Enhanced Lung Protective Ventilation With ECCO2R During ARDS (PROVE)

• ClinicalTrials.gov Identifier: NCT03525691
• Recruitment Status: Recruiting
• First Posted: May 16, 2018
• Last Update Posted: August 9, 2022
• Sponsor: Hôpital Européen Marseille
• Information provided by (Responsible Party): Jerome Allardet-Servent, MD, Hôpital Européen Marseille

Tracking Information

• First Submitted Date: May 3, 2018
• First Posted Date: May 16, 2018
• Last Update Posted Date: August 9, 2022
• Actual Study Start Date: May 23, 2018
• Estimated Primary Completion Date: July 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 17, 2018)

Change in PaCO2 [ Time Frame: 15 minutes after initiation of ECCO2R at tidal volume of 4 ml/kg PBW. ]

20 % decrease in PaCO2 after initiation of ECCO2R at tidal volume of 4 ml/kg PBW (as compared to 4 ml/kg without ECCO2R)

Original Primary Outcome Measures (submitted: May 3, 2018)

Change in PaCO2 [ Time Frame: 15 min after initiation of ECCO2R (PrismaLung) at tidal volume of 4 ml/kg PBW (during the first part of the study) ]

20 % decrease in PaCO2 after initiation of ECCO2R (PrismaLung) at tidal volume of 4 ml/kg PBW versus 4 ml/kg PBW without ECCO2R.

Current Secondary Outcome Measures (submitted: May 17, 2018)

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

Original Secondary Outcome Measures (submitted: May 3, 2018)

• PaCO2 [ Time Frame: q15 min during part 1 and part 2 of the study. In the third part, measurement at baseline, 1 hour and 22 hours in each arm. ]
  Arterial blood gas analyser (RAPIDPoint 500)
• CO2 removal rate [ Time Frame: 15 min during part 1 and part 2 of the study. In the third part, measurement at baseline, 1 hour and 22 hours in each arm ]
  Using measurement methods from both the blood side and the gas side
• Transpulmonary pressure and work of breathing [ Time Frame: q15 min during part 1 and part 2 of the study. In the third part, measurement at baseline, 1 hour and 22 hours in each arm ]
  Using oesophageal ballon (NutriVent catheter) and FluxMed monitor (MBMed)
• Regional tidal ventilation [ Time Frame: q15 min during part 1 and part 2 of the study. In the third part, measurement at baseline, 1 hour and 22 hours in each arm ]
  Using Electrical Impedance Tomography using BB² (Swisstom)
• End-expiratory Lung Volume [ Time Frame: q15 min during part 1 and part 2 of the study. In the third part, measurement at baseline, 1 hour and 22 hours in each arm ]
  Using the nitrogen wash-in wash-out method (Engstrom GE)
• Plasma Cytokines [ Time Frame: Only in the third part, measurement at baseline, 1 hour and 22 hours in each arm ]
  Using Elisa custom kit (Qiagen) from plasma samples
• Pulmonary Cytokines [ Time Frame: Only in the third part, measurement at baseline, 1 hour and 22 hours in each arm ]
  Using Elisa custom kit (Qiagen) from BAL samples
• Type III Procollagen [ Time Frame: Only in the third part, measurement at baseline, 1 hour and 22 hours in each arm ]
  Using both RIA and Elisa methods from plasma and BAL samples
• Pulmonary Inflammatory and Fibrotic pathway [ Time Frame: Only in the third part, measurement at baseline, 1 hour and 22 hours in each arm ]
  Using mRNA custom kit RT-PCR analysis (Qiagen) from BAL samples

Current Other Pre-specified Outcome Measures (submitted: May 17, 2018)

• Plasma Free Hemoglobin [ Time Frame: every 24 hours, up to 72 hours. ]
  serum samples
• Haptoglobin [ Time Frame: every 24 hours, up to 72 hours. ]
  serum samples
• Lacticodéshydrogenase (LDH) [ Time Frame: every 24 hours, up to 72 hours. ]
  serum samples
• schizocytes [ Time Frame: every 24 hours, up to 72 hours. ]
  serum samples
• Bilirubin [ Time Frame: every 24 hours, up to 72 hours. ]
  serum samples

Original Other Pre-specified Outcome Measures (submitted: May 3, 2018)

• Plasma Free Hemoglobin [ Time Frame: q24 h, up to 72 h ]
• Haptoglobin [ Time Frame: q24 h, up to 72 h ]
• Lacticodéshydrogenase (LDH) [ Time Frame: q24 h, up to 72 h ]
• schizocytes [ Time Frame: q24 h, up to 72 h ]
• Bilirubin [ Time Frame: q24 h, up to 72 h ]

Descriptive Information

• Brief Title: Enhanced Lung Protective Ventilation With ECCO2R During ARDS
• Official Title: Enhanced Lung Protective Ventilation With Extracorporeal CO2 Removal During Acute Respiratory Distress Syndrome

Brief Summary

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).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Supportive Care

Condition

• ARDS, Human
• Ventilator-Induced Lung Injury

Intervention

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)

Study Arms

• 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)
  Intervention: Device: Low flow Extracorporeal CO2 removal
• 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)
  Intervention: Device: Low flow Extracorporeal CO2 removal
• 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)
  Intervention: Device: Low flow Extracorporeal CO2 removal

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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 3, 2018): 14
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 21, 2024
• Estimated Primary Completion Date: July 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jérôme ALLARDET-SERVENT, MD; +33413427155; j.allardetservent@hopital-europeen.fr

Contact: Wahiba BIDAUT; w.bidaut@hopital-europeen.fr

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT03525691
• Other Study ID Numbers: 2017-A03647-46
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Jerome Allardet-Servent, MD, Hôpital Européen Marseille
• Original Responsible Party: Jerome Allardet-Servent, MD, Hôpital Européen Marseille, MD, MSc
• Current Study Sponsor: Hôpital Européen Marseille
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jérôme ALLARDET-SERVENT, MD; Hopital Européen Marseille

• PRS Account: Hôpital Européen Marseille
• Verification Date: August 2022