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 (PEPER)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Respiratory Distress Syndrome (ARDS); Intensive Care Units (ICUs)
• Intervention / Treatment: Other: Minimal distension; Other: Maximal Recruitment; Other: Prone position + rescue NMBAs; Other: Prone position + early NMBAs

• Study Type: Interventional
• Enrollment (Estimated): 1200
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jérôme Lambert, MD PhD; Phone Number: +33 +33142499742; Email: jerome.lambert@u-paris.fr
• Study Contact Backup: Name: Alexandre Demoule, MD PhD; Phone Number: +33 +33 1 42 16 38 31; Email: alexandre.demoule@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: First randomization : Arm A : Routine care Minimal distention; Decision of the ventilation strategy according to the routine care	Other: Minimal distension; Patients receive tidal volume (VT) of 6 mL/kg and conservative positive end-expiratory pressure (PEEP) setting.
Active Comparator: First randomization : Arm B Routine care maximal recruitment; Decision of the ventilation strategy according to the routine care	Other: Maximal Recruitment; Patients receive tidal volume adjusted to limit plateau pressure (∆P) to 14 cmH2O and the highest possible PEEP while maintaining plateau pressure (PPLAT) ≤ 27 cmH2O.
Experimental: First randomization: Arm C : Decision of th ventilation strategy according to the PRT result; Maximal recruitment strategy in patients with positive PEEP responsiveness test (PRT) or minimal distension strategy in patients with negative PRT.	Other: Minimal distension; Patients receive tidal volume (VT) of 6 mL/kg and conservative positive end-expiratory pressure (PEEP) setting.; Other: Maximal Recruitment; Patients receive tidal volume adjusted to limit plateau pressure (∆P) to 14 cmH2O and the highest possible PEEP while maintaining plateau pressure (PPLAT) ≤ 27 cmH2O.
Active Comparator: Second randomization : NMBAs used as a rescue	Other: Prone position + rescue NMBAs; NMBAs given only as a rescue
Experimental: Second randomization : early NMBAs used as soon as possible	Other: Prone position + early NMBAs; NMBAs given as soon as possible after randomization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
28-day all-cause mortality	28 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio of arterial oxygen partial pressure to inspired oxygen fraction	PaO2/FiO2	24 hours after randomization
Ratio of arterial oxygen partial pressure to inspired oxygen fraction	PaO2/FiO2	48 hours after randomization
Ratio of arterial oxygen partial pressure to inspired oxygen fraction	PaO2/FiO2	72 hours after randomization
Ratio of arterial oxygen partial pressure to inspired oxygen fraction	PaO2/FiO2	7 days after randomization
Ratio of arterial oxygen partial pressure to inspired oxygen fraction	PaO2/FiO2	14 days after randomization
Oxygen index		24 hours after randomization
Oxygen index		48 hours after randomization
Oxygen index		72 hours after randomization
Oxygen index		7 days after randomization
Oxygen index		14 days after randomization
Tidal volume	Amount of air that is inhaled or exhaled during a normal, relaxed breath	24 hours after randomization
Tidal volume	Amount of air that is inhaled or exhaled during a normal, relaxed breath	48 hours after randomization
Tidal Volume	Amount of air that is inhaled or exhaled during a normal, relaxed breath	72 hours after randomization
Tidal Volume		7 days after randomization
Tidal Volume		14 days after randomization
Respiratory Rate		24 hours after randomization
Sequential Organ Failure Assessment (SOFA) score	Sequential Organ Failure Assessment Score varies from 0 to 4 and permit to assess organ failure. A higher score indicates better neurological function	24 hours after randomization
Sequential Organ Failure Assessment (SOFA) score	Sequential Organ Failure Assessment Score varies from 0 to 4 and permit to assess organ failure. A higher score indicates better neurological function	48 hours after randomization
Sequential Organ Failure Assessment (SOFA) score	Sequential Organ Failure Assessment Score varies from 0 to 4 and permit to assess organ failure. A higher score indicates better neurological function	72 hours after randomization
Sequential Organ Failure Assessment (SOFA) score	Sequential Organ Failure Assessment Score varies from 0 to 4 and permit to assess organ failure. A higher score indicates better neurological function	7 days after randomization
Sequential Organ Failure Assessment (SOFA) score	Sequential Organ Failure Assessment Score varies from 0 to 4 and permit to assess organ failure. A higher score indicates better neurological function	14 days after randomization
All-cause mortality		90 days after inclusion
All-cause mortality		1 year after inclusion
All-cause Intensive care unit mortality		90 days after inclusion
All-cause Intensive care unit mortality		1 year after inclusion
All-cause hospital mortality		90 days after inclusion
All-cause hospital mortality		1 year after inclusion
Duration of mechanical ventilation		Up to 1 year
Ventilator Free Days		28 days after inclusion
Intensive Care Unit length of stay		Up to 1 year
Hospital length of stay		Up to 1 year
ICU free-days		28 days after inclusion
Respiratory Rate		48 hours after randomization
Respiratory Rate		72 hours after randomization
Respiratory Rate		7 days after randomization
Respiratory Rate		14 days after randomization
Total Postitive end-expiratory pressure (PEEP)		24 hours after randomization
Total Positive end-expiratory pressure (PEEP)		48 hours after randomization
Total Positive end-expiratory pressure (PEEP)		72 hours after randomization
Total Positive end-expiratory pressure (PEEP)		7 days after randomization
Total Positive end-expiratory pressure (PEEP)		14 days after randomization
Peak Pressure		24 hours after randomization
Peak Pressure		48 hours after randomization
Peak Pressure		72 hours after randomization
Peak Pressure		7 days after randomization
Peak Pressure		14 days after randomization
Plateau Pressure		24 hours after randomization
Plateau Pressure		48 hours after randomization
Plateau Pressure		7 days after randomization
Plateau Pressure		14 days after randomization
compliance of the respiratory system		24 hours after randomization
compliance of the respiratory system		48 hours after randomization
compliance of the respiratory system		72 hours after randomization
compliance of the respiratory system		7 days after randomization
compliance of the respiratory system		14 days after randomization
Hospital-free-days		28 days after inclusion
Hospital-free-days		90 days after inclusion
Occurence of barotrauma	Defined as any pneumothorax, subcutaneous emphysema, pneumomediastinum, or pneumatocele of more than 2 cm detected on image examinations	7 days after inclusion
Occurrence of acute cor pulmonale	Defined by the combination of a right/left ventricular diameter ratio greater than 0.6 and a paradoxical septum	7 days after inclusion
ICU acquired weakness	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	Up to 1 year
Number of days using other rescue procedures	Other rescue procedure including inhaled nitric oxide, almitrine, epoprostenol sodium, extracorporeal membrane oxygenation (ECMO), extracorporeal CO2 removal (ECCO2R)	Up to 1 year
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
Muscle relaxants-free days	Between inclusion and day 7	Up to day 7
Number of days alive and without continuous IV administration of sedatives/analgesics		At day 7
Number of days alive and without continuous IV administration of sedatives/analgesics		At day 28
Presence of delirium (CAM-ICU)		At day 14
Presence of delirium (CAM-ICU)	At ICU discharge	Up to 1 year
Disability	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.	At 1 year
Quality of life questionnaire	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.	At 1 year
Post-Traumatic Stress Disorder (PTSD)	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.	At 1 year
Cognitive dysfunction	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.	At 1 year
Return to work status	Subsequent return to work. Return to work status: employment status	At 1 year
Place of residence		At 1 year
Paralysis recall assessment	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	At 1 year
Severe acidosis	pH<7.10	Within 8 hours after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death with refractory hypoxemia	Defined as PaO2/FiO2< 80 mmHg outside a care incident	Up to day 7
Death with refractory acidosis	Defined as Ph<7.10 despite Respiratory Rate (RR) ≥ 35 /min & VT 8 ml/kg	Up to day 7
Death with barotrauma		Up to day 7
Need of commencement or 30% increase in vasopressors or hypotension (MAP<60 mmHg)		Within 8 hours after randomization
Refractory hypoxemia	Defined as PaO2/FiO2< 50 mmHg for more than one hour	Within 8 hours after randomization

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2025
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: December 16, 2024
• First Submitted That Met QC Criteria: February 25, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 25, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Disease; Lung Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: APHP240459

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No