Acute respiratory distress syndrome is characterized by diffuse alveolar-capillary membrane disruption that results in increased permeability and subsequent pulmonary edema and atelectasis. ARDS may be due to pulmonary (pneumonia, aspiration of gastric content, toxic inhalation, lung contusion, near drowning) or extrapulmonary (sepsis, trauma, burns, pancreatitis, blood transfusion, cardiopulmonary bypass) inflammatory factors [1, 2, 20]. Alveolar damage however is not homogeneously distributed, as atelectasis mainly affects the dependent lung regions (namely, those most subjected to hydrostatic pressure), while nondependent regions remain better aerated [2, 4]. For these reasons, also the volume that needs to be ventilated decreases (hence the term “baby lung”) [21].

Although barotrauma (e.g., pneumothorax) may occur as a consequence of mechanical ventilation with high volumes, the main determinant of VILI is thought to be alveolar overdistension (volutrauma) rather than airway pressure [4]. Therefore, it would be reasonable that low-V _T ventilation could potentially prevent or minimize VILI in ARDS patients, by avoiding overinflation of the decreased normally aerated regions. However, VILI can occur even during a low-V _T ventilation, due to cyclic alveolar opening and closure (atelectrauma), which leads to epithelial sloughing, hyaline membranes, and pulmonary edema [2, 4]. Since atelectrauma is intensified in presence of broad heterogeneities in ventilation [4], as in ARDS, higher levels of PEEP may contribute to minimize VILI by reducing alveolar collapse during expiration [2, 4].

Low-V _T ventilation (with P _PLAT ≤ 30 cmH₂O) is indicated in patients with ARDS of any severity (mild to severe) [19]. However, probably not all ARDS patients (e.g., those with stiff chest wall and, consequently, high pleural pressure) really need a very low P _PLAT (and V _T) in order to avoid alveolar overdistension [4].

Data are also accumulating to support the prophylactic use of low V _T in mechanically ventilated patients without lung injury, in order to prevent ARDS [7]. For instance, in abdominal surgical patients ventilated with V _T ≤8 mL/kg PBW, Futier and colleagues [12] reported a reduction in major pulmonary and extrapulmonary complications, as well as a reduction in hospital length of stay (LOS), while Severgnini et al. [22] found an improved pulmonary function and a reduced modified Clinical Pulmonary Infection Score [23], but no differences in hospital LOS. A recent meta-analysis of RCTs [6] corroborated partially the finding of the previous studies (which were also included in the meta-analysis) showing that low V _T in patients without lung injury is associated with a reduced incidence of ARDS and of pulmonary infection but not associated with a reduced hospital LOS or mortality. Accordingly, the extensive use of prophylactic protective ventilation in all mechanically ventilated patients cannot be recommended at the time, but it is advisable in patients with risk factors for ARDS [7, 16, 24].

Low-V _T ventilation often results in hypercapnia and acidosis, with possible metabolic complications such as acute hyperkalemia [2, 7]. These abnormalities can be counteracted by increasing respiratory rate (RR), but it should be considered that high RR (usually >30 breaths/min) may lead to dynamic hyperinflation and auto-PEEP [7]. However, since low-V _T ventilation was shown to reduce mortality despite hypercapnia [9, 10], it may be speculated that the latter itself may be beneficial due to rightward shift of the oxyhemoglobin dissociation curve, systemic and microcirculatory vasodilation, and inhibitory effects on inflammatory cells. Moreover, mean pCO₂ levels of 66.5 mmHg or higher and a pH up to 7.15 can be tolerated unless specific contraindications exist, such as increased intracranial pressure [2].

The use of extracorporeal arteriovenous CO₂ removal, allowing “ultraprotective” ventilation (V _T ≈ 3 mL/kg PBW), has been investigated in severe ARDS patients, but its impact on survival remains to be determined [17].

According to current evidences, higher levels of PEEP should be reserved for moderate to severe forms of ARDS [19]. Maybe, in patients with mild ARDS, the potential adverse effects of higher PEEP levels (e.g., impairment of venous return, circulatory depression, lung overdistension) may overcome the advantages [4, 13]. On the other hand, it is also possible that clinical trials failed to show a clear benefit of higher PEEP levels [13, 14] due to the difficulty in tailoring PEEP on the single patient [5]. In fact, lung inflation is strictly dependent on transpulmonary pressure (P _TP), that is, the difference between alveolar and pleural pressure [4, 5]. Since pleural pressure is broadly and unpredictably variable among ARDS patients, it is difficult to determine which level of PEEP is needed to prevent alveolar collapse and, therefore, atelectrauma in the individual patient.

As already mentioned, a promising approach would be to use esophageal pressure, which provides (with some important limitations) an estimation of pleural pressure useful to set PEEP [2, 4, 5, 15]. Talmor and colleagues [15] used this approach in a small, single-center trial and reported, in addition to improved oxygenation, a trend toward reduced 28-day mortality. A large mRCT is currently underway [5] and could clarify the impact of such an approach on the outcome of ARDS.