Extracorporeal Carbon Dioxide Removal to Avoid Invasive Ventilation During Exacerbations of Chronic Obstructive Pulmonary Disease: VENT-AVOID Trial – A Randomized Clinical Trial

Duggal et al. 2024; American Journal of Respiratory and Critical Care Medicine March 1, 2024 Pages xv-616

Clinical Question

• In patients with acute exacerbations of COPD who are either failing noninvasive ventilation (NIV) or failing to wean from invasive mechanical ventilation (IMV), does extracorporeal CO2 removal compared to usual care increase ventilator free days within 5 days of randomisation (VFD-5)?

Background

• Acute exacerbations of COPD (AECOPD) are a common reason for ICU admissions and invasive mechanical ventilation
• IMV is associated with increased mortality and morbidity in patients with AECOPD. The iatrogenic harms of IMV may amplified in patients with COPD who are at increased risk of ventilator associated lung injury due to underlying lung disease and the complications of immobility and sedation due to comorbidities and frailty.
• Extracorporeal CO2 removal (ECCO2R) is a extracorporeal therapy that removes CO2 from the blood but has insufficient blood flow to provide meaningful oxygenation unlike VV ECMO

• Previous research includes:
  • Two previous RCTs in patients with hypoxaemic respiratory failure
    • REST (JAMA 2021, n=412), utilised ECCO2R to facilitate low tidal volume ventilation in patients with hypoxaemic respiratory failure
      • REST showed that the ECCO2R facilitated lower tidal volumes but was associated with increased time on the ventilator and more than double the rates of serious adverse events including intracranial haemorrhage and infection, without a mortality benefit.
    • Xtravent (ICM 2013, n=79) randomised patients with hypoxaemic respiratory failure to ARDSnet ventilation or low tidal volume ventilation with ECCO2R and found no difference in ventilator free days or survival. Ceased early due to slow enrollment
  • A single arm phase 2 Trial: SUPERNOVA (ICM 2019, n=95) demonstrated successful ultra-low tidal volume ventilation but high complication rates
  • A case control study: ECLAIR (ICM 2016, n=25) demonstrated avoidance of IMV in half of cases with hypercapnic respiratory failure but serious adverse events in nearly half of cases without a survival or length of stay benefit

Design

• Investigator initiated, prospective, multicenter, open-label, two-strata pivotal randomised clinical trial
• Two strata of patients
  • NIV stratum
    • AECOPD with high risk of requiring intubation after at least 1 hour of NIV due to worsening or severe respiratory acidosis, tachypnea, intolerance of NIV, worsening mentation
  • IMV stratum
    • Intubated and ventilated for </= 5 days and failed spontaneous breathing trial or not suitable for SBT or extubation
• Primary outcome – Ventilator free days within first 5 days of randomisation (VFD-5)
  • Death within 5 days penalized with VFD-5 of -1
• Randomisation via interactive web response system
• Trial terminated early by funding group due to slow enrollment

Setting

• 41 centers in the USA
  • Only 29 sites enrolled patients included in final analysis
  • Highest enrolling site had 16 patients, many sites had 0 or 1 patients on ECCO2R
• Enrollment from Feb 2018 – May 2022

Population

• Inclusion:
  • Age >/=40
  • Previously diagnosed COPD, Asthma-COPD overlap with supportive spirometry (proceduralised checklist available to facilitate inclusion of suspected undiagnosed COPD or no spirometry)
  • Hypercapnic respiratory failure
  • NIV stratum
    • High risk of requiring intubation after at least 1 hour on NIV due to (respiratory acidosis pH <7.25, worsening hypercarbia or acidosis, moderate-severe dyspnea, tachypnea >30brpm, intolerance of NIV
    • Progressive clinical deterioration despite NIV (decreased mental capacity, intolerance of NIV, increasing or decreasing respiratory rate with worsening or unchanged acidosis)
  • IMV stratum
    • Currently intubated and receiving IMV for </= 5 days and
    • Failed SBT or not suitable for SBT or not suitable for extubation
• Exclusion: extensive exclusion criteria including
  • DNI/DNR orders or terminal illness
  • Significant haemodynamic instability, ACS or heart failure
  • Significant hypoxia P:F <120 despite PEEP 5
  • Contraindications to cannulation or anti-coagulation including anaemia, thrombocytopenia, hypersensitivty to heparin, aberrant vasculature
  • Unable to protect airway
  • Pregnancy
  • Neutropenia
  • Fulminant liver failure
  • ” Any disease or condition that, in the judgment of the investigator, either places the subject at undue risk of complications from the Hemolung RAS device or may reduce the subject’s likelihood of benefitting from therapy with the Hemolung RAS”
• 113 subjects randomised out of 5992 screened (1.8%)
  • 372 excluded at principal investigator discretion
  • NIV stratum – 26 ECCO2R vs 22 SOC
  • IMV stratum 32 ECCO2R vs 33 SOC
• Comparing baseline characteristics of intervention vs. control group
  • Groups generally well matched
  • Median age 63
  • 65% female

Intervention

• ECCO2R via Hemolung system
  • A 15.5 Fr dual-lumen catheter placed in femoral or right internal jugular vein.
  • ECCO2R therapy commenced with extracoporeal blood flow 350 – 550 mL/min and sweep gas to achieve sufficient CO2 removal (max 10L/min).
  • ECCO2R could be used up to 14 days

Control

• Standard of care guided by local protocols

Management common to both groups

• Standard of care treatments as clinician discretion guided by local protocols

Outcome

• Primary outcome: No significant difference in median VFD-5 in either stratum
  • In NIV stratum VFD-5 was 5 days in both groups (median shift = 0.0, 95% CI 0.0-0.0)
  • In IMV stratum, VFD-5 was numerically but not statistically significantly higher in the ECCO2R group (0.25 days vs 2 days, median shift = 0.0, 95% CI 0.0-1.25)
• Secondary outcomes:
  • In the NIV stratum
    • Favouring ECCO2R
      • Lower PaCO2 at 2-6 hours and 24 hours
    • Favouring SOC
      • Resolution of hypercapnia, time to ICU discharge, 60 day mortality
      • Lower rate of intubation (13% in intervention vs 5% in control)
      • Time to ICU discharge and hospital discharge
    • No difference in
      • VFD-30
  • In the IMV stratum – no statistically significant patient centered secondary outcomes in either direction
    • No difference in
      • Failed extubations
      • VFD-30
      • Time to ICU discharge and hospital discharge
  • No difference overall in
    • Rate of tracheostomy, ICU mobility, hospital readmission
• Safety outcomes
  • ECCO2R group had more than twice the rate of in-hospital mortality (19% vs 9%) with 2 deaths related to ECCOR2.
    • This was driven by a mortality difference in the NIV stratum (22% in hospital mortality in intervention group vs 0% in NIV group, p=0.02)
    • There were 3 deaths related to IMV in the control group, all in the IMV strata vs none in the intervention group
  • Significantly greater in the intervention group
    • Nonserious adverse events – 57% vs 31% (P0.03)

Authors’ Conclusions

• “In patients with ECOPD, the use of ECCO2R compared with SOC to either avoid intubation or facilitate extubation did not significantly improve VFD-5 s. Because of early termination and the intubation rate that was lower than anticipated in the SOC arm of the NIV group, the study may be underpowered to detect differences”

Strengths

• Largest trial to date of ECCO2R for EOCOPD
• Multicenter RCT with robust randomisation and statistical analysis

Weaknesses

• <2% of screened patients were enrolled, most due to improvement prior to randomisation
  • 3x the number of patients enrolled were excluded at the PI discretion raising the risk of selection bias
• A small number of patients were enrolled across a large number of centers.
  • Prior ECCO2R experience is not explicitly described in the manuscript although reference is made to mechanical and bleeding complications potentially resulting from operator inexperience
• This trial lacked a protocolised approach to defining NIV failure/need for intubation, and for weaning from mechanical ventilation which introduces heterogeneity into the trial population (especially in a multicentre trial) although may be reflective of real-world practice variations
• Very low intubation rate in the NIV stratum (13% in ECCO2R, 4% in SOC) suggest that the inclusion criteria may have failed to select a sufficiently sick group to see a true effect
  • The study was powered based on an expected 55% intubation rate and thus is underpowered
  • Enrollment rates were already very low, a further study with a more selective group is likely unfeasible
• Sponsored by manufacturers of ECCO2R system (as is common in trials of investigational devices) who stopped the trial early (63% of enrollment) and retained final decision on all trial modifications
  • The device has subsequently been withdrawn from the market

The Bottom Line

• The VENT-AVOID trial does not support use of ECCO2R in ECOPD patients to avoid intubation or wean from mechanical ventilation
• The preponderance of evidence after 3 RCTs is that ECCO2R should not be used outside of a trial environment as there is scant evidence of benefit and high rates of serious adverse events.

External Links

• article Extracorporeal Carbon Dioxide Removal to Avoid Invasive Ventilation During Exacerbations of Chronic Obstructive Pulmonary Disease: VENT-AVOID Trial – A Randomized Clinical

Metadata

Summary author: Daniel Chung
Summary date: 4/2/26
Peer-review editor: David Slessor

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