A system and method to in-exsufflate a subject is described. The system provides an effective non-invasive alternative to invasive treatments such as a tracheostomy for ALS patients. The system detects airway collapse during exsufflation and adjusts in-exsufflation therapy settings to minimize airway collapse, thus maximizing the efficacy of the in-exsufflation therapy. In some embodiments, tidal volume, tidal flow rate, and/or other parameters are monitored during in-exsufflation. Exsufflation pressure is adjusted based on the monitored parameters to maintain an open airway during exhalation of the subject. Exsufflation pressure is adjusted based on a comparison of an actual exhalation tidal volume to a target exhalation tidal volume, an actual exhalation flow rate to a target exhalation flow rate, an actual inhalation tidal volume to a target inhalation volume, and/or other comparisons.