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Background: Standardizing patient care is a challenging task in studies of patients with acute illness. Use of a lung-protective ventilation (LPV) protocol in studies of patients with acute lung injury is associated with reduced mortality and is the current standard for invasive ventilation in such studies. However, achieving the goals of an LPV protocol can be challenging. Methods: In a Phase III clinical study of pulmonary surfactant administration to patients with acute respiratory insufficiency due to pneumonia or aspiration of gastric contents, we performed an observational analysis to assess whether the goals of a specified ventilation protocol were achieved. Ventilation parameters, including tidal volume (VT) and peak inspiratory pressure (PIP), of the first 200 patients enrolled were analyzed. Subsequently, an intensified training program was initiated to improve achievement of protocol goals, and this achievement was assessed again in the next 643 randomized patients. Results: Implementation of intensified training measures was accompanied by a significant reduction in median values of VT from 7.8 to 7.0 mL/kg predicted body weight (PBW) and PIP from 29.5 to 28.5 cm H2O. Use of VT based on actual body weight, as opposed to PBW, may impair goal achievement. Goal achievement varied among countries and improved significantly in some with intensified training measures. Conclusions: Specific training measures may be effective in promoting achievement of goals of a pre-specified ventilation protocol in multinational clinical trials. Strategies described in this study may be helpful in achieving compliance with complex protocol demands in a variety of clinical trials.