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Although a significant number of patients with severe brain injury develop acute lung injury, only intracranial risk factors have previously been studied. We investigated the role of extracranial predisposing factors, including hemodynamic and ventilatory management, as independent predictors of acute lung injury in brain-injured patients.Prospective multicenter observational study.Four European intensive care units in university-affiliated hospitals.Eighty-six severely brain-injured patients enrolled in 13 months.None.All patients with severe brain injury (Glasgow Coma Scale score <9) were studied for 8 days from admission. Ventilatory pattern, respiratory system compliance, blood gas analysis, and hemodynamic profile were recorded and entered in a stepwise regression model. Length of stay in the intensive care unit, ventilator-free days, and mortality were collected. Eighteen patients (22%) developed acute lung injury on day 2.8 ± 1. They were initially ventilated with significantly higher tidal volume per predicted body weight (9.5 ± 1 vs. 10.4 ± 1.1), respiratory rate, and minute ventilation and more often required vasoactive drugs (p < .05). In addition to a lower Pao2/Fio2 (odds ratio 0.98, 95% confidence interval 0.98–0.99), the use of high tidal volume (odds ratio 5.4, 95% confidence interval 1.54–19.24) and relatively high respiratory rate (odds ratio 1.8, 95% confidence interval 1.13–2.86) were independent predictors of acute lung injury (p < .01). After the onset of acute lung injury, patients remained ventilated with similar tidal volumes to maintain mild hypocapnia and had a longer length of stay in the intensive care unit and fewer ventilator-free days (p < .05).In addition to a lower Pao2/Fio2, the use of high tidal volume and high respiratory rate are independent predictors of acute lung injury in patients with severe brain injury. In this patient population, alternative ventilator strategies should be considered to protect the lung and guarantee a tight CO2 control.