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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr McNamee reported receiving grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme during the conduct of the study and speaking fees from Baxter outside the submitted work. Dr Barrett reported receiving grants from ALung Technologies during the conduct of the study and grants from ALung for a separate study using the investigational device outside the submitted work. Dr Perkins reported receiving grants from NIHR HTA Programme and the NIHR Applied Research Collaboration West Midlands during the conduct of the study. Dr Young reported receiving grants from the NIHR during the conduct of the study. Dr Harrison reported receiving grants from the NIHR during the conduct of the study. Dr Brodie reported receiving grants from ALung Technologies; personal fees from Baxter, Xenios, and Abiomed; and nonfinancial support from Hemovent outside the submitted work and being the chair of the executive committee of the International ECMO Network. Dr Boyle reported receiving grants from the Northern Ireland Health and Social Care Research and Development Agency to undertake a clinical trial of extracorporeal carbon dioxide removal, grants from the NIHR HTA Programme for a clinical trial of extracorporeal carbon dioxide removal (13/143/02), and nonfinancial support from ALung Technologies in provision of equipment and consumables to undertake a clinical trial of ECCO2R. Dr Agus reported the Northern Ireland Clinical Trials Unit receiving funds from the NIHR HTA Programme for its involvement during the conduct of the study. Dr McDowell reported receiving grants from the NIHR HTA Programme during the conduct of the study. Dr Jackson reported receiving grants from the NIHR HTA Programme during the conduct of the study. Dr McAuley reported receiving grants from the NIHR HTA Programme during the conduct of the study and personal fees from Bayer for consultancy for treatment of acute respiratory distress syndrome (ARDS), GlaxoSmithKline for consultancy for treatments of ARDS and being an educational seminar speaker, Boehringer Ingelheim for consultancy for treatment of ARDS, Novartis for consultancy for treatment of COVID-19, Eli Lilly for consultancy for treatment of COVID-19, and Vir Biotechnology as a member data monitoring and ethics committee and grants from NIHR as an investigator in ARDS and COVID-19 studies, Wellcome Trust as an investigator in ARDS and COVID-19 studies, Innovate UK as an investigator in ARDS and COVID-19 studies, the Medical Reserve Corpse as an investigator in ARDS studies, and Northern Ireland Health and Social Care Research and Development Division as an investigator in ARDS and COVID-19 studies outside the submitted work; having a patent issued by Queen's University Belfast for a novel treatment for inflammatory disease (US8962032); and being co-director of research for the intensive care society and NIHR/Medical Reserve Corps Efficacy and Mechanism Evaluation Programme. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients in a Study of Lower Tidal Volume Facilitated by Extracorporeal Carbon Dioxide Removal in Patients With Acute Hypoxemic Respiratory Failure

aPatients could meet more than 1 ineligibility criterion. bChild-Pugh score >11. cOther was used when the reason for a patient’s exclusion was not among those predefined in the protocol; the most commonly specified free-text explanations included rapid improvement or deterioration in clinical status. dRandomization was stratified by site. eThis patient was randomized twice in error and was randomized to the same group.

Figure 2.. Kaplan-Meier Curve of the Time to Death in a Study of Lower Tidal Volume Facilitated by Extracorporeal Carbon Dioxide Removal in Patients With Acute Hypoxemic Respiratory Failure

Median (interquartile range) time to death was 6 (4-14) days in the ECCO2R group and 9 (5-16) days in the ventilation alone group. The unadjusted hazard ratio for death at 90 days in the ECCO2R group was 1.1 (95% CI, 0.8-1.5). The proportionality P = .40, suggesting that the proportionality assumption was met.

Figure 3.. Physiological Parameters by Treatment Group to Day 7 in a Study of Lower Tidal Volume Facilitated by Extracorporeal Carbon Dioxide Removal in Patients With Acute Hypoxemic Respiratory Failure

Driving pressure is equal to plateau pressure minus PEEP.