REST: Extracorporeal CO₂ Removal in Acute Hypoxemic Respiratory Failure (2018)

“Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate ultra-protective lung ventilation did not significantly reduce 90-day mortality.”

  • The REST Investigators

1. Publication Details

  • Trial Title: A Randomized Trial of Extracorporeal Carbon Dioxide Removal for Acute Respiratory Failure
  • Citation: McNamee JJ, Gillies MA, Barrett NA, et al. Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial. JAMA. 2021;326(11):1013-1023. DOI: 10.1001/jama.2021.15312
  • Published: September 21, 2021, in The Journal of the American Medical Association (JAMA)
  • Author: James J. McNamee, Ph.D., on behalf of the REST Investigators
  • Funding: UK National Institute for Health Research.

2. Keywords

  • ARDS, Acute Hypoxemic Respiratory Failure, Extracorporeal Carbon Dioxide Removal (ECCO₂R), Ultra-Protective Ventilation, Mechanical Ventilation, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute hypoxemic respiratory failure (Population), does a strategy of ultra-protective ventilation (tidal volume 4 ml/kg) facilitated by extracorporeal carbon dioxide removal (ECCO₂R) (Intervention) compared to standard lung-protective ventilation (6 ml/kg) (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The ARMA trial (2000) established that low tidal volume ventilation (6 ml/kg) improves survival in ARDS. It was hypothesized that further reducing tidal volumes to “ultra-protective” levels (e.g., 4 ml/kg) could be even more beneficial by further minimizing ventilator-induced lung injury.
  • Knowledge Gap: The main barrier to ultra-protective ventilation is the development of severe respiratory acidosis from carbon dioxide retention. Extracorporeal CO₂ removal (ECCO₂R) is a technology that can remove CO₂ directly from the blood, potentially enabling this more protective ventilation strategy. However, it was unknown if this complex and invasive strategy would improve patient-centered outcomes.
  • Proposed Hypothesis: The authors hypothesized that an ECCO₂R-facilitated, ultra-protective ventilation strategy would be superior to standard lung-protective ventilation in reducing 90-day mortality.

5. Study Design and Methods

  • Design: A multicenter, international, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 41 intensive care units (ICUs) in the United Kingdom.
  • Trial Period: Enrollment ran from June 2016 to February 2020.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with acute hypoxemic respiratory failure (PaO2:FiO2 ratio < 150 mm Hg) who had been mechanically ventilated for less than 48 hours.
    • Exclusion Criteria: Included contraindications to anticoagulation, severe chronic lung disease, and a decision to withhold life-sustaining treatment.
  • Intervention: Patients were randomized to an ECCO₂R-facilitated strategy, where the tidal volume was reduced to 4 ml/kg of predicted body weight, and an ECCO₂R device was used to maintain a normal pH and PaCO2.
  • Control: Patients were randomized to a standard care strategy, receiving lung-protective ventilation with a tidal volume of 6 ml/kg.
  • Management Common to Both Groups: All patients were managed with a standardized PEEP/FiO2 table and other supportive care according to best practices.
  • Power and Sample Size: The authors calculated that a sample size of 1120 patients would be required to have 90% power to detect a 7.5% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included ventilator-free days, ICU length of stay, and the incidence of complications.

6. Key Results

  • Enrollment and Baseline: 412 patients were randomized (199 to ECCO₂R and 213 to standard care). The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board for futility due to slow recruitment, particularly after the start of the COVID-19 pandemic.
  • Primary Outcome: There was no significant difference in 90-day mortality. 83 of 199 patients (41.7%) in the ECCO₂R group died, compared with 81 of 213 patients (38.0%) in the standard care group (p=0.46).
  • Secondary Outcomes: There were no significant differences between the groups in ventilator-free days or ICU length of stay.
  • Adverse Events: The incidence of serious adverse events was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.46 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a novel therapeutic strategy.
  • Generalizability: The pragmatic design and inclusion of 41 diverse ICUs increase the applicability of the findings.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was a specific group of patients with early, hypoxemic respiratory failure.
  • Other: The trial was severely underpowered. It was stopped after enrolling only 412 of the planned 1120 patients, which makes it impossible to draw any definitive conclusions from the neutral result. A true, modest benefit or harm could easily have been missed.

10. Conclusion of the Authors

  • The authors concluded that among patients with acute hypoxemic respiratory failure, the use of ECCO₂R to facilitate ultra-protective lung ventilation did not significantly reduce 90-day mortality compared with standard care.

11. To Summarize

  • Impact on Current Practice: This trial, while underpowered, provided important evidence that a complex and invasive strategy of ECCO₂R-facilitated ultra-protective ventilation is unlikely to provide a large survival benefit in a general ARDS population.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute hypoxemic respiratory failure.
    • Actionable Intervention: The results do not support the routine use of ECCO₂R to facilitate ultra-protective ventilation.
  • What This Trial Does NOT Mean: This trial does NOT definitively prove that ECCO₂R is not beneficial. Due to its early termination and small sample size, it can only conclude that a large benefit is unlikely.
  • Implementation Caveats: The key takeaway is that standard lung-protective ventilation (6 ml/kg) remains the evidence-based standard of care, and more complex strategies require more robust evidence before adoption.

12. Context and Related Studies

  • Building on Previous Evidence: The REST trial (2021) was designed to test the next logical step in lung protection after the ARMA trial (2000) established the benefit of low tidal volumes.
  • Influence on Subsequent Research: The inconclusive result of this underpowered trial highlights the ongoing clinical uncertainty and the need for a larger, definitive international trial to provide a clear answer on the role of ultra-protective ventilation and ECCO₂R.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether there is a true, albeit smaller, benefit of this strategy that this underpowered trial was unable to detect, or if there is a specific subgroup of patients who might benefit.
  • Future Directions: A larger, international, multicenter randomized controlled trial is needed to definitively determine the role of ECCO₂R-facilitated ultra-protective ventilation in the management of ARDS.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and innovative, testing the next frontier of lung-protective ventilation.
  • Methods: The multicenter RCT design was appropriate. The main methodological limitation is the severe underpowering due to early termination for futility, which makes the results inconclusive and at high risk of a Type II error (i.e., missing a true difference between the groups).
  • Results: The study reported a clear neutral finding for its primary outcome. However, given the very small sample size, no definitive conclusions can be drawn from this. The confidence interval around the effect estimate would be very wide.
  • Conclusions and Applicability: The authors’ cautious conclusion is appropriate. The trial’s main contribution is to highlight the ongoing clinical equipoise and the need for a larger, definitive study. At present, the findings do not support the routine adoption of this complex and invasive strategy.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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