NCT02282657

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

Pilot Feasibility and Safety Study on Low-flow Extracorporeal CO2 Removal in Patients With Moderate ARDS to Enhance Lung Protective Ventilation

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 95 (actual)
• Sponsor: European Society of Intensive Care Medicine · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Moderate Acute Respiratory Distress Syndrome

Interventions

Type	Name	Description
DEVICE	ECCO2R will be initiated during the 2-hour run-in time	A single (15.5 to 19 Fr) veno-venous ECCO2R catheter will be inserted percutaneously (jugular vein strongly suggested). Catheters should be rinsed with heparinized saline solution before insertion Once the catheter has been inserted each line will be filled with an heparinized saline solution before its connection to the extracorporeal circuit The ECCO2R circuit will be connected to the catheter and blood flow set, depending on the device, up to 1000 mL/min. Initially, sweep gas flow through the ECCO2R device will be set at zero (0 LPM) such as to not initiate CO2 removal through the device. Anticoagulation will be maintained with unfractionated heparin to a target aPTT of 1.5 - 2.0X baseline. A bolus of heparin is suggested at the time of cannulation.
OTHER	Neuromuscular blocking agents (NMBA)	Patients will receive NMBA starting in the run-in period and continued for the first 24 hours and thereafter will be directed by the attending physician
DEVICE	Ventilation	Following the 2-hour run-in time, VT will be reduced gradually to 5 mL/kg. Sweep gas initiated then VT decreased to 4.5 then 4 mL/kg and PEEP adjusted to reach 23 ≤ Pplat ≤ 25 cm H2O.
OTHER	Level of carbon dioxide released at the end of expiration	EtCO2 will be monitored for safety purposes. Blood gases will be analyzed 20-30 minutes after each VT reduction
OTHER	Respiratory Rate	RR will be kept what it was at baseline
OTHER	Sweep gas flow	Sweep gas flow will be adapted to maintain the same EtCO2
OTHER	Ventilation will be adapted	If PaCO2\> 75 mmHg and/or pH \< 7.2, despite respiratory rate of 35/min and optimized ECCO2R, VT will be increased to the last previously tolerated VT.
OTHER	Respiratory rate will be adapted	If PaCO2 remains within the target range, respiratory rate will be progressively decreased to a minimum of 15/ min and facilitated by increases in sweep flow.

Timeline

• Start date: 2015-11-01
• Primary completion: 2017-07-01
• Completion: 2017-07-30
• First posted: 2014-11-04
• Last updated: 2017-08-04

Locations

1 site across 1 country: Belgium