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Mechanical ventilatory support is life-saving therapy for patients with respiratory failure in intensive care units (ICU) but is linked to ventilator-associated pneumonia and other nosocomial infections. Interventions that improve the efficiency of weaning from mechanical ventilation may improve patient outcomes.To determine whether inhaled budesonide decreases time-to-weaning in COPD stage 4 difficult-to-wean patients and reduces the release of pro-inflammatory cytokines in ICU patients.We recruited 55 difficult-to-wean COPD patients (Stage 4) within the ICU of the Masih Daneshvari Hospital. Subjects were randomly assigned to receive inhaled budesonide (0.5 mg/day) or placebo (normal saline). Dynamic compliance and BAL cytokines were measured.Budesonide significantly reduced the number of days on MV (days-to-weaning = 4.6 ± 1.6 days) compared to that seen in the control group (7.2 ± 2.7 days, p = 0.014). Dynamic compliance was significantly improved in the budesonide group on days 3 (p = 0.018) and 5 (p = 0.011) The levels of CXCL-8 and IL-6 diminished on days 3–5 after start of budesonide (p < 0.05).In COPD patients on MV, nebulized budesonide was associated with reduced BAL CXCL8 and IL-6 levels and neutrophil numbers as well as an improvement in ventilatory mechanics and facilitated weaning.In COPD patients on mechanical ventilation, nebulized budesonide improved ventilatory mechanics and facilitated weaning.Budesonide reduced the presence of inflammatory mediators and cells in BAL.Budesonide facilitates weaning from mechanical ventilation in difficult-to-wean very severe COPD patients.