Ultraprotective Lung Ventilation With Respiratory Extracorporeal Life Support for ARDS (NOVAEOLIA)

Acute respiratory distress syndrome (ARDS) accounts for approximately 10% of all ICU admissions and 23% of patients requiring mechanical ventilation (MV). Despite advances in care, hospital mortality remains high, ranging from 34% in mild cases to 46% in severe ARDS. Positive-pressure MV remains the cornerstone of ARDS management. However, when excessive stress and strain are applied to the lung parenchyma, it can exacerbate lung injury, leading to ventilator-induced lung injury (VILI). VILI substantially contributes to morbidity and mortality in ARDS. Strategies that reduce tidal volume (Vt), driving pressure (ΔP, defined as plateau pressure minus PEEP), and respiratory rate (RR) can lower the mechanical power (PowerRS), i.e., the energy delivered to the lungs by the ventilator. This reduction in pulmonary stress and strain may lessen VILI and potentially improve survival. Nonetheless, reducing Vt to <6 ml/kg in order to achieve plateau pressures <23-25 cm H₂O, driving pressures <9-11 cm H₂O, and RR <15-20/min can result in severe hypercapnia. This, in turn, may increase intracranial pressure, promote pulmonary hypertension, impair myocardial contractility, reduce renal perfusion, and trigger endogenous catecholamine release. Thus, such "ultraprotective" MV strategies are not feasible for most ARDS patients managed with conventional ventilation. The neutral findings of the REST trial further suggested that low-flow extracorporeal CO₂ removal (ECCO₂R) devices may provide insufficient CO₂ clearance to enable ultraprotective ventilation while adequately controlling respiratory acidosis. Moreover, since partial lung derecruitment may occur with substantial Vt reduction, extracorporeal membrane oxygenation (ECMO) may be necessary, particularly in patients with PaO₂/FiO₂ <120-130 at the time of Vt reduction. Therefore, respiratory extracorporeal life support (ECLS)-ranging from high-flow ECCO₂R to mid-flow venovenous ECMO (VV-ECMO)-can be employed in this setting. These modalities facilitate further reductions in ventilatory intensity while ensuring adequate oxygenation and CO₂ removal.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Respiratory Distress Syndrome (ARDS)
• Intervention / Treatment: Procedure: ECLS

• Study Type: Interventional
• Enrollment (Estimated): 290
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Alain COMBES, Professor of medicine; Phone Number: +33142163818; Email: alain.combes@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Intubation and Invasive mechanical ventilation ≤ 7 days

2. Presence of all of the following conditions for ≤48 hours:

   • 80 ≤ PaO2/FiO2 ≤300 with PEEP >5 cmH2O
   • Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules
   • Respiratory failure not fully explained by cardiac failure or fluid overload

3. One of the following criteria (with Vt set at 6 mL/kg PBW):

   • DeltaP ≥15 cm H2O OR
   • Ventilatory ratio ≥2.2
4. Signed Informed consent from a close relative or surrogate or a family member. According to the specifications of emergency inclusion, randomization without the close relative/surrogate consent could be performed if the patient is unable to give his/ger consent and when the close relative/surrogate/family member are absent. Close relative/surrogate/family member consent will be asked as soon as possible after randomization. The patient will be asked as soon as possible to give his/her consent for the continuation of the trial when his/her condition will allow.
5. Social security registration (AME excluded)

Exclusion Criteria:

1. Age <18 years
2. Pregnancy or breastfeeding
3. Catheter access to femoral vein or jugular vein impossible
4. Expected duration of mechanical ventilation < 48 hours
5. Chronic restrictive or obstructive (COPD) respiratory insufficiency with home ventilation or oxygen therapy
6. Currently receiving ECLS therapy
7. Severe cardiac failure or ongoing acute coronary syndrome
8. Heparin-induced thrombocytopenia
9. Severe underlying pre-existing condition with expected six-month mortality >50%
10. Contraindication for systemic anticoagulation (including platelet count <50G/L)
11. Patient moribund, decision to limit therapeutic interventions
12. Acute brain injury or irreversible neurological pathology
13. Bone marrow transplantation within the last 1 year
14. Actual body weight exceeding 1 kg per centimeter of height
15. Prior enrolment in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control : Conventional Treatment Arm; Conventional management of ARDS; Ventilatory settings:Volume assist control mode,VT 6 ml/kg of predicted body weightPEEP adjusted for Pplateau 28 29 cmH2O ;FiO2 for 88%≤SaO2≤95% or 55 mmHg≤PaO2≤80 mm HgRR up to 35/mn, for a PaCO2 resulting in 7.30<pH<7.42
Experimental: Expérimental : ECLS; ECLS catheter s inserted, and EC LS initiated no later than 12h after randomization; Vt decreased to a min of 3 ml/kg PBW (by 0.5ml/kg every 30 min) to reach ΔP 9-11 cm H2O and at least 5 cm H 2 O ΔP decrease; PEEP adjusted to keep the same mean airway pressure; Pump outflow set at 2-4 L/min , based on the need of blood oxygenation; RR decreased to a min of 12/min with gas flow rate adjusted to maintain PaCO2 45 mmHg.; Protocolized weaning of ECLS	Procedure: ECLS; ECLS catheters inserted, and EC LS initiated no later than 12h after randomization; Vt decreased to a min of 3 ml/kg PBW (by 0.5ml/kg every 30 min) to reach ΔP 9 -11 cmH2O and at least 5 cm H2O ΔP decrease; PEEP adjusted to keep the same mean airway pressure; Pump outflow set at 2-4 L/min , based on the need of blood oxygenation; RR decreased to a min of 12/min with gas flowrate adjusted to maintain PaCO2 45 mmHg.; Protocolized weaning of ECLS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hierarchical criterion assessed at day 30, including all-cause mortality followed by the number of days free from MV at day 30, and calculated in such a manner that death constitutes a worse outcome than duration of ventilation.	Each patient is compared with every other patient in the study and assigned a score (tie: 0, win: +1, loss: -1) for each pairwise comparison based on whom fared better. - If one patient survived at day 30 and the other did not, scores of +1 and -1 will be assigned, respectively, for that pairwise comparison. If both patients in the pairwise comparison survived at day 30, the assigned score will depend on which patient had more days free from MV at day 30: the patient with more days off MV will receive a score of +1, while the patient with fewer days will receive a score of -1. If both patients survived and had the same number of days off MV, or if both patients died, they will be both assigned a score of 0 for that pairwise comparison. For each patient, scores for all pairwise comparisons will be summed, resulting in a cumulative score.	Day 30

Secondary Outcome Measures

Outcome Measure	Time Frame
Mortality	Day 30, Day 60, Day 90
Duration of mechanical ventilation	From inclusion to Day 30, from inclusion to Day 60
Number of mechanical ventilation free days	Day 30, Day 60
Duration of catecholamine hemodynamic support	From inclusion to Day 30, from inclusion to Day 60
Number of catecholamine hemodynamic support free days	Day 30, Day 60
Number of organ failure(s) free days	Day 30, Day 60
Number of renal replacement therapy free days	Day 30, Day 60
Durations of ICU stay	Day 90
Duration of hospitalization	Day 90
Proportion of patients with Pneumothorax	Day 30, Day 60
Proportion of patient with rescue procedures and therapies for severe ARDS	Day 90
Incidence of pump malfunction related to ECLS	Day 90
Incidence of clotting related to ECLS	Day 90
Incidence of air embolism related to ECLS	Day 90
Incidence of hemolysis related to ECLS	Day 90
Incidence of vein perforation related to ECLS	Day 90
Incidence of significant bleeding (related to cannula insertion, at canula site) related to ECLS	Day 90
Incidence of major hemorrhage related to ECLS	Day 90
Incidence of infection at cannula site related to ECLS	Day 90
Incidence of thromboembolic events related to ECLS	Day 90
Incidence of stroke related to ECLS	Day 90
Incidence of thrombocytopenia related to ECLS	Day 90
Incidence of hypofibrinogenemia related to ECLS	Day 90
Number of packed red blood cells transfused	Day 90
Incidence of ventilator-associated pneumonia	From inclusion to Day 30, form inclusion to Day 60
Number of days without organ failure(s), defined with the SOFA score	Day 30, Day 60
Number of days without renal replacement therapy	Day 30, Day 60

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): May 11, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: April 1, 2026
• First Submitted That Met QC Criteria: April 1, 2026
• First Posted (Actual): April 8, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: ECLS; Acute Respiratory Distress Syndorme (ARDS)
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Respiratory Distress Syndrome
• Other Study ID Numbers: APHP240924; IDRCB number (Other Identifier: 2025-A02650-49)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No