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

NCT06849570 | Not Yet Recruiting DMC

• 1 other identifier: APHP240459
• Study Type: interventional
• Target: 1,200
• Locations: 0 countries
• Sites: N/A

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 28-day all-cause mortality

  28 days after randomization

Secondary Outcomes (75)

• Ratio of arterial oxygen partial pressure to inspired oxygen fraction

  24 hours after randomization

• Ratio of arterial oxygen partial pressure to inspired oxygen fraction

  48 hours after randomization

• Ratio of arterial oxygen partial pressure to inspired oxygen fraction

  72 hours after randomization

• Ratio of arterial oxygen partial pressure to inspired oxygen fraction

  7 days after randomization

• Ratio of arterial oxygen partial pressure to inspired oxygen fraction

  14 days after randomization

Other Outcomes (5)

• Death with refractory hypoxemia

  Up to day 7

• Death with refractory acidosis

  Up to day 7

• Death with barotrauma

  Up to day 7

Study Arms (5)

First randomization : Arm A : Routine care Minimal distention

ACTIVE COMPARATOR

Decision of the ventilation strategy according to the routine care

Other: Minimal distension

First randomization : Arm B Routine care maximal recruitment

ACTIVE COMPARATOR

Decision of the ventilation strategy according to the routine care

Other: Maximal Recruitment

First randomization: Arm C : Decision of th ventilation strategy according to the PRT result

EXPERIMENTAL

Maximal recruitment strategy in patients with positive PEEP responsiveness test (PRT) or minimal distension strategy in patients with negative PRT.

Other: Minimal distension; Other: Maximal Recruitment

Second randomization : NMBAs used as a rescue

ACTIVE COMPARATOR

Other: Prone position + rescue NMBAs

Second randomization : early NMBAs used as soon as possible

EXPERIMENTAL

Other: Prone position + early NMBAs

Interventions

Minimal distension OTHER

Patients receive tidal volume (VT) of 6 mL/kg and conservative positive end-expiratory pressure (PEEP) setting.

First randomization : Arm A : Routine care Minimal distention; First randomization: Arm C : Decision of th ventilation strategy according to the PRT result

Maximal Recruitment OTHER

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.

First randomization : Arm B Routine care maximal recruitment; First randomization: Arm C : Decision of th ventilation strategy according to the PRT result

Prone position + early NMBAs OTHER

NMBAs given as soon as possible after randomization

Second randomization : early NMBAs used as soon as possible

Prone position + rescue NMBAs OTHER

NMBAs given only as a rescue

Second randomization : NMBAs used as a rescue

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Age \< 18 years
• Known pregnancy or breastfeeding
• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

MeSH Terms

Conditions

Respiratory Distress Syndrome

Interventions

Prone Position

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Posture; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Central Study Contacts

Alexandre Demoule, MD PhD

CONTACT

+33 1 42 16 38 31; alexandre.demoule@aphp.fr

Jérôme Lambert, MD PhD

CONTACT

+33142499742; jerome.lambert@u-paris.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: CARE PROVIDER, INVESTIGATOR
• Masking Details: Medical team blinded for first randomization. The second randomization is open label.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: December 16, 2024
• First Posted: February 27, 2025
• Study Start: April 1, 2025
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2029
• Last Updated: February 27, 2025

Record last verified: 2024-12