Flow-flow ECCO2-R and 4 ml/kg Tidal Volume vs. 6 ml/kg Tidal Volume to Enhance Protection From VILI in Acute Lung Injury

Study Overview
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Brief Summary
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The main objective of this randomized multicenter clinical trial is to test the hypothesis that further reduction of VT to 4mL/kg may enhance lung protection in patients with ARDS as compared to the conventional ARDS-Net ventilation. Control of PaCO2 in the  4 ml/kg arm would be accomplished by LFPPV- ECCO2-R.

Detailed Description
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The trial will test the hypothesis that a VT of 4 ml/kg PBW combined with low flow CO2 removal improves outcome in patients with severe ARDS (PFs ≤ 200 and PEEP ≥ 10) compared to ventilation with a VT of 6 ml/kg PBW. The study will accrue a maximum of 230 patients over approximately 12-18 months. PRIMARY END-POINT: Number of ventilator-free days (VFDs) during the 28 days immediately after randomization SECONDARY END-POINTS: 28 and 90-day all-cause mortality; number of ICU-free days during the 28 days immediately after randomization; cumulative incidence of: first episode of refractory hypoxemia (during 28 days after randomization), use of rescue therapies, first day that meet criteria for weaning, SOFA-free and severe adverse events. Patients in CONTROL will be treated according to a modified, simplified version of The ARDS-Network lung protective lower tidal volume. Patients in TREATMENT group will be treated according to the ARDS-Net protocol modified (VT reduced by 1 ml/kg PBW at intervals ≤ 2 hours until VT = 4ml/kg PBW and the use of low-flow CO2 removal with a Plateau Pressure Goal: ≤ 25 cm H2O).

Official Title
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Flow-flow ECCO2-R and 4 ml/kg Tidal Volume vs. 6 ml/kg Tidal Volume to Enhance Protection From Ventilator Induced Lung Injury in Acute Lung Injury (ELP)

Conditions
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Acute Respiratory Distress Syndrome

Intervention / Treatment
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* Other: ARDS-Net Strategy
* Other: ECCO2-R


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age > 18 years are on invasive assisted breathing less then 48 hours less than 24 hours since diagnosis for ARDS: with PF<=200 and PEEP>=10, bilateral infiltrate on chest X-Ray and no clinical evidence of left atrial hypertension have a commitment to full support Exclusion Criteria: intubation and mechanical ventilation (any form) for > 48 hours risk of systemic bleeding with anticoagulation acute brain injury body mass index > 40 neuromuscular disease that impairs ability to ventilate without assistance severe chronic respiratory disease burns > 40% total body surface area malignancy or other irreversible disease or condition for which 6- month mortality is estimated to be greater than 50% allogeneic bone marrow transplant within the last 5 years chronic respiratory condition making patient respirator dependent patient, surrogate, or physician not committed to full support acute myocardial infarction or acute coronary syndrome within 30 days moribund patient: not expected to survive 24 hours no consent/inability to obtain consent patients receiving high frequency ventilation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ARDS-Net strategy (Control)<br> | Other: ARDS-Net Strategy<br>* Treatment according to the ARDS-Net protocol (The Acute Respiratory Distress Syndrome Network N Engl J Med 2000; 342:1301-1308May 4, 2000)<br>* Other names: Protective ventilation;|
| Experimental: ECCO2-R with 4 mL/Kg Vt (Treatment)<br> | Other: ECCO2-R<br>* Ventilation with Tidal Volume of 4 ml/kg PBW and low flow CO2 removal<br>* Other names: Further protective ventilation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of ventilator-free days during the 28 days immediately after randomization | VFDs is a composite endpoint. VFD to day 28 is defined as the number of days after initiating unassisted breathing to day 28 after randomization, assuming a patient survives for at least two consecutive calendar days after initiating nassisted breathing and remains free of assisted breathing. If a patient dies prior to day 28 or is still receiving assisted breathing at day 27, his/her VFDs will be zero. | 28 DAYS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day all-cause mortality | All patients will be classified as either alive at Study Day 28 or, if dead, dead at Study Day 28. For example, day zero is the day of randomization and day 1 is the next day and encompasses all events that occur midnight-to-midnight, etc. | 28 days | 
| 90-day all-cause mortality. | All patients will be classified as either alive at Study Day 90 or, if dead, dead at Study Day 90. Patients alive in hospital or in any health care facility at day 90 will be considered to have survived. | 90 days | 
| Number of ICU-free days during the 28 days immediately after randomization (ICU-FD). | ICU-FDs are defined as the number of days from the time of ICU discharge to day 28 after randomization, assuming survival for at least two consecutive calendar days after ICU discharge and continued stay outside the ICU setting to day 28. If a patient returns to the ICU and subsequently needs ICU admission to day 28, ICU-FDs will be counted from the end of the last period of ICU discharge to day 28. | 28 days | 
| Cumulative incidence of first episode of refractory hypoxemia (during 28 days after randomization). | Refractory hypoxemia is defined as PaO2 < 60 mm Hg for at least 1 hour while receiving an FIO2 of 1.0 | 28 days | 
| Cumulative incidence of the use of rescue therapies. | The first day inhaled nitric oxide or prone position or high-frequency oscillation or high-frequency oscillatory ventilation or extracorporeal membrane oxygenation or any combinations of these therapies will be tabulated. | 28 days | 
| Cumulative incidence of first day that meet criteria for weaning readiness during 28 days after randomization. | Weaning readiness will be defined if the following 4 criteria are met for the last 30 minutes during a spontaneous breathing trial (SBT). SpO2 ≥ 90% and / or PaO2 ≥ 60 mm Hg; PaO2 to take precedence if both available Respiratory Rate ≤ 35 / min pH ≥ 7.30 No respiratory distress | 28 days | 
| Cumulative SOFA-free score between randomization and day 28. | The SOFA-free score is calculated as the maximum daily score, minus the observed SOFA score. To monitor the degree of variation of the patient's SOFA score (as improvement or worsening) the daily difference between the maximum score and the observed score will be summed up for each day between randomization and day 28. Patients dying before the 28th day cannot continue to increase their cumulative SOFA-free score. In this way, the larger the cumulative score reached, the higher is the improvement of the patient and the probability of being alive at day 28. | 28 days | 
| Cumulative incidence of severe adverse events during 28 days after randomization. | Adverse events that are considered to be related to ECCO2-R and that follows a reasonable temporal sequence from the ECCO2-R and that could readily have been produced by ECCO2-R will be classified as: DEVICE RELATED or PATIENT RELATED | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ARDS: Acute Respiratory Distress Syndrome, LOW FLOW ECCO2-R: EXTRA-CORPOREAL CO2 REMOVAL, VILI: Ventilator Induced Lung Injury