The use of helium-oxygen (HeO(2)) was tested in combination with noninvasive ventilation (NIV) in 10 patients with acute exacerbation of chronic obstructive pulmonary disease (COPD). Effort to breathe as assessed by the respiratory muscle pressure-time index (PTI), work of breathing (WOB), and gas exchange were the main endpoints. Results of NIV-HeO(2) were compared with those obtained with standard NIV (AirO(2)), at two levels of pressure-support ventilation (PSV), 9 +/- 2 cm H(2)O and 18 +/- 3 cm H(2)O. Significant reductions in PTI were observed between HeO(2) and AirO(2) at both the low PSV level (n = 9; 160 +/- 58 versus 198 +/- 78 cm H(2)O/s/ min; p < 0.05) and the high PSV level (n = 10; 100 +/- 45 versus 150 +/- 82 cm H(2)O/s/min; p < 0.01). WOB also differed significantly between HeO(2) and AirO(2) (7.8 +/- 4.1 versus 10.9 +/- 6.1 J/min at the low PSV level, p < 0.05; and 5.7 +/- 3.3 versus 9.2 +/- 5. J/min, p < 0.01 at the high PSV level). HeO(2) reduced Pa(CO(2)) at both the low PSV level (61 +/- 13 versus 64 +/- 15 mm Hg; p < 0.05) and the high PSV level (56 +/- 13 versus 58 +/- 14 mm Hg; p < 0.05), without significantly changing breathing pattern or oxygenation. We conclude that use of HeO(2) during NIV markedly enhances the ability of NIV to reduce patient effort and to improve gas exchange.