BACKGROUND: Hyperoxygenation and hyperinflation, preferably with a mechanical ventilator, is the most commonly used technique to prevent the adverse effects of open endotracheal suctioning on arterial oxygenation and pulmonary volume. However, limited data are available on the effects of oxygen concentrations < 100% and PEEP with zero end-expiratory pressure (0 PEEP) to improve oxygenation and to maintain adequate ventilation during open endotracheal suctioning. The aim of this study was to analyze the behavior of S pO 2 and end-tidal CO 2 pressure (P ETCO 2) in open endotracheal suctioning using the 0 PEEP technique with baseline F IO 2 (0 PEEP baseline F IO 2) and 0 PEEP + hyperoxygenation of 20% above the baseline value (0 PEEP F IO 2 + 0.20) in critically ill subjects receiving mechanical ventilation. METHODS: This was a prospective, randomized, single-blind crossover study, for which 48 subjects with various clinical and surgical conditions were selected; of these, 38 subjects completed the study. The subjects were randomized for 2 interventions: 0 PEEP baseline F IO 2 and 0 PEEP F IO 2 + 0.20 during the open endotracheal suctioning procedure. Oxygenation was assessed via oxygen saturation as measured with pulse oximetry (S pO 2), and changes in lung were monitored via P ETCO 2 using volumetric capnography. RESULTS: In the intragroup analysis with 0 PEEP baseline F IO 2 , there was no significant increase after open endotracheal suctioning in either S pO 2 (P 5 .63) or P ETCO 2 (P 5 .11). With 0 PEEP F IO 2 + 0.20, there was a significant increase in S pO 2 (P < .001), with no significant changes in P ETCO 2 (P 5 .55). In the intergroup comparisons, there was a significant increase compared to the basal values only with the 0 PEEP + 0.20 method at 1 min after hyperoxygenation (P < .001), post-immediately (P < .001), at 1 min after (P < .001), and at 2 min after open endotracheal suctioning (P < .001). CONCLUSIONS: The appropriate indication of the hyperinflation strategy via mechanical ventilation using 0 PEEP with or without hyperoxygenation proved to be efficient to maintain S pO 2 and P ETCO 2 levels. These results suggest that the technique can minimize the loss of lung volume due to open endotracheal suctioning. (ClinicalTrials.gov registration NCT02440919).