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To review the use of high-frequency oscillatory ventilation (HFOV) with adjunctive therapies (inhaled nitric oxide [iNO] and prone positioning [PP]) in adult patients with acute respiratory distress syndrome (ARDS).Published studies evaluating the use of iNO, PP, and HFOV in adult patients with ARDS.Despite ongoing preclinical and clinical research, the therapeutic armamentarium for ARDS remains limited. Although a pressure- and volume-limited strategy aimed at mitigating ventilator-associated lung injury has demonstrated mortality benefit, patients with severe ARDS may still develop life-threatening hypoxemia. As a result, various salvage therapies aimed at improving oxygenation, including HFOV, iNO, and PP alone or in combination, have been evaluated in patients with refractory ARDS. Although the few preclinical and clinical trials of combination therapy to date have shown promising improvements in oxygenation and other physiological variables, with few adverse clinical events, the impact on survival awaits the performance of large randomized trials.There is limited clinical data to recommend the widespread use of combination therapy in patients with ARDS. In the subset of patients with life-threatening hypoxemia from refractory ARDS, combination therapy is safe and may be considered for salvage therapy. More rigorous randomized, controlled trials are needed to help delineate the therapeutic role of combination therapy in adults with ARDS.