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To test the hypothesis that replacing 70:30 nitrogen:oxygen (Air-O2) with 70:30 helium:oxygen (He-O2) can decrease dynamic hyperinflation (“intrinsic” positive end-expiratory pressure) in mechanically ventilated patients with chronic obstructive pulmonary disease (COPD), and to document the consequences of such an effect on arterial blood gases and hemodynamics.Prospective, interventional study.Medical intensive care unit, university tertiary care center.Twenty-three intubated, sedated, paralyzed, and mechanically ventilated patients with COPD enrolled within 36 hrs after intubation.Measurements were taken at the following time points, all with the same ventilator settings: a) baseline; b) after 45 mins with He-O2; c) 45 mins after return to Air-O2. The results were then compared to those obtained in a test lung model using the same ventilator settings.Trapped lung volume and intrinsic positive end-expiratory pressure decreased during He-O2 ventilation (215 ± 125 mL vs. 99 ± 15 mL and 9 ± 2.5 cm H2O vs. 5 ± 2.7 cm H2O, respectively;p < .05). Likewise, peak and mean airway pressures declined with He-O2 (30 ± 5 cm H2O vs. 25 ± 6 cm H2O and 8 ± 2 cm H2O vs. 7 ± 2 cm H2O, respectively;p < .05). These parameters all rose to their baseline values on return to Air-O2 (p < .05 vs. values during He-O2). These results were in accordance with those obtained in the test lung model. There was no modification of arterial blood gases, heart rate, or mean systemic arterial blood pressure. In 12/23 patients, a pulmonary artery catheter was in place, allowing hemodynamic measurements and venous admixture calculations. Switching to He-O2 and back to Air-O2 had no effect on pulmonary artery pressures, right and left ventricular filling pressures, cardiac output, pulmonary and systemic vascular resistance, or venous admixture.In mechanically ventilated COPD patients with intrinsic positive end-expiratory pressure, the use of He-O2 can markedly reduce trapped lung volume, intrinsic positive end-expiratory pressure, and peak and mean airway pressures. No effect was noted on hemodynamics or arterial blood gases. He-O2 might prove beneficial in this setting to reduce the risk of barotrauma, as well as to improve hemodynamics and gas exchange in patients with very high levels of intrinsic positive end-expiratory pressure.