Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial

implications for trial design

for the SUPERNOVA investigators (European Society of Intensive Care Medicine trials group)  and for the International ECMO Network (ECMONet), Ewan C. Goligher, Alain Combes, Daniel Brodie, Niall D. Ferguson, Antonio M. Pesenti, V. Marco Ranieri, Arthur S. Slutsky

Research output: Contribution to journalArticle

Abstract

Purpose: To describe the variability and determinants of the effect of extracorporeal CO2 removal (ECCO2R) on tidal volume (Vt), driving pressure (ΔP), and mechanical power (PowerRS) and to determine whether highly responsive patients can be identified for the purpose of predictive enrichment in ECCO2R trial design. Methods: Using data from the SUPERNOVA trial (95 patients with early moderate acute respiratory distress syndrome), the independent effects of alveolar dead space fraction (ADF), respiratory system compliance (Crs), hypoxemia (PaO2/FiO2), and device performance (higher vs lower CO2 extraction) on the magnitude of reduction in Vt, ΔP, and PowerRS permitted by ECCO2R were assessed by linear regression. Predicted and observed changes in ΔP were compared by Bland–Altman analysis. Hypothetical trials of ECCO2R, incorporating predictive enrichment and different target CO2 removal rates, were simulated in the SUPERNOVA study population. Results: Changes in Vt permitted by ECCO2R were independently associated with ADF and device performance but not PaO2/FiO2. Changes in ΔP and PowerRS were independently associated with ADF, Crs, and device performance but not PaO2/FiO2. The change in ΔP predicted from ADF and Crs was moderately correlated with observed change in ΔP (R2 0.32, p < 0.001); limits of agreement between observed and predicted changes in ΔP were ± 3.9 cmH2O. In simulated trials, restricting enrollment to patients with a larger predicted decrease in ΔP enhanced the average reduction in ΔP, increased predicted mortality benefit, and reduced sample size and screening size requirements. The increase in statistical power obtained by restricting enrollment based on predicted ΔP response varied according to device performance as specified by the target CO2 removal rate. Conclusions: The lung-protective benefits of ECCO2R increase with higher alveolar dead space fraction, lower respiratory system compliance, and higher device performance. ADF and Crs, rather than severity of hypoxemia, should be the primary factors determining whether to enroll patients in clinical trials of ECCO2R.

Original languageEnglish
Pages (from-to)1219-1230
JournalIntensive Care Medicine
Volume45
Issue number9
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

Carbon Dioxide
Equipment and Supplies
Respiratory System
Compliance
Tidal Volume
Adult Respiratory Distress Syndrome
Sample Size
Linear Models
Clinical Trials
Pressure
Lung
Mortality
Population
Hypoxia

Keywords

  • Acute respiratory distress syndrome
  • Artificial ventilation
  • Extracorporeal carbon dioxide removal
  • Predictive enrichment
  • Ventilator-induced lung injury

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

for the SUPERNOVA investigators (European Society of Intensive Care Medicine trials group)  and for the International ECMO Network (ECMONet), Goligher, E. C., Combes, A., Brodie, D., Ferguson, N. D., Pesenti, A. M., ... Slutsky, A. S. (2019). Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design. Intensive Care Medicine, 45(9), 1219-1230. https://doi.org/10.1007/s00134-019-05708-9

Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial : implications for trial design. / for the SUPERNOVA investigators (European Society of Intensive Care Medicine trials group)  and for the International ECMO Network (ECMONet); Goligher, Ewan C.; Combes, Alain; Brodie, Daniel; Ferguson, Niall D.; Pesenti, Antonio M.; Ranieri, V. Marco; Slutsky, Arthur S.

In: Intensive Care Medicine, Vol. 45, No. 9, 01.01.2019, p. 1219-1230.

Research output: Contribution to journalArticle

for the SUPERNOVA investigators (European Society of Intensive Care Medicine trials group)  and for the International ECMO Network (ECMONet), Goligher, EC, Combes, A, Brodie, D, Ferguson, ND, Pesenti, AM, Ranieri, VM & Slutsky, AS 2019, 'Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design', Intensive Care Medicine, vol. 45, no. 9, pp. 1219-1230. https://doi.org/10.1007/s00134-019-05708-9
for the SUPERNOVA investigators (European Society of Intensive Care Medicine trials group)  and for the International ECMO Network (ECMONet), Goligher EC, Combes A, Brodie D, Ferguson ND, Pesenti AM et al. Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial: implications for trial design. Intensive Care Medicine. 2019 Jan 1;45(9):1219-1230. https://doi.org/10.1007/s00134-019-05708-9
for the SUPERNOVA investigators (European Society of Intensive Care Medicine trials group)  and for the International ECMO Network (ECMONet) ; Goligher, Ewan C. ; Combes, Alain ; Brodie, Daniel ; Ferguson, Niall D. ; Pesenti, Antonio M. ; Ranieri, V. Marco ; Slutsky, Arthur S. / Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial : implications for trial design. In: Intensive Care Medicine. 2019 ; Vol. 45, No. 9. pp. 1219-1230.
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TY - JOUR

T1 - Determinants of the effect of extracorporeal carbon dioxide removal in the SUPERNOVA trial

T2 - implications for trial design

AU - for the SUPERNOVA investigators (European Society of Intensive Care Medicine trials group)  and for the International ECMO Network (ECMONet)

AU - Goligher, Ewan C.

AU - Combes, Alain

AU - Brodie, Daniel

AU - Ferguson, Niall D.

AU - Pesenti, Antonio M.

AU - Ranieri, V. Marco

AU - Slutsky, Arthur S.

AU - Beale, Richard

AU - Brochard, Laurent

AU - Chiche, Jean Daniel

AU - Fan, Eddy

AU - de Backer, Daniel

AU - Francois, Guy

AU - Laffey, John

AU - Mercat, Alain

AU - McAuley, Daniel F.

AU - Müller, Thomas

AU - Quintel, Michael

AU - Vincent, Jean Louis

AU - Taccone, Fabio Silvio

AU - Peperstraete, Harlinde

AU - Morimont, Philippe

AU - Schmidt, Matthieu

AU - Levy, Bruno

AU - Diehl, Jean Luc

AU - Guervilly, Christophe

AU - Capelier, Gilles

AU - Vieillard-Baron, Antoine

AU - Messika, Jonathan

AU - Karagiannidis, Christian

AU - Moerer, Onnen

AU - Urbino, Rosario

AU - Antonelli, Massimo

AU - Mojoli, Francesco

AU - Alessandri, Francesco

AU - Grasselli, Giacomo

AU - Donker, Dirk

AU - Ferrer, Ricard

AU - Mancebo, Jordi

AU - Fanelli, Vito

AU - Pham, Tai

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: To describe the variability and determinants of the effect of extracorporeal CO2 removal (ECCO2R) on tidal volume (Vt), driving pressure (ΔP), and mechanical power (PowerRS) and to determine whether highly responsive patients can be identified for the purpose of predictive enrichment in ECCO2R trial design. Methods: Using data from the SUPERNOVA trial (95 patients with early moderate acute respiratory distress syndrome), the independent effects of alveolar dead space fraction (ADF), respiratory system compliance (Crs), hypoxemia (PaO2/FiO2), and device performance (higher vs lower CO2 extraction) on the magnitude of reduction in Vt, ΔP, and PowerRS permitted by ECCO2R were assessed by linear regression. Predicted and observed changes in ΔP were compared by Bland–Altman analysis. Hypothetical trials of ECCO2R, incorporating predictive enrichment and different target CO2 removal rates, were simulated in the SUPERNOVA study population. Results: Changes in Vt permitted by ECCO2R were independently associated with ADF and device performance but not PaO2/FiO2. Changes in ΔP and PowerRS were independently associated with ADF, Crs, and device performance but not PaO2/FiO2. The change in ΔP predicted from ADF and Crs was moderately correlated with observed change in ΔP (R2 0.32, p < 0.001); limits of agreement between observed and predicted changes in ΔP were ± 3.9 cmH2O. In simulated trials, restricting enrollment to patients with a larger predicted decrease in ΔP enhanced the average reduction in ΔP, increased predicted mortality benefit, and reduced sample size and screening size requirements. The increase in statistical power obtained by restricting enrollment based on predicted ΔP response varied according to device performance as specified by the target CO2 removal rate. Conclusions: The lung-protective benefits of ECCO2R increase with higher alveolar dead space fraction, lower respiratory system compliance, and higher device performance. ADF and Crs, rather than severity of hypoxemia, should be the primary factors determining whether to enroll patients in clinical trials of ECCO2R.

AB - Purpose: To describe the variability and determinants of the effect of extracorporeal CO2 removal (ECCO2R) on tidal volume (Vt), driving pressure (ΔP), and mechanical power (PowerRS) and to determine whether highly responsive patients can be identified for the purpose of predictive enrichment in ECCO2R trial design. Methods: Using data from the SUPERNOVA trial (95 patients with early moderate acute respiratory distress syndrome), the independent effects of alveolar dead space fraction (ADF), respiratory system compliance (Crs), hypoxemia (PaO2/FiO2), and device performance (higher vs lower CO2 extraction) on the magnitude of reduction in Vt, ΔP, and PowerRS permitted by ECCO2R were assessed by linear regression. Predicted and observed changes in ΔP were compared by Bland–Altman analysis. Hypothetical trials of ECCO2R, incorporating predictive enrichment and different target CO2 removal rates, were simulated in the SUPERNOVA study population. Results: Changes in Vt permitted by ECCO2R were independently associated with ADF and device performance but not PaO2/FiO2. Changes in ΔP and PowerRS were independently associated with ADF, Crs, and device performance but not PaO2/FiO2. The change in ΔP predicted from ADF and Crs was moderately correlated with observed change in ΔP (R2 0.32, p < 0.001); limits of agreement between observed and predicted changes in ΔP were ± 3.9 cmH2O. In simulated trials, restricting enrollment to patients with a larger predicted decrease in ΔP enhanced the average reduction in ΔP, increased predicted mortality benefit, and reduced sample size and screening size requirements. The increase in statistical power obtained by restricting enrollment based on predicted ΔP response varied according to device performance as specified by the target CO2 removal rate. Conclusions: The lung-protective benefits of ECCO2R increase with higher alveolar dead space fraction, lower respiratory system compliance, and higher device performance. ADF and Crs, rather than severity of hypoxemia, should be the primary factors determining whether to enroll patients in clinical trials of ECCO2R.

KW - Acute respiratory distress syndrome

KW - Artificial ventilation

KW - Extracorporeal carbon dioxide removal

KW - Predictive enrichment

KW - Ventilator-induced lung injury

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