Explanation for the choice of comparators

Patients who meet all the inclusion criteria and none of the exclusion criteria will receive a 12-region LUS exam (supplement 1) to determine lung morphology using the algorithm presented in Fig. 1. Patients will be randomly assigned within 12 h after ARDS diagnosis to the intervention group, with personalized mechanical ventilation, or to the standard care, where patients will receive standard care. The standard care group will be ventilated according to the current guidelines advised by the European Society of Intensive Care Medicine (ESICM) (Table 1). In these patients, the PEEP level will be selected according to the low PEEP/ high FiO2 table from the ALVEOLI study maintaining an end-inspiratory plateau pressure (Pplat) below 30 cmH2O (Table 2) [18]. Prone position is encouraged if PaO2/FiO2 ratio is ≤ 150 and recruitment maneuvers will be used as rescue therapy.

Fig. 1

This logarithm is used to determine the lung morphology by ultrasound of eligible patients. The scores are LUS aeration scores explained in supplement 1 based on a 12-region LUS exam. LUS lung ultrasound

Table 1 Ventilation strategy for randomization and lung morphology groupsTable 2 FiO2 and PEEP strategy for the standard care groupIntervention description

Patients assigned to the intervention group will have their ventilator settings adjusted based on the lung morphology (Table 1). A detailed handbook for mechanical ventilation in study participants can be found in supplement 2. In “focal” patients randomized to the personalized ventilation group, a LUS exam will be repeated every 48–72 h to assess whether they have developed “non-focal” ARDS during their ICU stay. When a patient classified as “focal” develops “non-focal” ARDS, the settings are adjusted to the “non-focal” group (Fig. 2, Table 1).

Fig. 2

Flow diagram for enrollment of a PEGASUS participant. Patients with “focal” ARDS randomized in the intervention group will receive follow-up LUS exams to evaluate if their condition deteriorates to a “non-focal” ARDS. * ventilation strategy in Table 1. ARDS acute respiratory distress syndrome, LUS lung ultrasound

Criteria for discontinuing or modifying allocated interventions

Criteria for discontinuation or modification of the intervention targets are described in the supplement 2. The oxygenation, pressure, and ventilation targets can be loosened during interventions (e.g., bronchoscopy, placing the patient in the prone position) or modified when the patient is not ventilated in a lung-protective way (e.g., Pplat > 30 cm H2O). Specifically, in patients with “focal” ARDS and personalized ventilation, the PEEP can be increased when the FiO2 is higher than 80% and the PaO2/FiO2 is below 100 mmHg in the prone position for more than 6 h, the physician is allowed to set the PEEP above 9 cmH2O and recruitment maneuvers can be applied. In patients with “non-focal” ARDS, prone positioning can be applied when the PaO2/FiO2 is lower than 150 mmHg for 6 h in supine position and the FiO2 is higher than 80%. When a “non-focal” ARDS patient is breathing spontaneously, PEEP can be decreased to 10 cmH2O, and recruitment maneuvers are now only performed at the physician’s discretion. For patient-triggered breaths, the tidal volume margins are no longer required.

Strategies to improve adherence to interventions

At every study site, there will be a dedicated study team that is trained by a member of the steering committee. Training consists of attending an initiation visit, reading standard operating procedures (SOP’s), and a study handbook. Furthermore, to mitigate the potential for misclassification in centers with limited LUS experience, we provide each center with comprehensive training via e-learning, including an exam and live support during the first two included patients. The Steering Committee provided a ventilation handbook for detailed guidance on how to ventilate patients according to the study protocol and other best practices in lung-protective mechanical ventilation to minimize heterogeneity in patient management within the study. The dedicated study team will give clinical lessons to all nurses and physicians before starting the trial. Furthermore, they will monitor the ventilation settings of included patients on a daily basis. A ventilator card with study guidelines will be placed at the bedside of the patient to enhance protocol adherence. If the ventilation parameters deviate from the protocol, a member of the study site is required to write a protocol deviation form. The protocol adherence will be evaluated in the pilot study and in every meeting with the Data and Safety Monitoring Board (DSMB).

Relevant concomitant care permitted or prohibited during the trial

It is not allowed to perform LUS exams for the determination of the lung morphology outside of the study protocol. Furthermore, ventilator settings cannot be changed based on LUS exams that were performed outside of the study protocol. Other imaging modalities are permitted during the study. However, the classification of lung morphology conducted through the LUS exam is leading.

In controlled modes of ventilation, the default inspiration-to-expiration ratio will be 1:2. Expiratory time will be prolonged in case expiratory flow limitation is detected. The respiratory rate will be adjusted to obtain an arterial blood pH > 7.25 but preferably under 35 breaths per minute. The oxygenation target ranges for SpO2 and PaO2 are 88 to 95%, and 7.3 to 10.7 kPa, respectively [19].

The attending physician decides when to extubate a patient, based on general extubation criteria or with following a successful spontaneous breathing trial (SBT) with a T–piece or ventilation with minimal support (pressure support level < 10 cm H2O).

Early tracheostomy provides no advantage over late tracheotomy [20]. Therefore, tracheostomy is only to be performed on strict indications and preferably not earlier than 10 days after intubation. If a patient is treated with ECMO, the ventilator is set according to the local protocol for ventilation under ECMO. This means that the patient does not have to be ventilated according to the ventilation strategy of the randomization arm anymore. Sedation will follow the local guidelines for sedation in each participating unit. In general, these guidelines favor the use of analgo-sedation over hypno-sedation and use of bolus over continuous infusion of sedating agents. A Richmond Agitation Sedation Scale (RASS) score of − 2 to 0 is seen as adequate sedation [21, 22].

The routine use of neuromuscular blockage is not recommended. If neuromuscular blockade is required, single injections are preferred over continuous infusions.

If patients are expected to need ventilation for longer than 48 h and/or are expected to stay in the ICU for longer than 72 h, preventive measurements against VAP must be instituted according to the local guidelines.

A fluid balance targeted at normovolemia and diuresis of ≥ 0.5 ml/kg/h should be maintained with diuretics or by crystalloid infusions.

Thrombosis prophylaxis will be given according to local guidelines.

Provisions for post-trial care

There is no need for provisions for post-trial care after the patient is discharged from the ICU. The organization of study insurance depends on local regulations.

Outcomes

The primary endpoint is all-cause mortality at day 90 (diagnosis of ARDS considered as day 0). Secondary outcomes are mortality at day 28, VFD at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (VAP using the clinical pulmonary infection score (CPIS), pneumothorax, and need for rescue therapy). After a pilot phase, feasibility of LUS, correct interpretation of LUS images, and correct application of the intervention within the safe limits of mechanical ventilation is evaluated to inform a stop–go decision.

Participant timeline

The time points for enrolment, interventions, and follow-up can be found in Fig. 3.

Fig. 3

Timeline for a study participant from enrollment until last day of follow-up. aIf a patient has “focal” ARDS and is randomized to personalized ventilation, a LUS will be repeated every 72 h. bInformed consent is obtained before randomization or deferred consent is obtained within 72 h after randomization depending on the local regulations. cUntil day 7 or until extubation. dUntil day 7 or ICU discharge. eUntil day 90 or ICU discharge. fUntil day 90 or hospital discharge. SOFA, Sequential Organ Failure Assessment; ICU, intensive care unit

Sample size

A sample of 538 patients (269 per group) is needed to detect an absolute between-group difference in 90-day mortality of 10% in favor of the intervention group, assuming a 27% mortality in the standard care, with a power of 80% at a two-tailed significance level of 0.047 [8]. In the sample size calculation, an interim analysis of the primary endpoint after the recruitment of 269 patients (using a p-value of 0.003) with alpha spending has been considered.

The first 80 included patients will be used for the pilot phase of the trial. At least 20 patients in each personalized group are necessary to assess clinical feasibility and protocol adherence. As the expected ratio between “focal” and “non-focal” and the ratio between the intervention and standard care is 1:1, we would need a sample size of 80 patients for this pilot study. We expect an interobserver agreement among experts of κ: 0.85 [16]. To be able to detect a clinically relevant decrease of κ towards 0.7 between experts and bedside clinicians, a total of 77 patients is needed for a power of 80% at a one-sided α level of 0.05. The primary endpoint will not be evaluated in the analysis of the pilot phase.

Recruitment

Given the above sample size of 538 patients and an expected inclusion rate of 1 patient per 2 months, the recruitment period is approximately 2 years after all 40 sites started enrolling patients [23]. To ensure the inclusion of patients from 40 centers, we will actively promote participation through conference announcements, via our website, and direct outreach to centers. Once a center begins enrolment, we will periodically request a consort figure to identify any missed patients and optimize the recruitment process accordingly.