Despite best supportive care, mortality of the Acute Respiratory Distress Syndrom (ARDS) remains high. In the absence of specific treatments, providing safe and efficient mechanical ventilation (MV) is key to survival.
The use of low tidal volumes (VT) and plateau pressures (PPLAT) improves survival in randomized controlled trials (RCTs), but the safest VT to be applied for each patient remains unknown. Whether targeting low ∆P instead of a 6 mL/kg VT improves outcome has not been tested prospectively. The optimal method to set PEEP is also a matter of debate. As the amount of potentially recruitable lung vary widely among patients and is strongly associated with the response to PEEP, it may be necessary to tailor PEEP settings based on the response to a PEEP trial.
The first aim is to test a personalized approach to set PEEP widely supported by the literature. The first hypothesis is that i) patients with greater amounts of recruitable lung may benefit from higher PEEP levels, provided that attention is paid to maintain ∆P below 14 cmH2O, ii) setting PEEP based on results of a PEEP-responsiveness test improves survival as compared to low- and high-PEEP strategies applied independently of the patient response.
Apart from VT reduction and PPLAT control below 30 cmH2O, only 2 interventions demonstrated a reduction of mortality in large RCTs: a 48-hour continuous infusion of neuromuscular blocking agents (NMBAs) at the acute phase of ARDS6 and the use of prone positioning (PP). Whereas there is little doubt on the utility of PP in patients with PaO2/FiO2 ratio \< 150 mmHg, there is more controversy on the impact of NMBAs on survival. Despite a strong rationale and a very widespread use in clinical practice, no current guidelines answer the question of the best timing of muscle relaxation in moderate to severe ARDS patients treated with PP.
As a second aim, the hypothesis is that the early systematic and combined use of NMBAs improved survival of patients with moderate to severe ARDS requiring prone positioning after optimization of PEEP settings.
Invasive mechanical ventilation within 96 hours of ICU admission and within 72 hours of tracheal intubation for first randomization and then within 72 hours of the first randomization for the second randomization
Patients meeting the Berlin ARDS definition criteria with hypoxemia characterized as
for first randomization: PaO2/FiO2 ≤150 mmHg on a PEEP ≥5 cmH2O with FiO2≥0.6 while VT is 6 ml/kg Predicted Body Weight (PBW) and adequate sedation level to adjust mechanical ventilation settings
for second randomization: PaO2/FiO2 ≤150 mmHg on optimized ventilatory settings according to the first randomization, confirmed by two Arterial blood gas (ABG) analyses separated by an interval time of 4 hours and observed within 72 hours of the first randomization
Age < 18 years
Known pregnancy or breastfeeding
Participation in another interventional studies as long as these studies do not interfere with the primary endpoint and the secondary safety objectives of PEPER, or being in the exclusion period at the end of a previous study.
Intracranial pressure > 30 mm Hg or cerebral perfusion pressure < 60 mmHg
Parallel
Minimal distension
Other interventionPatients receive tidal volume (VT) of 6 mL/kg and conservative positive end-expiratory pressure (PEEP) setting.
Maximal Recruitment
Other interventionPatients receive tidal volume adjusted to limit plateau pressure (∆P) to 14 cmH2O and the highest possible PEEP while maintaining plateau pressure (PPLAT) ≤ 27 cmH2O.
Prone position + early NMBAs
Other interventionNMBAs given as soon as possible after randomization
Prone position + rescue NMBAs
Other interventionNMBAs given only as a rescue
28-day all-cause mortality
Ratio of arterial oxygen partial pressure to inspired oxygen fraction
PaO2/FiO2
Ratio of arterial oxygen partial pressure to inspired oxygen fraction
PaO2/FiO2
Ratio of arterial oxygen partial pressure to inspired oxygen fraction
PaO2/FiO2
Ratio of arterial oxygen partial pressure to inspired oxygen fraction
PaO2/FiO2
Death with refractory hypoxemia
Defined as PaO2/FiO2\< 80 mmHg outside a care incident
Death with refractory acidosis
Defined as Ph\<7.10 despite Respiratory Rate (RR) ≥ 35 /min \& VT 8 ml/kg
Death with barotrauma
Need of commencement or 30% increase in vasopressors or hypotension (MAP<60 mmHg)
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