The goal of this interventional study is to compare standard mechanical ventilation to a lung-stress oriented ventilation strategy in patients with Acute Respiratory Distress Syndrome (ARDS). Participants will be ventilated according to one of two different strategies. The main question the study hopes to answer is whether the personalized ventilation strategy helps improve survival.

ARDS is a devastating condition that places a heavy burden on public health resources. Recent changes in the practice of mechanical ventilation have improved survival in ARDS, but mortality remains unacceptably high.

This application is for support of a phase III multi-centered, randomized controlled trial of mechanical ventilation, directed by driving pressure and esophageal manometry, in patients with ARDS. The primary hypothesis is that precise ventilator titration to maintain lung stress within 0-12 centimeters of water (cm H2O), the normal physiological range experienced during relaxed breathing, will improve 60-day mortality, compared to guided usual care.

Specific Aim 1: To determine the effect on mortality of the precision ventilation strategy, compared to guided usual care, in patients with ARDS.

• Hypothesis 1: The precision ventilation strategy will decrease 60-day mortality (primary trial endpoint).

Specific Aim 2: To evaluate the effects on lung injury of the precision ventilation strategy, compared to guided usual care, in patients with ARDS.

• Hypothesis 2a: The precision ventilation strategy will improve clinical pulmonary recovery, defined using the composite endpoint alive and ventilator-free (AVF).
• Hypothesis 2b: The precision ventilation strategy will attenuate alveolar epithelial injury.

Specific Aim 3: To evaluate the hemodynamic safety profile of the precision ventilation strategy, compared to guided usual care, in patients with ARDS.

• Hypothesis 3: The precision ventilation strategy will decrease hemodynamic instability, measured as shock-free days through Day 14.

Inclusion Criteria:

1. Age ≥ 18 years

2. Ventilator-dependent ARDS, with all of the following (a-e):

   1. Invasive ventilation with positive end-expiratory pressure (PEEP) ≥ 8 cm H2O or FiO2 ≥ 0.5

   2. Hypoxemia as characterized by: • If arterial blood gas (ABG) available: the partial pressure of oxygen in the arterial blood (PaO2)/FiO2 ≤ 300 mm Hg, or, • if ABG not available OR overt clinical deterioration in oxygenation since last ABG: SpO2/FiO2 ≤ 316 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 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 pathology that, in judgement of the site investigator, significantly increases risk of esophageal catheter placement, including high-risk esophageal varices, 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: cystic fibrosis, acute bronchiectasis exacerbation, acute exacerbation of a chronic interstitial lung disease (ILD), chronic pulmonary hypertension (PH) on PH-targeted vasoactive medication, or lung transplant
9. End-stage chronic cirrhosis with Child-Pugh Class C (Section 12.3)
10. ICU admission for burn injury
11. Current ICU stay > 2 weeks or acute care hospital stay > 4 weeks
12. 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
13. 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.
14. Treating clinician refusal or unwilling to use protocol-specified ventilator settings/modes
15. Prisoner
16. Previous enrollment in this trial

Data will be made publicly available via the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) repository. As per BioLINCC policy, data will be submitted within one year of completion of the final follow up assessment, or within one year of primary manuscript publication, whichever comes first.

Data will become available within one year of completion of the final follow up assessment, or within one year of primary manuscript publication, whichever comes first. Data will be available for 10 years.

Outside investigators who wish to use data will submit a formal request, including rationale, analysis plan, and local Institutional Review Board (IRB) determination. The PREVENT VILI Executive Committee will review and respond to all requests. All data sharing will be codified by the appropriate contract / data use agreement. Recipient researchers must promise in writing to never attempt to access identifiable health/medical information or to attempt to identify the subject(s) who provided the specimen/data. Any intent to use materials or data for commercial purposes must be clearly disclosed as part of the request.

Study team and leadership will be blinded to all analyses throughout the study. Unblinded statistician will perform analyses for the Data and Safety Monitoring Board (DSMB) and be sequestered from the remainder of the team.