The Variable Ventilation Trial (Part A)

The goal of this clinical trial is to learn if a breathing machine (ventilator) method called "variable ventilation" can help protect the lungs of adult patients with acute respiratory distress syndrome (ARDS) who need help breathing through a ventilator. In variable ventilation, the size of each breath given by the machine changes slightly from breath to breath, instead of staying the same size in every breath. The study has two parts, A (safety and feasibility) and B (efficacy). This entry will cover the part A (safety study). The main questions part A aims to answer are: 1. Is variable ventilation safe to use in adults with ARDS? 2. Is it feasible to deliver this method of ventilation to patients? Researchers will compare variable ventilation to the standard breathing machine method used today to see if variable ventilation is safe and feasible. Participants will be placed on an FDA approved ventilator that can deliver conventional mechanical ventilation and variable ventilation. Participants will: * Have a period of stabilization on conventional ventilation, followed by 24 hours of variable ventilation, followed by 24 hours of conventional ventilation. * Be checked regularly for breathing, oxygen levels, lung function, and plasma biomarkers.

Inclusion Criteria: 1. Patients ≥21 years old admitted to the Surgical, Trauma, Burn, Coronary or Medical ICUs with ARDS according to the Berlin criteria \[50\] and requiring mechanical ventilation will be eligible for inclusion. 2. Not more than 96 hours of mechanical ventilation before randomization 3. Anticipated need for at least 48 more hours of controlled mechanical ventilation 4. Intubated and mechanically ventilated for ARDS according to the Berlin criteria * Hypoxemia of acute onset, within the past 7 days * Mild or moderate hypoxemia, PaO2/FiO2 ratio 100 - 300 mm Hg * Presence of a risk factor for ARDS * Respiratory failure not fully explained by cardiac failure or fluid overload * Bilateral opacities not explained by effusions, lobar collapse, or nodules Exclusion Criteria: Demographic 1. Age less than 21 years 2. Pregnant or breastfeeding 3. Prisoner 4. Concurrent participation in another investigational drug study 5. Patient, surrogate, or physician not committed to full support (exception: a patient will not be excluded if they would receive all supportive care except for attempts at resuscitation from cardiac arrest) 6. No consent or inability to obtain consent or appropriate legal representative not available 7. Physician refusal to allow enrollment in the trial 8. Moribund patient not expected to survive 24 hours 9. Treating team unwilling to use ARDS network low tidal volume strategy or variable ventilation mode 10. Use, or planned use of ECMO 11. Stroke (ischemic or hemorrhagic) or traumatic brain injury (TBI) within the prior 3 months 12. Burns \> 40% total body surface area (TBSA) 13. Severe airway inhalational injury 14. Diffuse alveolar hemorrhage 15. Any of the following hallmarks of Severe COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 3 or 4 1. FEV1 \< 50% predicted 2. Resting arterial blood gas values PaO2\ 60 mm Hg. 19. Other respiratory instability PEEP ≥18 cmH2O, suctioning more than hourly, Pplateau \> 35 cm H2O, severe respiratory acidosis pH\ 20 cmH2O or mechanism of injury leading to concern for increased ICP 21. Active bleeding with hemodynamic instability.