Multi-center, randomized, controlled, open-label Phase 2 feasibility trial. Subjects on mechanical ventilation (MV) for acute hypoxemic respiratory failure (AHRF) with lung injury (including subjects who meet criteria for acute respiratory distress syndrome (ARDS)) will be randomized 2:1 to diaphragm neurostimulation-assisted ventilation (DNAV) using the AeroNova System plus lung-protective ventilation (Treatment) vs. lung-protective ventilation alone (Control).

Inclusion Criteria:

1. Male or female, 18 years or older, and

2. Able to provide informed consent or have a legally authorized representative (LAR) / Substitute Decision Maker (SDM) who can provide consent, and

3. Have acute onset of new respiratory symptoms or dysfunction within the 2 weeks before onset of need for respiratory support, and

4. Have arterial hypoxemia defined by one of:

   • PaO2:FiO2 ratio ≤300 mm Hg on PEEP ≥5 cm H2O, or
   • In the absence of an available arterial blood gas, SpO2 ≤97% on FiO2 ≥0.5 and PEEP ≥5 cm H2O with reliable SpO2 trace for the 2 hours immediately preceding eligibility assessment (this correlates to an upper limit of SpO2:FiO2 ratio of 316%) or
   • Are receiving pulmonary vasodilators for acute hypoxemia, or
   • Are being ventilated in the prone position for acute hypoxemia, and

5. Have been mechanically ventilated for AHRF in the ICU for <96 hours at the time of enrolment, and

6. Are expected to require invasive mechanical ventilation ≥48 hours after enrollment in the opinion of the treating clinician

Exclusion Criteria:

1. Hypoxemia is primarily attributable to acute exacerbation of chronic obstructive pulmonary disease, status asthmaticus, cardiogenic pulmonary edema, or pulmonary embolism.
2. Underlying chronic parenchymal lung disease that may make recovery/extubation a challenge (e.g., COPD, pulmonary fibrosis).
3. Broncho-pleural fistula at the time of eligibility assessment.
4. Require extracorporeal membrane oxygenation.
5. Pre-existing neurological, neuromuscular or muscular disorder or known phrenic nerve injury that could affect the respiratory muscles.
6. BMI >70 kg/m2.
7. Contraindications to left internal jugular vein or left subclavian vein catheterization (e.g., infection at the access site, known central venous stenosis, septic thrombophlebitis, left internal jugular ECMO cannula in situ, poor target vessels).
8. Patient expected to transition to fully palliative care within 72 hours of enrollment.
9. Chronic severe liver disease (e.g., Child-Pugh Score ≥10)
10. Treating clinician deems enrollment not clinically appropriate.
11. Currently enrolled in any other study of an investigational drug or device, which may affect the outcomes of the current study.
12. Any electrical device (implanted or external) that may be prone to interaction with or interference from the AeroNova System, including neurological pacing/stimulator devices and cardiac pacemakers and defibrillators.
13. Known or suspected to be pregnant or lactating.