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Refractory hypoxemia is the hallmark of severe acute respiratory distress syndrome. Mechanical ventilation utilizing low-tidal volumes remains the standard of care for these patients; however, correction of the hypoxemia does not always correlate with improved mortality. Nevertheless, clinical management aims at achieving adequate oxygenation while minimizing ventilator-induced lung injury. Continued assessment of the patient’s hemodynamics is required, as acute respiratory distress syndrome is often associated with hemodynamic instability, which may be a significant factor in the high mortality rate reported in this condition. Even when ventilator settings are optimized, mechanical ventilation alone may not provide adequate gas exchange in severe cases, requiring the use of rescue therapies to improve oxygenation. Prone positioning, neuromuscular blocking agents, and extracorporeal membrane oxygenation are salvage therapies, which may improve mortality, but other rescue therapies, such as recruitment maneuvers, pulmonary vasodilators, and alternative modes of ventilation, can acutely improve oxygenation and serve as a “bridge” to these other therapies. A timely, multimodal approach along with a firm understanding of the potential benefits and limits of rescue therapies is vital to improving outcomes in patients with severe hypoxemia.