Project Summary Presentations of respiratory failure can vary from mild requiring supplemental oxygen to more severe requiring invasive mechanical ventilation (i.e., acute respiratory distress syndrome or ARDS). Early in respiratory failure patients often have abnormalities in gas exchange, control of breathing, and/or pulmonary mechanics. During the ongoing COVID-19 pandemic, some studies have demonstrated that increased respiratory drive is associated with worse clinical outcomes while others have demonstrated contrary findings. We have also demonstrated that a noninvasive assessment of gas exchange using the alveolar gas meter (AGM) is predictive of who will require supplemental oxygen from COVID-19 infection. Additional studies predating the COVID-19 pandemic showed that increased inspiratory effort, large transpulmonary pressure changes, and elevated dead space were all associated with worse outcomes in ARDS. However, many of these studies focused on patients already intubated and mechanically ventilated. Less is known about the relevance of these parameters in spontaneously breathing individuals. For a few years now the notion of patient self-inflicted lung injury (P-SILI) has been gaining traction in the medical literature. The basic concept is that patients with impending respiratory failure from existing lung injury can cause worsening damage to their lungs. If patients are spontaneously breathing with excessively high respiratory drive, then they may generate excessively negative inspiratory efforts leading to major transpulmonary pressure changes. The results of these abnormalities are large tidal volumes like mechanically ventilating someone with injurious tidal volumes prior to the advent of low tidal volume ventilation (LTVV). Also, retrospective review of large cohort studies and randomized controlled trials of ARDS patients have demonstrated that spontaneously breathing patients prior to intubation often generated excessively large tidal volumes. Whether their subsequent lung injury was entirely due to their underlying ARDS pathology or partially due to superimposed P-SILI is not known. If a physiological signature of impending respiratory failure in spontaneously breathing individuals exists and it is associated with elevated respiratory drive, steps can subsequently be taken to mitigate the increased drive and study the longitudinal effects of these variables in patients who develop respiratory failure. Moreover, if such a signature exists and intervention abrogates some of the subsequent lung injury, this is a strong proof of concept for P-SILI in vivo. We aim to test three independent but related hypotheses. First, the AGM is a novel and simple technique which can be used to identify patients at increased risk for respiratory failure better than traditional metrics. Second, the breath hold maneuver is a validated technique to assess control of breathing that can identify patients with poor respiratory prognosis. Third, the air...