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BACKGROUND: Mechanical ventilation is a common life-saving procedure but can lead to serious complications, including ARDS and oxygen toxicity. Nonadherence to lung-protective ventilation guidelines is common. We hypothesized that a respiratory therapist-driven mechanical ventilation bundle could increase adherence to lung-protective ventilation and decrease the incidence of pulmonary complications in the ICU. METHODS: A respiratory therapist-driven protocol was implemented on August 1, 2018, in all adult ICUs of a Midwestern academic tertiary center. The protocol targeted low tidal volume, adequate PEEP, limiting oxygen, adequate breathing frequency, and head of the bed elevation. Adherence to lung-protective guidelines and clinical outcomes were retrospectively observed in adult subjects admitted to the ICU and on ventilation for ≥ 24 h between January 2011 and December 2019. RESULTS: We included 666 subjects; 68.5% were in the pre-intervention group and 31.5% were in the post-intervention group. After adjusting for body mass index and intubation indication, a significant increase in overall adherence to lung-protective ventilation guidelines was observed in the post-intervention period (adjusted odds ratio 2.48, 95% CI 1.73-3.56). Fewer subjects were diagnosed with ARDS in the post-intervention group (adjusted odds ratio 0.22, 95% CI 0.08-0.65) than in the pre-intervention group. There was no difference in the incidence of ventilator-associated pneumonia, ventilator-free days, ICU mortality, or death within 1 month of ICU discharge. CONCLUSIONS: A respiratory therapist-driven protocol increased adherence to lung-protective mechanical ventilation guidelines in the ICU and was associated with decreased ARDS incidence. [ABSTRACT FROM AUTHOR]