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
Overview
- Phase
- Not Applicable
- Status
- Not yet recruiting
- Enrollment
- 1,200
- Primary Endpoint
- 28-day all-cause mortality
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Other
- Masking
- Double (Care Provider, Investigator)
Masking Description
Medical team blinded for first randomization. The second randomization is open label.
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Outcomes
Primary Outcomes
28-day all-cause mortality
Time Frame: 28 days after randomization
Secondary Outcomes
- Hospital-free-days(90 days after inclusion)
- Disability(At 1 year)
- Quality of life questionnaire(At 1 year)
- Return to work status(At 1 year)
- Ratio of arterial oxygen partial pressure to inspired oxygen fraction(14 days after randomization)
- 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)
- Tidal Volume(14 days after randomization)
- Respiratory Rate(14 days after randomization)
- Sequential Organ Failure Assessment (SOFA) score(14 days after randomization)
- 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)
- All-cause mortality(1 year after inclusion)
- All-cause Intensive care unit mortality(1 year after inclusion)
- ICU acquired weakness(Up to 1 year)
- 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)
- Occurrence of acute cor pulmonale(7 days after inclusion)
- Muscle relaxants-free days(Up to 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)
- 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)
- Cognitive dysfunction(At 1 year)
- Place of residence(At 1 year)
- Paralysis recall assessment(At 1 year)
- Severe acidosis(Within 8 hours after randomization)