Personalized mechanical ventilation guided by ultrasound in patients with acute respiratory distress syndrome (PEGASUS): study protocol for an international randomized clinical trial

Background
 Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on “focal” or “non-focal” lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish “focal” from “non-focal” lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation. Methods The Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as “focal” or “non-focal”. Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for “non-focal” ARDS and lower PEEP and prone positioning for “focal” ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated. Discussion PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach. Trial registration The PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344). Supplementary Information The online version contains supplementary material available at 10.1186/s13063-024-08140-7.

Start Lung ultrasound exam 1. Start the lung ultrasound (LUS) machine.
2. Choose the linear probe, use of other probes is allowed when use of the linear probe does not result in assessable LUS images.
3. Choose the lung setting on the ultrasound machine.Most ultrasound machines have software that will minimize artefacts.For the assessment of the lungs, we would like to preserve these artefacts.
4. Place the patient in a semi recumbent position (figure 1) and place the arms of the patient.If the patient was just placed from a prone to a supine position, please wait 30 minutes before the start of the LUS exam to mobilize fluid that has moved to the anterior lung fields due to the prone positioning towards the posterior lung fields.Position the patient's arms as shown in figure 2. This makes performing the ultrasound easier.5.After pre-oxygenation and increasing the FiO2, set the PEEP to 5 cm H2O.If too much desaturation is expected with a PEEP of 5 cm H2O, the LUS exam can also be performed at a maximum PEEP level of 8 cm H2O.
6. Start the LUS exam by placing the probe longitudinal on region of interest with the pointer facing towards the cranial side of the patient (figure 3).8. Set the depth at 10 cm, then adjust it in order to have the pleural line at 1/3 of the screen.
9. Focus should be on pleural line or on the point of interest if any alteration (i.e.consolidation).
10. Gain adjusted such that the pleural line is clearly visible but not overexposed.
11. Turn the probe with 90 degrees in which the pointer will face te right side of the patient (figure 4).13.Save the image as a clip when the image is of sufficient quality to score lung aeration.
14. Repeat this for the twelve different regions of the lungs, six locations for each hemithorax, shown on the picture below (figure 6).15.When all regions have been scored, the results can be entered into the Castor database.This will automatically assess the lung morphology phenotype by using the flow diagram below (figure 7).
Figure 7 -Assessment of lung morphology.
16.If due to any reason a region could not have been scored, the lung morphology phenotype of the patient must be assessed by the investigator him-/herself.The missing score can be complemented by using the scores of the other fields in the same area (anterior 1&2, lateral 3&4 or posterior 5&6).The missing region needs to be complemented for the morphology classification, but in the Castor database the region should be registered as missing.17.For example, if region R2 is missing and the scores of the other anterior regions are known (for example L1 = 1, L2 = 0, R1 = 2) take the sum of the scores and divide it by the number of regions.Use the result for the missing region.In this case; (1 + 0 + 2)/3 = 1 = R2.
18. Please send the images to j.s.sinnige@amsterdamumc.nl19.Apply the correct ventilator strategy depending on the randomization and ARDS phenotype of the patient.

Figure 2 .
Figure 2. Placing of the arms of the patient.

Figure 3 -
Figure 3 -Longitudinal position of the probe

Figure 4 -
Figure 4 -Transversal position of the probe

Figure 5 .
Figure5.Score 0: "A-pattern" (i.e., repeating horizontal A-lines parallel to the pleural line, suggesting normal aeration).Score 1: a "B-pattern" (i.e., three or more vertical B-lines starting from the pleural line and reaching the bottom of the screen, suggesting partial loss of aeration) and B-lines are well-spaced and cover ≤ 50% of the pleural line, Score 2: if B-lines cover ≥ 50% of the pleural line.Score 3: a "Cpattern" when the consolidation is > 2cm (i.e., consolidation, suggesting nearcomplete to complete loss of aeration).

Figure 6 -
Figure 6 -Twelve regions to perform the LUS.