Enhanced Lung Protective Ventilation With ECCO2R During ARDS

Study Overview
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Brief Summary
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Acute Respiratory Distress Syndrome (ARDS) is associated with a mortality rate of 30 - 45 % and required invasive mechanical ventilation (MV) in almost 85 % of patients[1]. During controlled MV, driving pressure (i.e., the difference between end-inspiratory and end-expiratory airway pressure) depends of both tidal volume and respiratory system compliance. Either excessive tidal volume or reduced lung aeration may increase the driving pressure. ARDS patients receiving tidal volume of 6 ml/kg predicted body weight (PBW) and having a day-1 driving pressure ≥ 14 cmH2O have an increased risk of death in the hospital[2]. Seemly, in the LUNG SAFE observational cohort, ARDS patients having a day-1 driving pressure < 11 cmH2O had the lowest risk of death in the hospital[1]. Hence, driving pressure acts as a major contributor of mortality in ARDS, and probably reflects excessive regional lung distension resulting in pro-inflammatory and fibrotic biological processes. Whether decreasing the driving pressure by an intervention change mortality remains an hypothesis; but one of means is to decrease the tidal volume from 6 to 4 ml/ kg predicted body weight (PBW). However, this strategy promotes hypercarbia, at constant respiratory rate, by decreasing the alveolar ventilation. In this setting, implementing an extracorporeal CO2 removal (ECCO2R) therapy prevents from hypercarbia. A number of low-flow ECCO2R devices are now available and some of those use renal replacement therapy (RRT) platform. The investigators previously reported that combining a membrane oxygenator (0.65 m²) within a hemofiltration circuit provides efficacious low flow ECCO2R and blood purification in patients presenting with both ARDS and Acute Kidney injury[3]. This study aims to investigate the efficacy of an original ECCO2R system combining a 0.67 m² membrane oxygenator (Lilliput 2, SORIN) inserted within a specific circuit (HP-X, BAXTER) and mounted on a RRT monitor (PrismafleX, BAXTER). Such a therapy only aims to provide decarboxylation but not blood purification and has the huge advantage to be potentially implemented in most ICUs without requiring a specific ECCO2R device. The study will consist in three periods: The first period will address the efficacy of this original ECCO2R system at tidal volume of 6 and 4 ml/kg PBW using an off-on-off design. The second part will investigate the effect of varying the sweep gas flow (0-2-4-6-8-10 l/min) and the mixture of the sweep gas (Air/O2) on the CO2 removal rate. The third part will compare three ventilatory strategies applied in a crossover design: Minimal distension: Tidal volume 4 ml/kg PBW and positive end-expiratory pressure (PEEP) based on the ARDSNet PEEP/FiO2 table (ARMA). Maximal recruitment: 4 ml/kg PBW and PEEP adjusted to maintain a plateau pressure between 23 - 25 cmH2O. Standard: Tidal volume 6 ml/kg and PEEP based on the ARDSNet PEEP/FiO2 table (ARMA).

Official Title
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Enhanced Lung Protective Ventilation With Extracorporeal CO2 Removal During Acute Respiratory Distress Syndrome

Conditions
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ARDS, Human, Ventilator-Induced Lung Injury

Intervention / Treatment
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* Device: Low flow Extracorporeal CO2 removal


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ARDS moderate or severe (Berlin criteria) Onset < 48 h Driving pressure ≥ 11 cmH2O Exclusion Criteria: Lack of consent or social protection Chronic respiratory failure (requiring Oxygen or NIPPV) Severe hypoxemia: PaO2/FIO2 < 80 with PEEP ≥ 18 cmH2O AND FIO2= 1 Acute Renal Failure requiring RRT DNR order or death expected within the next 72 hours Planned surgery or transport out-of-ICU expected within the next 72 hours Heparin allergy Contraindication to jugular vein catheterization Intracranial Hypertension

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: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Minimal distension<br>Tidal volume 4 ml/kg PBW and positive end-expiratory pressure (PEEP) based on the ARDSNet PEEP/FiO2 table (ARMA) + ECCO2R (sweep gas = 8 L/min, blood flow = 400 mL/min) | Device: Low flow Extracorporeal CO2 removal<br>* Low flow Extracorporeal CO2 removal using a 0.67 m² membrane oxygenator (Lilliput 2) and a specific circuit (HP-X) mounted on a RRT monitor (PrismafleX)<br>|
| Experimental: Maximal recruitment<br>Tidal volume 4 ml/kg PBW and PEEP adjusted to maintain a plateau pressure between 23 - 25 cmH2O + ECCO2R (sweep gas = 8 L/min, blood flow = 400 mL/min) | Device: Low flow Extracorporeal CO2 removal<br>* Low flow Extracorporeal CO2 removal using a 0.67 m² membrane oxygenator (Lilliput 2) and a specific circuit (HP-X) mounted on a RRT monitor (PrismafleX)<br>|
| Active Comparator: Standard<br>Tidal volume 6 ml/kg PBW and positive end-expiratory pressure (PEEP) based on the ARDSNet PEEP/FiO2 table (ARMA) without ECCO2R (no sweep gas flow, blood flow = 400 mL/min) | Device: Low flow Extracorporeal CO2 removal<br>* Low flow Extracorporeal CO2 removal using a 0.67 m² membrane oxygenator (Lilliput 2) and a specific circuit (HP-X) mounted on a RRT monitor (PrismafleX)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PaCO2 | 20 % decrease in PaCO2 after initiation of ECCO2R at tidal volume of 4 ml/kg PBW (as compared to 4 ml/kg without ECCO2R) | 15 minutes after initiation of ECCO2R at tidal volume of 4 ml/kg PBW. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PaCO2 | Arterial blood gas analyser (RAPIDPoint 500) | each 15 minutes up to the third hour (Part I and II of the study). In the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. | 
| CO2 removal rate | Using measurements from both the blood side and the gas side (two methods) | each 15 minutes up to the third hour (Part I and II of the study). In the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. | 
| Transpulmonary pressure and work of breathing | Using an oesophageal balloon catheter (NutriVent catheter) and a dedicated monitor (FluxMed, MBMed) | each 15 minutes up to the third hour (Part I and II of the study). In the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. | 
| Regional tidal ventilation | Using an Electrical Impedance Tomography device (BB², Swisstom) | each 15 minutes up to the third hour (Part I and II of the study). In the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. | 
| End-expiratory Lung Volume | Using the nitrogen wash-in wash-out method (Engstrom GE) | each 15 minutes up to the third hour (Part I and II of the study). In the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. | 
| Plasma Cytokines | Using Elisa custom kit (Qiagen) from plasma samples | Only in the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. | 
| Pulmonary Cytokines | Using Elisa custom kit (Qiagen) from BAL samples | Only in the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. | 
| Type III Procollagen | Using both RIA and Elisa methods from plasma and BAL samples | Only in the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. | 
| Pulmonary Inflammatory and Fibrotic pathway | Using mRNA custom kit RT-PCR analysis (Qiagen) from BAL samples | Only in the third part, measurement at baseline and at 1 hour and at 22 hours into each arm. |