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To examine the effects of a mechanical ventilation weaning management protocol that was implemented as a hospital-wide, quality improvement program on clinical and economic outcomes.Prospective, before-and-after intervention study. Data from a preimplementation year are compared with those of the first 2 yrs after protocol implementation.Patients older than 18 yrs in diagnosis-related group 475 and group 483, who were admitted to the adult medical, surgical, and cardiac intensive care units (ICU) in a university hospital.After the baseline year, a weaning management program was implemented throughout our institution. Primary endpoints were mortality, days on mechanical ventilation, ICU and hospital lengths of stay, hospital costs, and the percentage of patients requiring tracheostomy.The number of patients increased from 220 in the baseline year (year 0) to 247 in the first year (year 1), then to 267 in the second year (year 2). The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score increased from 22.2 to 24.4 in year 1 (p = .006) and to 26.2 in year 2 (p < .0005). When year 0 was compared with year 1, mean days on mechanical ventilation decreased from 23.9 to 21.9 days (p = .608), hospital length of stay decreased from 37.5 to 31.6 days (p = .058), ICU length of stay decreased from 30.5 to 25.9 days (p = .133), and total cost per case decreased from $92,933 to $78,624 (p = .061). When year 0 was compared with year 2, mean days on mechanical ventilation decreased from 23.9 days to 17.5 days (p = .004), mean hospital length of stay decreased from 37.5 to 24.7 days, mean ICU length of stay decreased from 30.5 to 20.3 days, total cost per case decreased from $92,933 to $63,687, and percentage of patients requiring tracheotomy decreased from 61% to 41% (all p < .0005). There was also a reduction in the percentage of patients requiring more than one course of mechanical ventilation during the hospitalization from 33% to 26% (p = .039), a total cost savings of $3,440,787 and a decrease in mortality between all 3 yrs from 32% to 28% (p = .062).A multifaceted, multidisciplinary weaning management program can change the process of care used for weaning patients from mechanical ventilation throughout an acute care hospital and across multiple services. This change can lead to large reductions in the duration of mechanical ventilation, length of stay, and hospital costs, even at a time when patients are sicker.