This phase II multi-centered, randomized controlled trial of mechanical ventilation directed by esophageal pressure measurement will test the primary hypothesis that using a strategy of maintaining a minimal but positive transpulmonary pressure (Ptp = airway pressure minus pleural pressure) throughout the ventilatory cycle will lead to an improvement in patient survival.

This phase II prospective randomized controlled trial of ventilation directed by esophageal pressure measurements will enroll 200 patients with moderate to severe ARDS by the Berlin conference definition in several academic medical centers in North America. The control group will be ventilated using an alternative high-PEEP strategy with PEEP and FiO2 set using to an empiric table.

Plasma samples will be obtained at enrollment and days 3 and 7 and assessed for a variety of lung injury biomarkers to better assess the association between our intervention and the inflammation associated with mechanical ventilation and the development of ARDS. Hospital survivors will undergo a brief follow up phone survey to assess survival, functional status (Barthel Index), health-related QOL (Short Form 12), and frailty (VES) twelve months after enrollment.

The study length will be six years with a six month start-up period followed by a planned 50 month enrollment and twelve month follow-up.

Inclusion Criteria:

• Acute onset of ARDS as defined by the Berlin Consensus Conference definitions:

  1. Hypoxemic respiratory failure with PaO2 / FIO2 ratio < 200 mmHg
  2. b) Bilateral alveolar/interstitial infiltrates on chest x-ray, with opacities not present for more than 7 days
  3. Respiratory failure not fully explained by cardiac failure or fluid overload
  4. Intubation on controlled ventilation and receiving PEEP ≥ 5 cm H2O

• Age 16 years or older

• Duration of ARDS 36 hours or less from meeting final Berlin criterion.

Exclusion Criteria:

• Received mechanical ventilation more than 96 hours
• Recently treated or bleeding varices, esophageal stricture, hematemesis, esophageal trauma, recent esophageal surgery or other contraindication for nasogastric tube placement
• Severe coagulopathy (platelet count < 5000/microliter or INR > 4)
• History of lung transplantation
• Elevated intracranial pressure or conditions where hypercapnia-induced elevations in intracranial pressure should be avoided
• Evidence of active air leak from the lung
• not committed to full support
• Participation in other intervention trials for ARDS or for sepsis within the past 30 days.
• Neuromuscular disease that impairs ability to ventilate spontaneously
• Severe chronic liver disease, defined as Child-Pugh Score of ≥12
• Treating clinician refusal, or unwillingness to commit to controlled ventilation for at least 24 hours
• Inability to get informed consent from the patient or surrogate.
• Use of rescue therapies for prior to enrollment (e.g. nitric oxide, ECMO, prone positioning, high frequency oscillation). This does not exclude cases where these therapies were used as the initial mode of ventilation