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)?

Background

• 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

Design

• 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

Setting

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

Population

• 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]
  • P_plt (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%)

Intervention

• 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 P_plt 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 P_plt 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

Outcome

• 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
    • P_plt 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

Strengths

• 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

Weaknesses

• 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 clinicaltrials.gov
• 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

• [Article] Feasibility and Safety of Extracorporeal CO2 Removal to Enhance Protective Ventilation in Acute Respiratory Distress Syndrome: The SUPERNOVA Study
• [further reading] An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome
• [further reading] Ultra-protective tidal volume: how low should we go?
• [further reading] pRotective vEntilation With Veno-venouS Lung assisT in Respiratory Failure (REST)

Metadata

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