(A) Graphical representation (not to scale) of the alveolar epithelial glycocalyx, a layer of GAGs — heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA) — that lines the apical alveolar epithelial surface. In murine models of acute lung injury, the glycocalyx is damaged, leading to shedding of GAGs into the airspace fluid. (B) Graphical representation of a patient on a ventilator circuit containing a heat and moisture exchanger (HME) filter, from which airspace fluid can be noninvasively sampled in mechanically ventilated patients. (C) Assessment of airspace fluid GAG shedding in mechanically ventilated patients was performed by mass spectrometry analysis of HMEF. (D) Partitioning around k-medoids clustering using the variables HS, CS, and HA was performed to group patients into high, medium, and low shedding clusters based on the degree of GAG shedding. (E) Assessment of the effect of patients’ sex on airspace GAG levels in patients with respiratory failure. n = 153 participants with respiratory failure. *P < 0.05 by Wilcoxon’s rank sum test. Data are represented as median and IQR with individual data points for those outside of 1.5 × IQR. A and B were created with BioRender (biorender.com).