Strategy of UltraProtective Lung Ventilation With Extracorporeal CO2 Removal for New-Onset Moderate to seVere ARDS

Phase 1

Completed

• Conditions: Moderate Acute Respiratory Distress Syndrome
• Interventions: Device: ECCO2R will be initiated during the 2-hour run-in time; Other: Neuromuscular blocking agents (NMBA); Device: Ventilation; Other: Level of carbon dioxide released at the end of expiration; Other: Respiratory Rate; Other: Sweep gas flow; Other: Ventilation will be adapted; Other: Respiratory rate will be adapted

• Registration Number: NCT02282657
• Lead Sponsor: European Society of Intensive Care Medicine

Brief Summary

Pathophysiological, experimental and clinical data suggest that an '"ultraprotective" mechanical ventilation strategy may further reduce VILI and ARDS-associated morbidity and mortality. Severe hypercapnia induced by VT reduction in this setting might be efficiently controlled by ECCO2R devices. A proof-of-concept study conducted on a limited number of ARDS cases indicated that ECCO2R allowing VT reduction to 3.5-5 ml/kg to achieve Pplat\<25 cm H2O may further reduce VILI.

Detailed Description

Over the past few decades, highly significant progress has been made in understanding the pathophysiology of the acute respiratory distress syndrome (ARDS). Recognition of ventilation-induced lung injuries (VILI) has led to the radical modification of the ventilatory management of these patients. The landmark trial by the ARDSnet trial group demonstrated in 2000 that ventilating ARDS patients with a low tidal volume (VT) of 6 ml/kg (calculated from predicted body weight), and with a maximum end-inspiratory plateau pressure (Pplat) of 30 cmH2O decreased mortality from 39.8% (in the conventional arm treated with a VT of 12 ml/kg PBW) to 31% . However, recent studies have shown that lung hyperinflation still occurs in approximately 30% of ARDS patients even though they are being ventilated using the ARDSNet strategy. Additionally, Hager and coworkers found that mortality decreased as Pplat declined from high to low levels at all levels of Pplat on the data collected by the "ARDSNet" trial group. Their analysis suggested a beneficial effect of VT reduction even for patients who already had Pplat\<30 cm H2O before VT reduction.Similar observation was also recently reported by Needham et al on a cohort of 485 patients with ARDS. Because VT reduction to \<6 ml/kg to achieve very low Pplat may induce severe hypercapnia and may cause elevated intracranial pressure, pulmonary hypertension, decreased myocardial contractility, decreased renal blood flow, and the release of endogenous catecholamines, this strategy using "ultraprotective" MV settings is not possible for most patients on conventional mechanical ventilation for moderate to severe ARDS.

Extracorporeal carbon dioxide removal (ECCO2R) may be used in association with mechanical ventilation to permit VT reduction to \<6 ml/kg and to achieve very low Pplat (20-25 cm H2O). In an observational study conducted in the 80's, Gattinoni showed that use of venovenous ECCO2R at a flow of 1.5-2.5 l/min in addition to quasi apneic mechanical ventilation with peak inspiratory pressures limited to 35-45 cmH2O and PEEP set at 15-25 cmH2O resulted in lower than expected mortality in an observational cohort of severe ARDS patients. However, a randomized, controlled single-center study using that same technology and conducted in the 1990s by Morris's group in Utah was stopped early for futility after only 40 patients had been enrolled and failed to demonstrate a mortality benefit with this device (58% in the control group vs. 70% in the treatment group).

In recent years, new-generation ECCO2R devices have been developed. They offer lower resistance to blood flow, have small priming volumes and have much more effective gas exchange. With ECCO2R the patient's PaCO2 is principally determined by the rate of fresh gas flow through the membrane lung. In an ECCO2R animal model, CO2 removal averaged 72±1.2 mL/min at blood flows of 450 mL/min, while CO2 production by the lung decreased by 50% with reduction of minute ventilation from 5.6 L/min at baseline to 2.6 L/min after insertion of the device. Lastly, Terragni et al (15)demonstrated that ECCO2R could improve pulmonary protection by allowing very low tidal volume ventilation (3.5-5 ml/kg of PBW) in a proof-of-concept study of ten patients with ARDS. This strategy was also associated with a significant decrease in pulmonary inflammatory biomarkers.

Study Timeline

• Study First Submitted: 2014-10-21
• Study First Submitted QC: 2014-11-03
• Study First Posted: 2014-11-04
• Study Start: 2015-11
• Primary Completion: 2017-07
• Study Completion: 2017-07-30
• Status Verified: 2017-08
• Last Update Submitted: 2017-08-03
• Last Update Posted: 2017-08-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 95

Inclusion Criteria

• Mechanical ventilation with expected duration of >24h
• Moderate ARDS according to the Berlin definition(16) PaO2/FiO2: 200-100 mmHg, with PEEP ≥ 5 cmH2O

Exclusion Criteria

• Age <18 years
• Pregnancy
• Decompensated heart insufficiency or acute coronary syndrome
• Severe COPD
• Major respiratory acidosis PaCO2>60 mmHg
• Acute brain injury
• Severe liver insufficiency (Child-Pugh scores >7) or fulminant hepatic failure
• Heparin-induced thrombocytopenia
• Contraindication for systemic anticoagulation
• Patient moribund, decision to limit therapeutic interventions
• Catheter access to femoral vein or jugular vein impossible
• Pneumothorax
• Platelet <50 G/l

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
One single arm	ECCO2R will be initiated during the 2-hour run-in time	Procedure: Baseline ventilator settings will be established per the EXPRESS protocol: VT = 6 mL/kg (ideal body weight); inspiratory flow will be set at 50-70 L/min resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3, PEEP set so that the plateau pressure (Pplat), measured during the end-inspiratory pause of 0.2 to 0.5 s, will be within the following limits: 28 cm H2O ≤ Pplat ≤ 30 cm H2O; Set RR to 20-35 to maintain approximately the same minute ventilation as before study initiation. Baseline ventilator settings will be maintained for a 2-hour run-in time (time to setup ECCO2R devices). Use heated humidifiers for gas humidification and minimize instrumental dead space. ECCO2R will be initiated during the 2-hour run-in time. Neuromuscular blocking agents (NMBA) will be used. EtCO2 will be monitored. RR will be kept what it was at Baseline. Sweep gas flow will be adapted. Ventilation will be adapted. Respiratory rate will be adapted.
One single arm	Ventilation	Procedure: Baseline ventilator settings will be established per the EXPRESS protocol: VT = 6 mL/kg (ideal body weight); inspiratory flow will be set at 50-70 L/min resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3, PEEP set so that the plateau pressure (Pplat), measured during the end-inspiratory pause of 0.2 to 0.5 s, will be within the following limits: 28 cm H2O ≤ Pplat ≤ 30 cm H2O; Set RR to 20-35 to maintain approximately the same minute ventilation as before study initiation. Baseline ventilator settings will be maintained for a 2-hour run-in time (time to setup ECCO2R devices). Use heated humidifiers for gas humidification and minimize instrumental dead space. ECCO2R will be initiated during the 2-hour run-in time. Neuromuscular blocking agents (NMBA) will be used. EtCO2 will be monitored. RR will be kept what it was at Baseline. Sweep gas flow will be adapted. Ventilation will be adapted. Respiratory rate will be adapted.
One single arm	Respiratory Rate	Procedure: Baseline ventilator settings will be established per the EXPRESS protocol: VT = 6 mL/kg (ideal body weight); inspiratory flow will be set at 50-70 L/min resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3, PEEP set so that the plateau pressure (Pplat), measured during the end-inspiratory pause of 0.2 to 0.5 s, will be within the following limits: 28 cm H2O ≤ Pplat ≤ 30 cm H2O; Set RR to 20-35 to maintain approximately the same minute ventilation as before study initiation. Baseline ventilator settings will be maintained for a 2-hour run-in time (time to setup ECCO2R devices). Use heated humidifiers for gas humidification and minimize instrumental dead space. ECCO2R will be initiated during the 2-hour run-in time. Neuromuscular blocking agents (NMBA) will be used. EtCO2 will be monitored. RR will be kept what it was at Baseline. Sweep gas flow will be adapted. Ventilation will be adapted. Respiratory rate will be adapted.
One single arm	Ventilation will be adapted	Procedure: Baseline ventilator settings will be established per the EXPRESS protocol: VT = 6 mL/kg (ideal body weight); inspiratory flow will be set at 50-70 L/min resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3, PEEP set so that the plateau pressure (Pplat), measured during the end-inspiratory pause of 0.2 to 0.5 s, will be within the following limits: 28 cm H2O ≤ Pplat ≤ 30 cm H2O; Set RR to 20-35 to maintain approximately the same minute ventilation as before study initiation. Baseline ventilator settings will be maintained for a 2-hour run-in time (time to setup ECCO2R devices). Use heated humidifiers for gas humidification and minimize instrumental dead space. ECCO2R will be initiated during the 2-hour run-in time. Neuromuscular blocking agents (NMBA) will be used. EtCO2 will be monitored. RR will be kept what it was at Baseline. Sweep gas flow will be adapted. Ventilation will be adapted. Respiratory rate will be adapted.
One single arm	Respiratory rate will be adapted	Procedure: Baseline ventilator settings will be established per the EXPRESS protocol: VT = 6 mL/kg (ideal body weight); inspiratory flow will be set at 50-70 L/min resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3, PEEP set so that the plateau pressure (Pplat), measured during the end-inspiratory pause of 0.2 to 0.5 s, will be within the following limits: 28 cm H2O ≤ Pplat ≤ 30 cm H2O; Set RR to 20-35 to maintain approximately the same minute ventilation as before study initiation. Baseline ventilator settings will be maintained for a 2-hour run-in time (time to setup ECCO2R devices). Use heated humidifiers for gas humidification and minimize instrumental dead space. ECCO2R will be initiated during the 2-hour run-in time. Neuromuscular blocking agents (NMBA) will be used. EtCO2 will be monitored. RR will be kept what it was at Baseline. Sweep gas flow will be adapted. Ventilation will be adapted. Respiratory rate will be adapted.
One single arm	Neuromuscular blocking agents (NMBA)	Procedure: Baseline ventilator settings will be established per the EXPRESS protocol: VT = 6 mL/kg (ideal body weight); inspiratory flow will be set at 50-70 L/min resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3, PEEP set so that the plateau pressure (Pplat), measured during the end-inspiratory pause of 0.2 to 0.5 s, will be within the following limits: 28 cm H2O ≤ Pplat ≤ 30 cm H2O; Set RR to 20-35 to maintain approximately the same minute ventilation as before study initiation. Baseline ventilator settings will be maintained for a 2-hour run-in time (time to setup ECCO2R devices). Use heated humidifiers for gas humidification and minimize instrumental dead space. ECCO2R will be initiated during the 2-hour run-in time. Neuromuscular blocking agents (NMBA) will be used. EtCO2 will be monitored. RR will be kept what it was at Baseline. Sweep gas flow will be adapted. Ventilation will be adapted. Respiratory rate will be adapted.
One single arm	Level of carbon dioxide released at the end of expiration	Procedure: Baseline ventilator settings will be established per the EXPRESS protocol: VT = 6 mL/kg (ideal body weight); inspiratory flow will be set at 50-70 L/min resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3, PEEP set so that the plateau pressure (Pplat), measured during the end-inspiratory pause of 0.2 to 0.5 s, will be within the following limits: 28 cm H2O ≤ Pplat ≤ 30 cm H2O; Set RR to 20-35 to maintain approximately the same minute ventilation as before study initiation. Baseline ventilator settings will be maintained for a 2-hour run-in time (time to setup ECCO2R devices). Use heated humidifiers for gas humidification and minimize instrumental dead space. ECCO2R will be initiated during the 2-hour run-in time. Neuromuscular blocking agents (NMBA) will be used. EtCO2 will be monitored. RR will be kept what it was at Baseline. Sweep gas flow will be adapted. Ventilation will be adapted. Respiratory rate will be adapted.
One single arm	Sweep gas flow	Procedure: Baseline ventilator settings will be established per the EXPRESS protocol: VT = 6 mL/kg (ideal body weight); inspiratory flow will be set at 50-70 L/min resulting in an end-inspiratory pause of 0.2-0.5 sec, I:E ratio 1:1 to 1:3, PEEP set so that the plateau pressure (Pplat), measured during the end-inspiratory pause of 0.2 to 0.5 s, will be within the following limits: 28 cm H2O ≤ Pplat ≤ 30 cm H2O; Set RR to 20-35 to maintain approximately the same minute ventilation as before study initiation. Baseline ventilator settings will be maintained for a 2-hour run-in time (time to setup ECCO2R devices). Use heated humidifiers for gas humidification and minimize instrumental dead space. ECCO2R will be initiated during the 2-hour run-in time. Neuromuscular blocking agents (NMBA) will be used. EtCO2 will be monitored. RR will be kept what it was at Baseline. Sweep gas flow will be adapted. Ventilation will be adapted. Respiratory rate will be adapted.

Primary Outcome Measures

Name	Time	Method
Achievement of VT reduction to 4 mL/kg while maintaining pH and PaCO2 to ± 20% of baseline values obtained at VT of 6 mL/kg.	maximum 28 days

Secondary Outcome Measures

Name	Time	Method
Assessment of the changes in pH/ PaO2 /PaCO2	maximum 28 days	Assessment of the changes in pH/ PaO2 /PaCO2
Amount of CO2 removed by the ECCO2R device	maximum 28 days	During the first 12 hours (every hour) Thereafter at least twice daily at 08:00 ± 2 hours and 20:00 ± 2 hours.
Evaluation of lung recruitment/derecruitment (FRC measurement by the ventilator, ECHO-LUS…)	maximum 28 days
Device CO2 clearance in the first 24 hours of ECCO2R	maximum 28 days	device CO2 clearance in the first 24 hours of ECCO2R following VT reduction from 6 mL/kg to 4 ml/kg.
The frequency of serious adverse events (SAE).	maximum 28 days	Examples of adverse events that are expected in the course of ARDS include transient hypoxemia, agitation, delirium, nosocomial infections, intolerance of gastric feeding, or skin breakdown. Such events, which are often the focus of prevention efforts as part of usual ICU care, will not be considered reportable adverse events unless the event is considered by the investigator to be associated ECCO2-R, or events that are unexpectedly severe or frequent for an individual patient with ALI (Acute Lung Injury).

Trial Locations

Locations (1)

selected ICUs for the pilot phase; 🇧🇪 Different Locations and Several Countries, Belgium