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

European Society of Intensive Care Medicine

Status and phase

Completed

Phase 2

Phase 1

Conditions

Moderate Acute Respiratory Distress Syndrome

Treatments

Other: Respiratory rate will be adapted

Other: Ventilation will be adapted

Device: ECCO2R will be initiated during the 2-hour run-in time

Other: Sweep gas flow

Other: Level of carbon dioxide released at the end of expiration

Other: Respiratory Rate

Device: Ventilation

Other: Neuromuscular blocking agents (NMBA)

Study type

Interventional

Funder types

Other

Identifiers

NCT02282657

SUPERNOVA

Details and patient eligibility

About

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.

Full 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.

Enrollment

95 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

95 participants in 1 patient group

One single arm

Experimental group

Description:

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.

Treatment: