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

Not Applicable

Not yet recruiting

• Conditions: Acute Respiratory Distress Syndrome (ARDS); Intensive Care Units (ICUs)

• Registration Number: NCT06849570
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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.

Detailed Description

Not available

Study Timeline

• Status Verified: 2024-12
• Study First Submitted: 2024-12-16
• Study First Submitted QC: 2025-02-25
• Last Update Submitted: 2025-02-25
• Study First Posted: 2025-02-27
• Last Update Posted: 2025-02-27
• Study Start: 2025-04-01
• Primary Completion: 2028-04-01
• Study Completion: 2029-04-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1200

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
28-day all-cause mortality	28 days after randomization

Secondary Outcome Measures

Name	Time	Method
Hospital-free-days	90 days after inclusion
Disability	At 1 year	Assessed by the Activities of Daily Living score (Lawton IADL) The score is divided in 8 domains and ranges from 0 to 8. The higher the score, the more independent is the person.
Quality of life questionnaire	At 1 year	Using EQ-5D-5L It evaluates five dimensions : mobility, self-care, usual activities, pain/discomfort and anxiety/depression and each dimension has five levels : no problems, slight problems, moderate problems, severe problems and extreme problems. Answers are given on a 5-point scale by domain, the higher the score, the poorer the quality of life.
Return to work status	At 1 year	Subsequent return to work. Return to work status: employment status
Ratio of arterial oxygen partial pressure to inspired oxygen fraction	14 days after randomization	PaO2/FiO2
Oxygen index	14 days after randomization
Ventilator Free Days	28 days after inclusion
Hospital length of stay	Up to 1 year
ICU free-days	28 days after inclusion
compliance of the respiratory system	14 days after randomization
Tidal volume	48 hours after randomization	Amount of air that is inhaled or exhaled during a normal, relaxed breath
Tidal Volume	14 days after randomization
Respiratory Rate	14 days after randomization
Sequential Organ Failure Assessment (SOFA) score	14 days after randomization	Sequential Organ Failure Assessment Score varies from 0 to 4 and permit to assess organ failure. A higher score indicates better neurological function
Duration of mechanical ventilation	Up to 1 year
Total Positive end-expiratory pressure (PEEP)	14 days after randomization
Peak Pressure	14 days after randomization
Plateau Pressure	14 days after randomization
Number of days using other rescue procedures	Up to 1 year	Other rescue procedure including inhaled nitric oxide, almitrine, epoprostenol sodium, extracorporeal membrane oxygenation (ECMO), extracorporeal CO2 removal (ECCO2R)
All-cause mortality	1 year after inclusion
All-cause Intensive care unit mortality	1 year after inclusion
ICU acquired weakness	Up to 1 year	Assessed by the medical research council (MRC) score at ICU discharge. The score ranges from 0 to 60. A score \< 48 defines ICU acquired weakness
All-cause hospital mortality	1 year after inclusion
Intensive Care Unit length of stay	Up to 1 year
Total Postitive end-expiratory pressure (PEEP)	24 hours after randomization
Occurence of barotrauma	7 days after inclusion	Defined as any pneumothorax, subcutaneous emphysema, pneumomediastinum, or pneumatocele of more than 2 cm detected on image examinations
Occurrence of acute cor pulmonale	7 days after inclusion	Defined by the combination of a right/left ventricular diameter ratio greater than 0.6 and a paradoxical septum
Muscle relaxants-free days	Up to day 7	Between inclusion and day 7
Number of days alive and without continuous IV administration of sedatives/analgesics	At day 28
Presence of delirium (CAM-ICU)	Up to 1 year	At ICU discharge
Use of NMBAs during the first 3 days following the first randomization or following inclusion in the rescue arm of the second randomization	Up to day 28
Post-Traumatic Stress Disorder (PTSD)	At 1 year	Using the Impact Event Scale-Revised (IES-R) It contains 22 items scored on a 5-point Likert scale Total score ranges from 0 to 88. Higher scores indicate more severe symptoms.
Cognitive dysfunction	At 1 year	Using T-MoCA score It evaluates 8 cognitive domains. The total score ranges from 0 to 30 points. A score of 26 or higher is considered as normal.
Place of residence	At 1 year
Paralysis recall assessment	At 1 year	Using a modified Brice questionnaire Patient responses are categorized into levels of awareness and analyzed to determine if awareness occured and its nature. The result can be : no awareness, awareness with explicit recall, awareness with dreams, emotional distress, inconclusive responses
Severe acidosis	Within 8 hours after randomization	pH\<7.10