Inclusion Criteria:

1. Age ≥ 18 years
2. Moderate or severe ARDS, defined as meeting all of the following (a-e):

1. Invasive ventilation with positive end-expiratory pressure (PEEP) ≥ 5 cm H2O
2. Hypoxemia as characterized by: • If arterial blood gas (ABG) available: the partial pressure of oxygen in the arterial blood (PaO2)/FiO2 ≤ 200 mm Hg, or, • if ABG not available OR overt clinical deterioration in oxygenation since last ABG: SpO2/FiO2 ≤ 235 with SpO2 ≤ 97% (both conditions) on two representative assessments between 1 to 6 hours apart. • If patient is positioned prone or receiving inhaled pulmonary vasodilator at time of screening:

Qualifying PaO2/FiO2 or SpO2/FiO2 (as defined above) that was recorded within the 6 hours immediately prior to initiating either of these therapies may be used for eligibility determination. • If PEEP has been increased by \> 5 cm H2O within the last 12 hours immediately prior to screening:

Qualifying PaO2/FiO2 or SpO2/FiO2 (as defined above) prior to PEEP increase may be used for eligibility determination if recorded within this 12-hour window.
3. Bilateral lung opacities on chest imaging not fully explained by effusions, lobar collapse, or nodules
4. Respiratory failure not fully explained by heart failure or fluid overload
5. Onset within 1 week of clinical insult or new/worsening symptoms
3. Early in ARDS course

* Full criteria for moderate-severe ARDS (#2 above) first met within previous 3 days
* Current invasive ventilation episode not more than 4 days duration
* Current severe hypoxemic episode (receipt of invasive ventilation, noninvasive ventilation, or high-flow nasal cannula) not more than 10 days duration

Exclusion Criteria:

1. Esophageal manometry already in use clinically
2. Severe brain injury: including suspected elevated intracranial pressure, cerebral edema, or Glasgow coma score (GCS) ≤ 8 directly caused by severe brain injury (e.g., ischemia or hemorrhage)
3. Gross barotrauma or chest tube inserted to treat barotrauma (note: chest tube inserted strictly for drainage of pleural effusion is not an exclusion)
4. Esophageal varix or stricture that, in judgement of the site investigator, significantly increases risk of esophageal catheter placement; recent oropharyngeal or gastroesophageal surgery; or past esophagectomy
5. Ongoing severe coagulopathy (platelet \< 5000/μL or INR \> 4)
6. Extracorporeal membrane oxygenation (ECMO) or CO2 removal (ECCO2R)
7. Neuromuscular disease that impairs spontaneous breathing (including but not limited to amyotrophic lateral sclerosis, Guillain-Barré syndrome, spinal cord injury at C5 or above)
8. Any of the following severe chronic lung diseases: continuous home supplemental oxygen \> 3 liters/minute, pulmonary fibrosis, cystic fibrosis, lung transplant, or acute exacerbation of a chronic interstitial lung disease (ILD)
9. Severe shock: norepinephrine-equivalent dose ≥ 0.6 μg/kg/min or simultaneous receipt of ≥ 3 vasopressors
10. Severe liver disease, defined as Child-Pugh Class C (Section 12.3)
11. ICU admission for burn injury
12. Current ICU stay \> 2 weeks or acute care hospital stay \> 4 weeks
13. Estimated mortality \> 50% over 6 months due to underlying chronic medical condition (e.g. metastatic pancreatic cancer) as assessed by the study physician
14. Moribund patient not expected to survive 24 hours as assessed by the study physician; if cardiopulmonary resuscitation (CPR) was provided, assessment for moribund status must occur at least 6 hours after CPR was completed
15. Current limitation on life-sustaining care (other than do-not-resuscitate), or expectation by clinical team that a limitation on life-sustained care will be adopted within next 24 hours.
16. Treating clinician refusal or unwilling to use protocol-specified ventilator settings/modes
17. Prisoner
18. Previous enrollment in this trial

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/4/2025. Questions regarding updates should be directed to the study team contact.