Early observations that PEEP greatly improves oxygenation in patients with ARDS led to its widespread use in such patients, but the level of PEEP needed to achieve maximum benefit with minimum complications was never established. Additionally, animal models37 have suggested that repetitive opening and closing of the alveoli during the respiratory cycle can promote lung injury. Therefore, several randomized trials evaluated the efficacy of high levels of PEEP in the treatment of ARDS. In the study of a protective-ventilation strategy, by Amato and colleagues,10 PEEP was significantly higher in the intervention group compared with the control group (mean PEEP on days 2 to 7, 13.2 ± 0.4 vs 9.3 ± 0.5 cm H2O; p < 0.01). Villar et al36 evaluated a similar strategy in a randomized controlled trial that enrolled patients with persistent ARDS (the Pao2/Fio2 ratio remained ≤ 200 for at least 24 h while standard ventilator settings were used). Patients in the intervention group were ventilated with tidal volumes of 5 to 8 mL/kg predicted body weight, and PEEP was set on day 1 at 2 cm H2O above Pflex, defined as the lower inflection point on the pressure-volume curve of the respiratory system. The control group was ventilated with tidal volumes of 9 to 11 mL/kg predicted body weight and a PEEP of ≥ 5 cm H2O. This difference resulted in a significantly higher PEEP among intervention patients compared with control patients (mean PEEP on day 1, 14.1 ± 2.8 vs 9.0 ± 2.7 cm H2O, respectively; p < 0.001) as well as a significantly lower ICU mortality rate among intervention patients (32% vs 53.3%, respectively; p = 0.04). Ranieri et al38 determined that a similar ventilatory strategy (mean PEEP at 2 to 3 h, 14.8 ± 2.7 vs 6.5 ± 1.7 cm H2O, respectively; mean tidal volume at 2 to 3 h, 7.6 ± 1.1 vs 11.1 ± 1.9 mL/kg, respectively) resulted in an attenuation of the cytokine response observed in patients who were ventilated with higher tidal volumes and lower PEEP. But neither these findings nor the significantly lower mortality rates observed in the intervention groups in the trials of both Villar et al36 and Amato et al10 could be solely attributed to higher levels of PEEP since the intervention strategies in these trials employed both low tidal volumes and high levels of PEEP. The isolated benefit to survival of low tidal volume ventilation was demonstrated in ARMA,14 as discussed previously, since patients in the intervention group were treated with levels of PEEP that were no different than those utilized in the control group. But another trial was needed to evaluate the efficacy of high PEEP in which all patients received low tidal volume ventilation.