The pathobiology of ARDS has been elegantly elucidated over the last several decades using animal models of acute lung injury [17, 50]. The principal lesion is the breakdown of the lung’s alveolar-capillary barrier due to toxins and acute inammation (i.e., neutrophils), causing protein-rich exudative uid to ood the alveolar space. This is accompanied by further inammation and oxidative stress (i.e., reactive oxygen species) that cause mitochondrial, cellular, and tissue injury [49, 91]. The histopathologic hallmark of ARDS is diffuse alveolar damage (DAD) characterized by the formation of hyaline (brin) membranes, although some lung pathologists believe that hyaline membrane formation is exclusively a sign of oxy­gen toxicity. Pulmonary oxygen toxicity due to prolonged exposure to high FiO (>0.6) can worsen existing lung injury and is indistinguishable from ARDS itself. Despite DAD being the characteristic histopathologic pattern seen, other histologic diagnoses have been identied in open lung biopsies of patients thought to have ARDS, such as bacterial pneumonia, organizing pneumonia, pulmonary embolism, diffuse alveolar hemorrhage, and lymphangitic tumor, though the DAD pattern is associated with the highest mortality [16]. After approximately 7days, the lung begins to form a scar in the form of organizing pneumonia (“organization”), where the intra-alveolar brin serves as a scaffold for broblasts and myobroblasts to lay down collagen. By day 14, the acute phase of ARDS has fully transitioned to the late broproliferative phase. ARDS will slowly resolve over days to weeks in many

Other modalities of mechanical ventilation that offer theoretical lung protection have been explored, such as high-frequency oscillatory ventilation (HFOV). HFOV delivers a constant mean airway pressure to maintain alveolar recruitment and a respiratory rate of 3–15Hz, the equivalent of hundreds of small tidal breaths per minute. Unlike conventional mechanical ventilation, HFOV avoids low end­expiratory pressures and high peak pressures, reducing the risk of ventilator-induced lung injury and improving PaO2 [22]. However, in 2013, two landmark randomized, controlled trials demonstrated no mortality benet or even harm associated with HFOV compared with conventional low tidal volume ventilation [34, 93]. Routine use of HFOV for the treatment of moderate-to-severe ARDS is, therefore, not rec­ommended [32].

tables (a lower table and a higher

Prone positioning is the placement of the patient on the stomach rather than the back (supine). Mechanical ventilation is still delivered in the usual low-volume, low­pressure mode. While turning critically ill patients from supine to prone involves skilled nursing and respiratory therapy support, there are several physiologic effects of prone positioning that mitigate hypoxemia in moderate-to-severe ARDS: In the supine position, atelectasis preferentially develops in the dependent posterior and basilar portions of the lungs [38, 75]. In addition, the transpulmonary pressure, or distention pressure, is higher in the anterior region and lower in the posterior region, leading to overdistention of the anterior alveoli and exacerbating collapse of the posterior alveoli, even in the presence of PEEP [38, 73]. At the same time, blood preferentially ows to these dependent and poorly ventilated regions, creating a shunt. In the prone position, however, the posterior atelectasis is reduced, as pres­sure is instead placed on the sternum and heart, and circulation now favors the better aerated anterior regions. This diversion of blood into ventilated alveoli alleviates shunt and ventilation-perfusion mismatch [73]. In addition, the difference in

Years of case series described short-term improvement in oxygenation with the use of prone positioning [25, 66, 73], but its use gained traction following the PROSEVA trial which demonstrated a remarkable mortality benet (number needed to treat=6) [43] in moderate-to-severe ARDS (P/F<150). Later systematic reviews and meta-analyses conrmed that early prone positioning used in conjunc­tion with lung-protective ventilation offers the greatest mortality reduction in severe ARDS [46, 57, 67, 85]. The current consensus is that patients with severe ARDS should undergo prone positioning for ≥12hours per day (strong recommen­dation, moderate certainty of evidence) [76]. Due to discomfort associated with prone positioning, patients are generally expected to need increased sedation or even neuromuscular blockade (see next section), although neuromuscular blockade is not mandatory.