Findings  In this randomized clinical trial that included 961 patients in the ICU who were receiving invasive ventilation and expected to not be extubated within 24 hours of randomization, a ventilation strategy with low tidal volume did not result in a significant difference in ventilator-free days and alive at day 28 than a ventilation strategy with intermediate tidal volumes (median, 21 days vs 21 days).

Meaning  Among patients in the ICU receiving invasive ventilation, a strategy with low tidal volume was not more effective than a strategy using intermediate tidal volume.

Importance  It remains uncertain whether invasive ventilation should use low tidal volumes in critically ill patients without acute respiratory distress syndrome (ARDS).

Objective  To determine whether a low tidal volume ventilation strategy is more effective than an intermediate tidal volume strategy.

Design, Setting, and Participants  A randomized clinical trial, conducted from September 1, 2014, through August 20, 2017, including patients without ARDS expected to not be extubated within 24 hours after start of ventilation from 6 intensive care units in the Netherlands.

Interventions  Invasive ventilation using low tidal volumes (n = 477) or intermediate tidal volumes (n = 484).

Main Outcomes and Measures  The primary outcome was the number of ventilator-free days and alive at day 28. Secondary outcomes included length of ICU and hospital stay; ICU, hospital, and 28- and 90-day mortality; and development of ARDS, pneumonia, severe atelectasis, or pneumothorax.

Results  In total, 961 patients (65% male), with a median age of 68 years (interquartile range [IQR], 59-76), were enrolled. At day 28, 475 patients in the low tidal volume group had a median of 21 ventilator-free days (IQR, 0-26), and 480 patients in the intermediate tidal volume group had a median of 21 ventilator-free days (IQR, 0-26) (mean difference, –0.27 [95% CI, –1.74 to 1.19] P = .71). There was no significant difference in ICU (median, 6 vs 6 days; 0.39 [–1.09 to 1.89] ; P = .58) and hospital (median, 14 vs 15 days; –0.60 [–3.52 to 2.31]; P = .68) length of stay or 28-day (34.9% vs 32.1%; hazard ratio [HR], 1.12 [0.90 to 1.40]; P = .30) and 90-day (39.1% vs 37.8%; HR, 1.07 [0.87 to 1.31]; P = .54) mortality. There was no significant difference in the percentage of patients developing the following adverse events: ARDS (3.8% vs 5.0%; risk ratio [RR], 0.86 [0.59 to 1.24]; P = .38), pneumonia (4.2% vs 3.7%; RR, 1.07 [0.78 to 1.47]; P = .67), severe atelectasis (11.4% vs 11.2%; RR, 1.00 [0.81 to 1.23]; P = .94), and pneumothorax (1.8% vs 1.3%; RR, 1.16 [0.73 to 1.84]; P = .55).

Conclusions and Relevance  In patients in the ICU without ARDS who were expected not to be extubated within 24 hours of randomization, a low tidal volume strategy did not result in a greater number of ventilator-free days than an intermediate tidal volume strategy.