The study was terminated early due to slower than expected recruitment and limited resources for further enrollment.

The study examines individuals admitted to the intensive care unit due to breathing difficulties resulting in not getting enough oxygen into their bodies. These patient will receive mechanical ventilation and this study aims to determine how the pressure inside the lungs changes when using two different modes of mechanical ventilation. The goal is to improve management and care of breathing difficulties by gaining insight into changes in lung pressure during mechanical ventilation, as well as comparing the effectiveness of the two ventilator modes.

As hypoxic respiratory failure is an acute condition, this trial will enrol temporarily incompetent patients and obtain consent from the patient's next of kin and an independent medical doctor (trial guardian) as soon as possible after enrolment.

When included in the study, patients will be randomized 1:1 centrally in the RedCap system, using a computer-generated concealed assignment sequence, with permuted blocks of varying sizes, to start with either the intervention (APRV) followed by control (volume controlled mechanical ventilation) or control followed by intervention.

Esophageal manometry will be used as a surrogate to measure the transpulmonary pressure. Arterial blood gasses, blood samples and lung ultrasound will be used to investigate oxygenation, ventilation and aeration.

Treatment targets for both groups during the study are pH >7.20, saturation ≥ 88% and PaO2 ≥ 8.0 kPa, with FiO2 titrated as low as possible while complying to the oxygenation targets (PaO2 and saturation).

Both arms start with an 'adjustment phase' where the ventilator is adjusted so the respiratory values are within the targets. The intervention adjustment phase is at least 30 minutes. The adjustments will follow standardized protocols.

When the respiratory values are within range, the 'observation period begins' and no changes are made to the ventilator for 3 hours, unless it is necessary to achieve ventilatory treatment targets or deemed necessary by the treating physician. During the trial, the patient must be positioned in a supine position with the headboard elevated 0-30 degrees.

After the first 'observation period', the patient is switched to the opposite ventilation mode and will go through an 'adjustment phase' and 'observation period' again.

Once a patient regains competence, they will be provided with both written and oral information regarding the trial

By comparing volume controlled mechanical ventilation and APRV and their transpulmonary pressures, valuable insight can be gained regarding optimal ventilation strategy for patients with hypoxic respiratory failure. Understanding how various ventilation modes influence transpulmonary pressure and their potential effects on respiratory mechanics can potentially inform designs of trials with individualized respiratory care.

Inclusion Criteria:

• Admitted to the ICU
• Invasive mechanical ventilation with FiO2 ≥ 50% OR PaO2-to-FiO2 ratio <20 kPa, including PEEP 3 5 cmH20 for at least 6 hours

Exclusion Criteria:

• Meeting inclusion criteria for more than 24 hours
• Severe bronchospasm, defined as warranting treatment aimed at reversing this i.e. inhalation of anticholinergic or bronchodilator beyond what the patient normally use
• Emphysema where treating physician judges the patient at increased risk for pneumothorax from APRV
• Restrictive lung disease defined as a pre-admission diagnosis of restrictive lung disease
• Undrained pneumothorax
• Hemodynamic instability defined as more than 0.20 microgram/kg/min of norepinephrine or any dose of adrenaline infusion to maintain MAP ≥ 65 mmHg
• Age < 18 years
• Patients who have received APRV previously during the current ICU admission
• Patients in prone position within the last 24 hours

All data will be owned by the steering committee. De-identified data will be made available 1 year after the primary publication of the outcome data. The statistical code will be submitted as an appendix to primary publication.

A year after publication of the primary outcome data

By written request to the steering committee. The sharing of data must be subject to a written agreement between the Capital Region of Denmark and receiver, and in accordance with data regulations. The steering committe will ensure that this.