PEEP level. Likewise, the time from ventilator settings to PaO₂/FiO₂ measurement seems crucial. Indeed, Villar and colleagues reported that mortality was more reliably predicted according to the three categories of severity (mild, moderate, and severe) when PaO₂/FiO₂ ratio was measured with a PEEP level at least 10 cmH₂O and FiO₂ at least 0.5 [19, 20]. However, assessment of PaO₂/FiO₂ ratio yielded a more clinically relevant ARDS classification when measured 24 h after ARDS onset than immediately after FiO₂ and PEEP settings [19, 20]. This finding is illustrated by the inclusion criteria used in the PROSEVA trial, which found a significant reduction of mortality in patients treated with prone position for which patients with a PaO₂/FiO₂ below 150 mmHg were eligible if such a high degree of hypoxemia persisted more than 12 h after optimization of ventilator settings [23]. Therefore, standardized ventilator settings with a PEEP level of at least 10 cmH2O and the persistence of hypoxemia may perhaps help to improve ARDS classification.

The other main limitation is the difficulty in quantifying morphological lung injury. Since it was first reported, diffuse alveolar damage (DAD) has been regarded as the morphological hallmark of the lung in ARDS [24, 25]. However, the incidence of DAD in ARDS is highly variable from one study to another and largely depends on the type of examination (autopsy vs. open lung biopsy) (Table 1.2). In a large database of clinical autopsies including 356 patients with ARDS, overall incidence of DAD was only 45% [42]. However, the incidence of DAD depended on the severity of ARDS and time from ARDS onset to pathological examination. Hyaline membranes may take 2-3 days to appear [24] and this explains why the incidence of DAD was significantly higher (56%) in patients with ARDS for more than 72 h. The proportion of patients with DAD also increased in more severe patients with an incidence of 12, 40, and 58% in mild, moderate, and severe ARDS, respectively. The incidence of DAD was as high as 69% in patients with severe ARDS after 3 days of evolution [42]. In this study, whereas almost all patients with DAD on autopsy examination met the clinical criteria of the Berlin definition for ARDS (high sensitivity), fewer than half of the patients with ARDS had DAD (low specificity). Perhaps the low specificity of the Berlin definition in DAD detection is ascribable to the presence of other processes with a similar clinical picture. Many diseases may mimic ARDS such as alveolar hemorrhage due to vasculitis, drug- induced pulmonary toxic pneumonia with a lymphocytic pattern or acute

Table 1.2 Incidence of diffuse alveolar damage (DAD) on open lung biopsy or autopsy in patients with acute respiratory distress syndrome (ARDS)

eosinophilic pneumonia, organizing or diffuse interstitial pneumonia, cancer infiltration, and at times idiopathic lymphangitis [10, 45]. These ARDS without common risk factors, the so-called ARDS mimickers, represent around 7-8% of patients mechanically ventilated for ARDS and could have higher mortality than the others [45]. For such atypical ARDS cases, a complete diagnostic workup, including bron- choalveolar lavage fluid cytology and chest CT scan patterns, should be performed to identify patients who might benefit from specific therapies, including corticosteroids. A recent study suggests that the presence of DAD is associated with higher mortality as compared to patients without DAD [46]. Unfortunately, no biomarkers exist to diagnose alveolar damage.