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To test the hypothesis that, compared with air-oxygen, heliox would improve cardiac performance in mechanically ventilated patients with severe chronic obstructive pulmonary disease and systolic pressure variations >15 mm Hg and to determine clinical variables associated with favorable hemodynamic responses to heliox.A prospective interventional study.Medical and respiratory intensive care units at a university-affiliated tertiary medical center.Twenty-five consecutive mechanically ventilated patients with severe chronic obstructive pulmonary disease and acute respiratory failure who had systolic pressure variations >15 mm Hg.Respiratory and hemodynamic measurements were taken at the following time with the same ventilator setting: a) baseline; b) after 30 mins with heliox; and c) 30 mins after return to air-oxygen.Heliox ventilation decreased intrinsic positive end-expiratory pressure (air-oxygen vs. heliox [mean ± sd] 13 ± 4 cm H2O vs. 5 ± 2 cm H2O, p < .05), trapped lung volume (air-oxygen vs. heliox 362 ± 67 mL vs. 174 ± 86 mL, p < .05), and respiratory changes in systolic pressure variations (ΔPP) (air-oxygen vs. heliox 29 ± 5% vs. 13 ± 7%, p < .05). In the ten patients with pulmonary arterial catheters, heliox decreased mean pulmonary arterial pressure, right atrial pressure, and pulmonary arterial occlusion pressure and increased cardiac index. Preheliox ΔPP correlated with the magnitude of reduction in intrinsic positive end-expiratory pressure during heliox ventilation. Age, preheliox Paco2, and ratio of forced expiratory volume at first second to forced vital capacity correlated inversely, whereas preheliox ΔPP correlated positively with increases in cardiac index.Heliox may be a useful adjunct therapy in patients with severe chronic obstructive pulmonary disease during acute respiratory failure who have persistent intrinsic positive end-expiratory pressure-induced hemodynamic changes despite ventilator management.