Precision Ventilation vs Standard Care for Acute Respiratory Distress Syndrome

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 moderate or severe 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 moderate or severe 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 moderate or severe 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 moderate or severe ARDS.

• Hypothesis 3: The precision ventilation strategy will decrease hemodynamic instability, measured as shock-free days through Day 28.

Eligibility Criteria:
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
   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

   * Within 48 hours since meeting last moderate-severe ARDS criterion (#2 above)
   * 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 used 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/hemorrhage).
3. Gross barotrauma or chest tube inserted to treat barotrauma
4. Esophageal varix or stricture; recent oropharyngeal or gastroesophageal surgery; or past esophagectomy
5. Severe coagulopathy (platelet \< 5000/µL or international normalized ratio \[INR\] \> 4)
6. Extracorporeal membrane oxygenation or carbon dioxide (CO2) removal
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. Chronic supplemental oxygen, pulmonary fibrosis, or lung transplant
9. Refractory shock: norepinephrine-equivalent dose ≥ 0.4 µg/kg/min or simultaneous receipt of ≥ 3 vasopressors
10. Severe liver disease, defined as Child-Pugh Class C
11. ICU admission for burn injury
12. Current ICU stay \> 2 weeks or hospital stay (including subacute hospitalization) \> 4 weeks
13. Estimated mortality \> 50% over 6 months due to underlying chronic medical condition 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. Limitation on life-sustaining care, other than do-not-resuscitate, or expectation by treating clinical team that a limitation on life-sustained care will be adopted within next 24 hours.
16. Treating clinician refusal
17. Prisoner