Feasibility and Safety of Extracorporeal CO2 Removal to Enhance Protective Ventilation in Acute Respiratory Distress Syndrome: The SUPERNOVA Study

Combes A et al. Intensive Care Medicine February 2019; DOI: 10.1007/s00134-019-05567-4

Clinical Question

  • Can extracorporeal carbon dioxide removal (ECCO2R) safely facilitate ultra-low tidal volume ventilation in patients with moderate acute respiratory distress syndrome (ARDS)?


  • For patients with ARDS, use of a ventilation strategy which prioritizes low tidal volumes (4-6 mL/kg predicted body weight) and low inspiratory pressures (plateau pressure < 30 cmH2O) is strongly supported by consensus guidelines 
  • It is unclear whether ultra-low tidal volume ventilation (3-4 mL/kg PBW) provides additional protection beyond that achieved with traditional lung-protective ventilation. Additionally, attempts to significantly lower tidal volumes are often limited by severe respiratory acidosis
  • Extracorporeal carbon dioxide removal (ECCO2R) has been proposed as a way to facilitate ultra-low tidal volume ventilation although the safety and feasibility of this approach has not been well studied


  • Multicenter prospective phase 2 single-arm study
  • Blinding not performed given the nature of the intervention and the study design
  • Power calculation:
    • Based on the assumption that PaCO2 would be 40–60 mmHg with tidal volumes of 6 mL/kg Predicted Body Weight (PBW) and that PaCO2 would increase to 65–85 mmHg when tidal volumes were lowered to 4 mL/kg PBW.
    • Investigators estimated that a sample size of 90 patients would be required to establish the ability of ECCO2R to return PaCO2 levels to within 20% of baseline. This sample size would provide a two-sided 95% confidence interval of 70–90% if the incidence of meeting this condition was 80% and 54–75% if the incidence was 65%
    • The goal enrollment was increased to 100 patients to account for an expected 3% dropout rate
    • Data analysis was performed by a researcher who was not involved in data collection or a member of the study steering committee
    • Severe adverse events (SAEs) were reported to the clinical coordinator. Determination of whether SAEs were directly attributable to ECCO2R was performed by an independent safety monitoring board


  • 23 hospitals across Europe and Canada
  • October 2015 to June 2017


  • Inclusion:
    • 18 years of age or older
    • Moderate ARDS (PaO2/FiO2 100–200 mmHg on at least a PEEP of 5 cmH2O)
    • Anticipated duration of mechanical ventilation >24 hours
  • Exclusion:
    • Decompensated heart failure
    • Acute coronary syndrome
    • Severe chronic obstructive pulmonary disease
    • Major respiratory acidosis with PaCO2 >60mmHg
    • Acute brain injury
    • Severe liver insufficiency (Child-Pugh >7)
    • Fulminant hepatic failure
    • Heparin-induced thrombocytopenia
    • Contraindication to systemic anticoagulation
    • Platelet < 50 G/L
    • Moribund
    • Decision to limit therapeutic interventions
    • Inability to access femoral or jugular vein
    • Pneumothorax
  • 755 patients met entry criteria, 95 patients enrolled (each center enrolled a median of 3 patients)
  • No patients lost to follow-up
  • Baseline characteristics (mean +/- standard deviation or median [interquartile range])
    • Age (years): 60.2 +/- 14.0
    • Female: 31 (32.6%)
    • Pneumonia as the cause of ARDS: 78 (82.1%)
    • Tidal volume (mL/kg PBW): 6.0 +/- 0.2
    • PEEP (cmH2O): 15.5 [10.0;16.0]
    • Pplt (cmH2O): 26.6 +/- 3.0
    • Driving pressure (cmH2O): 13.2 +/- 4.3
    • PaCO2 (mmHg): 47.8 +/- 9.4
    • pH: 7.34 +/- 0.08
    • PaO2/FiO2 (mmHg): 173 +/- 61
    • Neuromuscular blockade: 80 (84.2%)
    • Prone positioning: 23 (24.2%)


  • Three different ECCO2R systems were used. Each trial site used only 1 device type during the study:
    • Hemolung Respiratory Assist System (ALung Technologies): Membrane lung with cross-sectional area of 0.59 m2, blood flow between 300–500 mL/min. 15.5 Fr catheter
    • iLA active (Novalung): Membrane lung with cross-sectional area of 1.30 m2 with blood flow 800–1000 mL/min (upper limit set by the trial protocol, not the capability of the machine). 18–20 Fr catheter
    • Cardiohelp HLS 5.0 (Getinge Cardiopulmonary Care): Membrane lung with cross-sectional area of 1.30 m2 with blood flow 800–1000 mL/min (upper limit set by the trial protocol, not the capability of the machine). 18–20 Fr catheter
  • Protocol:
    • Sedation and neuromuscular blockade administered for a minimum of 24 hours following enrollment
    • Tidal volume initially set at 6 mL/kg PBW and PEEP adjusted to maintain a Pplt between 28–30 cmH2O
    • ECCO2R catheter inserted in either the internal jugular or femoral vein
    • Unfractionated heparin given to achieve an activated partial thromboplastin time of 35–80 seconds
    • Tidal volume reduced step-wise to 4 mL/kg PBW and PEEP titrated to Pplt 23-25 cmH2O
    • Sweep gas and blood flow set to maintain a PaCO2 between 80–120% of the baseline value
    • Tidal volume increased if PaCO2 exceeded 75 mmHg and/or pH fell below 7.30 despite a respiratory rate of 35 breaths/minute
    • Data collected at baseline, 8 hours, and 24 hours. After 24 hours the attending physician was allowed to determine ventilator settings and need for continued ECCO2R


  • Primary outcome: Number of patients who successfully achieved a tidal volume of 4 mL/kg PBW with a PaCO2 not increasing more than 20% from baseline with an arterial pH > 7.30
    • 8 hours: 78% (95% CI: 68–89%)
    • 24 hours: 82% (95% CI: 76–88%)
  • Secondary outcomes
    • Duration of ECCO2R (days): 5 [3–8]
    • Duration of invasive mechanical ventilation (days): 17 [11–29]
    • Alive at day 28: 69 (73%)
    • Physiologic variables
      • Tidal volume at 24 hours (mL/kg PBW): 4.16 +/- 0.46
      • Pplt at 24 hours (cmH2O): 23.5 +/- 3.9
      • PEEP at 24 hours (cmH2O): 13.8 +/- 3.9
      • Driving pressure at 24 hours (cmH2O): 9.9 +/- 4.3
    • Adverse events
      • Severe adverse events
        • 6 total (massive right frontal parenchymal hematoma, severe hematemesis and melena, SVC thrombosis, sudden death, severe hypoxemia, pneumothorax during cannulation)
        • The brain bleed and pneumothorax were attributed directly to ECCO2R
      • Adverse events
        • 39% of patients experienced an AE
        • 26 patients (27%) experienced an AE in the first 24 hours
        • Membrane lung clotting: 13 (14%)
        • Pump malfunction: 3 (3%)
        • Catheter displacement: 2 (2%)
        • Hemolysis: 11 (12%)
        • Significant bleeding: 6 (6%)
        • Infectious complications: 2 (2%)
        • Thrombocytopenia: 12 (13%)

Authors’ Conclusions

  • ECCO2R can facilitate ultra-low tidal volume ventilation. A randomized trial is required to inform use of this intervention in patients with ARDS


  • The largest safety and feasibility study of ECCO2R – a novel and potentially beneficial extracorporeal therapy for patients with ARDS
  • International cohort of study centers increasing generalizability of the results
  • No patients lost to follow-up during the study period


  • Three different ECCO2R systems were used. It is not possible to tell from the data provided if efficacy or safety differed between the devices
  • CO2 clearance not quantified despite this being listed as a study endpoint on
  • Study halted short of enrollment goal due to lack of equipment
  • Not clearly powered for safety outcomes
  • The primary outcome of achieving an ultra-low tidal volume without severe hypercapnia, while appropriate for a feasibility and safety study, is not patient-centered and is of unclear clinical significance

The Bottom Line

  • ECCO2R can facilitate ultra-low tidal volume ventilation in patients with moderate ARDS
  • Whether ultra-low tidal volume ventilation improves outcomes for patients with ARDS remains unclear
  • In my opinion, the high number of adverse events (including 6 SAEs) observed in this study and the still unclear benefit of ultra-low tidal volume ventilation argues against use of ECCO2R in ARDS outside of a clinical trial
  • The study highlights just how hard it is to enroll patients in these types of trials, even at high volume centers experienced in studies of extracorporeal support
  • This study is a useful prelude to the ongoing REST trial – a randomized trial of ECCO2R vs standard care in patients with ARDS

External Links


Summary author: James M. Walter
Summary date: 19th March 2019
Peer-review editor: Steve Mathieu

One comment

  • Al

    This is a very interesting article, although very complex to who is new in this area. Has the REST trial been completed? The difficulty to enrol patients into the trial is a shame given that it would be very useful to know if it improves outcomes… Has any further data been collected? Please let me know where I can find it if so!

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