Extended Prone Positioning for Intubated ARDS: a Randomized Controlled Trial

Scientific justification Acute respiratory distress syndrome (ARDS) is an acutely induced respiratory failure characterised by the appearance of bilateral alveolar opacities on imaging and hypoxemia. Among strategies that have proved beneficial in terms of patient outcome, prone position (PP) is one associated with the greatest impact in terms of reduction in mortality, with PP sessions of 17h on average. The benefit of PP is to better homogenize the stress and strain applied to the lung by invasive ventilation. In a multicentric retrospective study involving COVID-19-related intubated ARDS patients, a strategy of extended PP, where PP was maintained for a median duration of 40 hours (h), was associated with increased survival compared to standard PP where each session lasted less than 24h. Our hypothesis to explain the improved survival observed with extended PP is grounded in the concept of a dose-response relationship. Maintaining patients prone beyond 24h probably augments the cumulative exposure to its beneficial effects during the initial stages of moderate to severe ARDS. This increased exposure potentially facilitates a more uniform distribution of stress and strain on the lungs during invasive ventilation, thus mitigating the risk of ventilator-induced lung injury. Additionally, we postulate that maneuvers to transition patients back to the supine position may be detrimental, potentially inducing derecruitment and exacerbating overdistension in remaining ventilated pulmonary regions. Finally, following 16-hour PP, the non-uniform distribution of strain probably immediately resumes upon patients returned in the supine position.

Design of the study The study is a prospective, randomised, open-label, two-group parallel, multicenter trial comparing 40-hour extended PP to 16-hour standard PP in patients with moderate to severe ARDS. After inclusion, patients will be randomised either to standard PP, or extended PP. In the control arm, patients will be turned prone for 16-hour sessions. In the intervention arm, patients will be turned prone for 40h. Maintaining PP for up to an extra 8-hour, will be allowed in both groups so that patients can be returned to the supine position when it is most convenient for the healthcare teams. In both groups, after randomization, positive end expiratory pressure (PEEP) will be set according to the low values of the PEEP- FiO2 table. Once back on the supine position, patients will be evaluated 6h (+/-2h) after the return on supine position (SP), or sooner in case of significant oxygenation degradation. In the absence of PP criteria, patients will be assessed: twice daily if FiO2 ≥ 60%, every time they present a significant worsening of oxygenation, and once daily if FiO2 < 60%. PP will be resume if, at any time, up to day 28, PP criteria are met, i.e. PaO2/FiO2 ratio of <150 mm Hg and PEEP set according to the PEEP-FiO2 table. The PaO2/FiO2 ratio will be analysed at the current FiO2 of the patient, not at FiO2 = 100% with an SpO2 objective between 92 and 96%.

Patients requiring inhaled NO will be kept in the protocol. Patients requiring ECMO will continue PP sessions according to their randomization arm for an extra 48 hours, corresponding to 2 standard PP sessions and one extended PP session. Afterward, subsequent PP sessions will be at the discretion of the attending physician.

For all patients, once FiO2 is < 50% a daily screening will be done to assess whether patients can be weaned from the ventilator.

Population of study participants : All patients admitted to the ICUs and intubated will be screened. We will include in the study, all patients who meet the following criteria: severe ARDS, with ARDS defined according to the 2012 Berlin definition; and the severity defined as a PaO2/FiO2 ratio of <150 mm Hg, with an FiO2 of ≥ 60% persisting for at least 4h after optimization of ventilatory setting. Optimization of ventilation setting will be done setting PEEP level to 10 cm of H2O and by optimising the level of sedation and neuromuscular blocking to obtain a volume tidal (VT) around 6 mL/kg PWB. In case of SpO2 < 92% in FiO2 = 100% and after optimization of ventilatory settings, no stabilisation period will be required before inclusion, finally, patients with persistent PaO₂/FiO₂ ratios <150 mm Hg on all arterial blood gases collected over a 24-hour period without this leading to inclusion, or inadequate protective ventilation criteria will be excluded.