BACKGROUND AND OBJECTIVES:Inhaled mucoactive agents are used to enhance airway clearance, however efficacy and safety are unclear in adults with acute respiratory conditions. METHODS:We systematically reviewed randomized controlled trials assessing respiratory function; safety; length of stay (LOS); mucus; radiology; and oxygenation. RESULTS:No adverse events were reported for dornase alfa (n = 63), N-acetylcysteine (NAC, n = 50), ambroxol (n = 140), hypertonic saline (n = 33), heparin (n = 384), mannitol (n = 20) or isotonic saline. During invasive ventilation, NAC, dornase alfa and saline had no effect on mucus. Postoperatively, mucus characteristics improved with NAC (n = 10). Ambroxol lowered LOS (mean difference 4 days) and halved complications following lung carcinoma resection (n = 140). Heparin improved ventilator-free days (n = 130, mean difference 3.9-4.6) and intensive care LOS (n = 223, 3.2 days), but not ventilator-acquired pneumonia. CONCLUSION:Dornase alfa, hypertonic saline and NAC were ineffective for atelectasis/mucus plugging while intubated. More data are required to support using NAC, ambroxol and heparin during acute illness.