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Background: During acute ventilatory failure in patients with chronic obstructive pulmonary disease (COPD), applying external positive end-expiratory pressure (PEEPe) will reopen small airways and, thus, may enhance peripheral deposition as well as the physiological effects of inhaled beta-2 agonists., Objective: To investigate the efficacy of inhaled fenoterol applied by zero end-expiratory pressure (ZEEPe) or PEEPe., Methods: Ten patients with COPD who were intubated and mechanically ventilated received fenoterol (10 mg/4 mL) via the ventilator using a jet nebulizer for 30 min on ZEEPe and PEEPe set at 80% of the total PEEP in a random order. The total resistance of the respiratory system (rapid airway occlusion technique), change in end-expiratory lung volume and expiratory flow limitation were assessed before and 5 min, 15 min, 30 min, 60 min and 240 min after fenoterol inhalation., Results: Before inhalation and 60 min after inhalation, the total PEEP, the change in end-expiratory lung volume and the total resistance of the respiratory system were 8+/-3 cmH2O and 6+/-3 cmH2O, 0.61+/-0.34 L and 0.43+/-0.32 L, and 26+/-7 cmH2O/L/s and 23+/-6 cmH2O/L/s, respectively, with ZEEPe, and 9+/-3 cmH2O and 8+/-3 cmH2O (P<0.05 versus ZEEPe), 0.62+/-0.34 L and 0.62+/-0.37 L (P<0.05 versus ZEEPe), and 26+/-9 H2O/L/s and 25+/-9 H2O/L/s, respectively, with PEEPe. Three patients became not flow-limited under the combination of PEEPe and fenoterol., Conclusions: In patients with COPD, fenoterol combined with PEEPe has opposing effects on respiratory mechanics. First, it does not significantly reduce lung hyperinflation or inspiratory resistances. Second, it allows expiratory flow limitation reversal in some patients. These findings result from the net effect on end-expiratory lung volume of each intervention. This implies that if fenoterol is used in combination with PEEPe, the level of PEEPe should be reassessed during the time course of the drug to prevent any further lung hyperinflation.