Enhanced Lung Protective Ventilation With ECCO2R During ARDS (PROVE)

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

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:

  1. Minimal distension: Tidal volume 4 ml/kg PBW and positive end-expiratory pressure (PEEP) based on the ARDSNet PEEP/FiO2 table (ARMA).
  2. Maximal recruitment: 4 ml/kg PBW and PEEP adjusted to maintain a plateau pressure between 23 - 25 cmH2O.
  3. Standard: Tidal volume 6 ml/kg and PEEP based on the ARDSNet PEEP/FiO2 table (ARMA).

Study Overview

• Status: Terminated
• Conditions: Ventilator-Induced Lung Injury; ARDS, Human
• Intervention / Treatment: Device: Low flow Extracorporeal CO2 removal

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Marseille, France
    • Service de REANIMATION, HOPITAL EUROPEEN MARSEILLE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Minimal distension; 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; 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)
Experimental: Maximal recruitment; 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; 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)
Active Comparator: Standard; 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; 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)

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Free Hemoglobin	serum samples	every 24 hours, up to 72 hours.
Haptoglobin	serum samples	every 24 hours, up to 72 hours.
Lacticodéshydrogenase (LDH)	serum samples	every 24 hours, up to 72 hours.
schizocytes	serum samples	every 24 hours, up to 72 hours.
Bilirubin	serum samples	every 24 hours, up to 72 hours.

Collaborators and Investigators

• Sponsor: Hôpital Européen Marseille
• Investigators: Principal Investigator: Jérôme ALLARDET-SERVENT, MD, Hopital Europeen Marseille

Publications and helpful links

General Publications

• Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291. Erratum In: JAMA. 2016 Jul 19;316(3):350. JAMA. 2016 Jul 19;316(3):350.
• Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, Stewart TE, Briel M, Talmor D, Mercat A, Richard JC, Carvalho CR, Brower RG. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015 Feb 19;372(8):747-55. doi: 10.1056/NEJMsa1410639.
• Allardet-Servent J, Castanier M, Signouret T, Soundaravelou R, Lepidi A, Seghboyan JM. Safety and Efficacy of Combined Extracorporeal CO2 Removal and Renal Replacement Therapy in Patients With Acute Respiratory Distress Syndrome and Acute Kidney Injury: The Pulmonary and Renal Support in Acute Respiratory Distress Syndrome Study. Crit Care Med. 2015 Dec;43(12):2570-81. doi: 10.1097/CCM.0000000000001296.

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2018
• Primary Completion (Actual): December 5, 2023
• Study Completion (Actual): December 5, 2023

Study Registration Dates

• First Submitted: May 3, 2018
• First Submitted That Met QC Criteria: May 3, 2018
• First Posted (Actual): May 16, 2018

Study Record Updates

• Last Update Posted (Estimated): December 12, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Wounds and Injuries; Thoracic Injuries; Respiratory Distress Syndrome; Lung Injury; Ventilator-Induced Lung Injury
• Other Study ID Numbers: 2017-A03647-46

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No