The Variable Ventilation Trial (Part A)

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\<55, SaO2\<88%, or PaCO2\>55 3. Home invasive or non-invasive ventilation other than for sleep apnea 4. Cor Pulmonale 5. Candidate for, or has received, lung volume reduction surgery, bronchoscopic intervention to reduce end-expiratory lung volume, or lung transplantation 16. Any of the following cardiac problems: 1. Acute myocardial infarction (MI) or acute coronary syndrome within the last 90 days 2. Coronary artery bypass graft (CABG) surgery within 30 days 3. Angina pectoris, or use of nitrates, with activities of daily living 4. Cardiopulmonary disease classified as NYHA class IV Physiological Exclusions 17. Evidence of current barotrauma (e.g., pneumothorax, pneumomediastinum, or subcutaneous emphysema) 18. Hemodynamic instability defined by inability to maintain a mean arterial pressure \> 60 mm Hg. 19. Other respiratory instability PEEP ≥18 cmH2O, suctioning more than hourly, Pplateau \> 35 cm H2O, severe respiratory acidosis pH\<7.25. 20. Increased ICP \> 20 cmH2O or mechanism of injury leading to concern for increased ICP 21. Active bleeding with hemodynamic instability.