Clinical trial NCT06849570: Assessment of the PEEP Responsiveness to Titrate End-expiratory Pressure and of the Need for Muscle Relaxation During Prone Positioning in Moderate-to-severe Acute Respiratory Distress Syndrome: A Master Protocol
Official title: Assessment of the PEEP Responsiveness to Titrate End-expiratory Pressure and of the Need for Muscle Relaxation During Prone Positioning in Moderate-to-severe Acute Respiratory Distress Syndrome: A Master Protocol
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Acute Respiratory Distress Syndrome (ARDS)
Intensive Care Units (ICUs)
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2025-02-27
Enrollment: 1200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Master Protocol, including two randomized, controlled, clinical trials with Bayesian adaptive designs

* First randomization with 3 parallel arms (first ratio 1:1:1) A. Minimal distension B. Maximal recruitment C. PRT-guided ventilation strategy
* Second randomization within 4 to 72 hours, if persistent PaO2/FiO2 ≤150 mmHg, with two parallel arms (ratio 1:1)

  1. Prone position with systematic NMBAs
  2. Prone position without systematic NMBAs
Primary purpose: OTHER

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* 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
* Informed consent signed:

  * by the patient
  * Or informed consent signed by a family members/trustworthy person if his condition does not allow him to express his consent by written as per L. 1111-6
  * Or in a situation urgently and in the absence of family members/trustworthy person, the patient can be enrolled. The consent to participate to the research will be requested as soon as the condition of the patient will allow him to consent.
* Health insurance coverage

Exclusion Criteria:

* 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
* Severe chronic respiratory disease requiring long-term O2 therapy or home mechanical ventilation (except Continuous positive arway pressure (CPAP)/ Bilevel positive airway pressure (BIPAP) used for sleep apnea syndrome)
* Chronic interstitial lung disease
* Continuous neuromuscular blockade infusion at enrolment
* Previous hypersensitivity or anaphylactic reaction to any NMBA
* Neuromuscular disease that may potentiate neuromuscular blockade or impair spontaneous ventilation: amyotrophic lateral sclerosis, Guillain-Barré syndrome, myasthenia gravis, upper spinal injury at level C5 or above
* Patients on ECMO or any technique of extracorporeal CO2 removal
* Sickle cell disease
* Actual body weight \>1 kg/cm of height
* Severe chronic liver disease defined as a Child-Pugh score of 12-15
* Pneumothorax at randomization
* Expected duration of mechanical ventilation \<48 hours
* Simplified acute physiology score SAPS II score \>75 at the time of enrolment or suffering from a disease with an estimated survival time of less than two months
* Decision to withhold life-sustaining treatment
* Patients deprived of freedom or under legal authority
* Unstable spine fracture

Primary outcomes:
measure: 28-day all-cause mortality
timeFrame: 28 days after randomization
Secondary outcomes:
measure: Ratio of arterial oxygen partial pressure to inspired oxygen fraction
timeFrame: 24 hours after randomization
measure: Ratio of arterial oxygen partial pressure to inspired oxygen fraction
timeFrame: 48 hours after randomization
measure: Ratio of arterial oxygen partial pressure to inspired oxygen fraction
timeFrame: 72 hours after randomization
measure: Ratio of arterial oxygen partial pressure to inspired oxygen fraction
timeFrame: 7 days after randomization
measure: Ratio of arterial oxygen partial pressure to inspired oxygen fraction
timeFrame: 14 days after randomization
measure: Oxygen index
timeFrame: 24 hours after randomization
measure: Oxygen index
timeFrame: 48 hours after randomization
measure: Oxygen index
timeFrame: 72 hours after randomization
measure: Oxygen index
timeFrame: 7 days after randomization
measure: Oxygen index
timeFrame: 14 days after randomization
measure: Tidal volume
timeFrame: 24 hours after randomization
measure: Tidal volume
timeFrame: 48 hours after randomization
measure: Tidal Volume
timeFrame: 72 hours after randomization
measure: Tidal Volume
timeFrame: 7 days after randomization
measure: Tidal Volume
timeFrame: 14 days after randomization
measure: Respiratory Rate
timeFrame: 24 hours after randomization
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: 24 hours after randomization
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: 48 hours after randomization
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: 72 hours after randomization
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: 7 days after randomization
measure: Sequential Organ Failure Assessment (SOFA) score
timeFrame: 14 days after randomization
measure: All-cause mortality
timeFrame: 90 days after inclusion
measure: All-cause mortality
timeFrame: 1 year after inclusion
measure: All-cause Intensive care unit mortality
timeFrame: 90 days after inclusion
measure: All-cause Intensive care unit mortality
timeFrame: 1 year after inclusion
measure: All-cause hospital mortality
timeFrame: 90 days after inclusion
measure: All-cause hospital mortality
timeFrame: 1 year after inclusion
measure: Duration of mechanical ventilation
timeFrame: Up to 1 year
measure: Ventilator Free Days
timeFrame: 28 days after inclusion
measure: Intensive Care Unit length of stay
timeFrame: Up to 1 year
measure: Hospital length of stay
timeFrame: Up to 1 year
measure: ICU free-days
timeFrame: 28 days after inclusion
measure: Respiratory Rate
timeFrame: 48 hours after randomization
measure: Respiratory Rate
timeFrame: 72 hours after randomization
measure: Respiratory Rate
timeFrame: 7 days after randomization
measure: Respiratory Rate
timeFrame: 14 days after randomization
measure: Total Postitive end-expiratory pressure (PEEP)
timeFrame: 24 hours after randomization
measure: Total Positive end-expiratory pressure (PEEP)
timeFrame: 48 hours after randomization
measure: Total Positive end-expiratory pressure (PEEP)
timeFrame: 72 hours after randomization
measure: Total Positive end-expiratory pressure (PEEP)
timeFrame: 7 days after randomization
measure: Total Positive end-expiratory pressure (PEEP)
timeFrame: 14 days after randomization
measure: Peak Pressure
timeFrame: 24 hours after randomization
measure: Peak Pressure
timeFrame: 48 hours after randomization
measure: Peak Pressure
timeFrame: 72 hours after randomization
measure: Peak Pressure
timeFrame: 7 days after randomization
measure: Peak Pressure
timeFrame: 14 days after randomization
measure: Plateau Pressure
timeFrame: 24 hours after randomization
measure: Plateau Pressure
timeFrame: 48 hours after randomization
measure: Plateau Pressure
timeFrame: 7 days after randomization
measure: Plateau Pressure
timeFrame: 14 days after randomization
measure: compliance of the respiratory system
timeFrame: 24 hours after randomization
measure: compliance of the respiratory system
timeFrame: 48 hours after randomization
measure: compliance of the respiratory system
timeFrame: 72 hours after randomization
measure: compliance of the respiratory system
timeFrame: 7 days after randomization
measure: compliance of the respiratory system
timeFrame: 14 days after randomization
measure: Hospital-free-days
timeFrame: 28 days after inclusion
measure: Hospital-free-days
timeFrame: 90 days after inclusion
measure: Occurence of barotrauma
timeFrame: 7 days after inclusion
measure: Occurrence of acute cor pulmonale
timeFrame: 7 days after inclusion
measure: ICU acquired weakness
timeFrame: Up to 1 year
measure: Number of days using other rescue procedures
timeFrame: Up to 1 year
measure: Use of NMBAs during the first 3 days following the first randomization or following inclusion in the rescue arm of the second randomization
timeFrame: Up to day 28
measure: Muscle relaxants-free days
timeFrame: Up to day 7
measure: Number of days alive and without continuous IV administration of sedatives/analgesics
timeFrame: At day 7
measure: Number of days alive and without continuous IV administration of sedatives/analgesics
timeFrame: At day 28
measure: Presence of delirium (CAM-ICU)
timeFrame: At day 14
measure: Presence of delirium (CAM-ICU)
timeFrame: Up to 1 year
measure: Disability
timeFrame: At 1 year
measure: Quality of life questionnaire
timeFrame: At 1 year
measure: Post-Traumatic Stress Disorder (PTSD)
timeFrame: At 1 year
measure: Cognitive dysfunction
timeFrame: At 1 year
measure: Return to work status
timeFrame: At 1 year
measure: Place of residence
timeFrame: At 1 year
measure: Paralysis recall assessment
timeFrame: At 1 year
measure: Severe acidosis
timeFrame: Within 8 hours after randomization
Other outcomes:
measure: Death with refractory hypoxemia
timeFrame: Up to day 7
measure: Death with refractory acidosis
timeFrame: Up to day 7
measure: Death with barotrauma
timeFrame: Up to day 7
measure: Need of commencement or 30% increase in vasopressors or hypotension (MAP<60 mmHg)
timeFrame: Within 8 hours after randomization
measure: Refractory hypoxemia
timeFrame: Within 8 hours after randomization
Locations:
Study officials:
References: