Primary Research Question for the Full ULTIMATE Randomized Clinical Trial (RCT): What is the effect of ultra-protective ventilation facilitated by extracorporeal membrane oxygenation (ECMO) versus best current conventional ventilation (CV) on all-cause hospital mortality among patients with early moderate-severe acute respiratory distress syndrome (ARDS)?

Secondary Research Questions: Among patients with early moderate-severe ARDS, what is the effect of ultra-protective ventilation versus CV on: (1) duration of mechanical ventilation; (2) duration of ICU and hospital stay; (3) organ dysfunction; (4) barotrauma; and (5) mortality at other time-points (ICU discharge, 28-day, 60-day)?

The ULTIMATE Pilot Study: Before embarking on a definitive multinational trial to address the questions listed above, the ULTIMATE Pilot Study has these 3 specific feasibility objectives:

1. To assess adherence to our explicit mechanical ventilation protocols, with particular focus on delivered tidal volumes in both groups;
2. To estimate the rate of patient recruitment and understand barriers to recruitment; and
3. To measure and understand the reasons for crossovers or rescue by ECMO in the control group.

In addition, we will monitor safety issues, recording serious adverse events in both groups.

Inclusion Criteria:

1. Age ≥ 18 years

2. Endotracheal mechanical ventilation for ≤ 5 days

3. Early moderate-severe ARDS (Berlin Definition) - all of the following conditions for ≤ 48 hours i. PaO2/FiO2 ≤200 with PEEP > 5 cmH2O ii. bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules iii. respiratory failure not fully explained by cardiac failure or fluid overload iv. within one week of a known insult of new or worsening respiratory symptoms

4. ARDS severity criterion - either 1 of:

   1. PaO2/FiO2 ≤ 150 mm Hg, on PEEP ≥ 10 cm H2O and FiO2 ≥ 0.5

Exclusion Criteria:

1. Currently receiving any form of ECMO (e.g., venovenous, venoarterial, or hybrid configuration)
2. Chronic hypercapnic respiratory failure defined as PaCO2 > 60 mmHg in the outpatient setting
3. Home mechanical ventilation (non-invasive ventilation or via tracheotomy), not CPAP
4. Actual body weight exceeding 1 kg per centimeter of height
5. Severe hypoxemia with PaO2/FiO2 < 80 mmHg
6. Expected mechanical ventilation duration < 48 hours
7. Treating team is in the process of moving to a palliative mode of care
8. Moribund patient not expected to survive 24 hours despite ongoing life-sustaining therapies
9. Confirmed diffuse alveolar hemorrhage from vasculitis
10. Contraindications to limited anticoagulation (e.g., active GI bleeding, bleeding diathesis)
11. Pregnancy - due to unknown effects of PaCO2 changes on placental blood flow