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Original Investigation
Caring for the Critically Ill Patient
August 31, 2021

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial

Author Affiliations
  • 1Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Belfast, United Kingdom
  • 2Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, United Kingdom
  • 3Department of Anaesthesia, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
  • 4Guy’s and St Thomas’ NHS Foundation Trust, King’s College London, United Kingdom
  • 5Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, United Kingdom
  • 6Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
  • 7University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
  • 8Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, United Kingdom
  • 9Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
  • 10Acute Intensive Care Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
  • 11Clinical Trials Unit, Intensive Care National Audit & Research Centre (ICNARC), London, United Kingdom
  • 12Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York
  • 13Center for Acute Respiratory Failure, New York-Presbyterian Hospital, New York, New York
  • 14Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
  • 15Department of Anaesthesia, Intensive Care and Pain Medicine, Division of Population Medicine, Cardiff University, Cardiff, United Kingdom
  • 16Critical Care Directorate, Royal Gwent Hospital, Aneurin Bevan University Health Board, Newport, Gwent, United Kingdom
  • 17Department of Critical Care, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, United Kingdom
  • 18Division of Infection, Immunity and Respiratory Medicine, The University of Manchester, Manchester, United Kingdom
  • 19Department of Anaesthetics and Intensive Care, Royal Oldham Hospital, Northern Care Alliance, Oldham, United Kingdom
  • 20Northern Ireland Clinical Trials Unit, Belfast, United Kingdom
JAMA. 2021;326(11):1013-1023. doi:10.1001/jama.2021.13374
Visual Abstract. Lower Tidal Volume via Extracorporeal Carbon Dioxide Removal and Mortality in Patients With Acute Hypoxemic Respiratory Failure
Lower Tidal Volume via Extracorporeal Carbon Dioxide Removal and Mortality in Patients With Acute Hypoxemic Respiratory Failure
Key Points

Question  In adults with acute hypoxemic respiratory failure receiving mechanical ventilation, does further reduction in tidal volumes, facilitated by extracorporeal carbon dioxide removal, improve 90-day mortality compared with conventional low tidal volume ventilation?

Findings  In this randomized clinical trial that included 412 adults, 90-day mortality was 41.5% in the extracorporeal carbon dioxide removal group and 39.5% in the standard care group, a difference that was not statistically significant.

Meaning  Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume ventilation, compared with conventional low tidal volume ventilation, did not significantly reduce 90-day mortality.

Abstract

Importance  In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes.

Objective  To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure.

Design, Setting, and Participants  This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020.

Interventions  Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210).

Main Outcomes and Measures  The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates.

Results  Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, −7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, −2.1 [95% CI, −3.8 to −0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device.

Conclusions and Relevance  Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference.

Trial Registration  ClinicalTrials.gov Identifier: NCT02654327

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