Ewan C Goligher1,2,3, Alain Combes4, Daniel Brodie5,6, Niall D Ferguson7,8,9,10,11, Antonio M Pesenti12,13, V Marco Ranieri14, Arthur S Slutsky7,15. 1. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada. ewan.goligher@utoronto.ca. 2. Department of Medicine, Division of Respirology, University Health Network, Toronto, Canada. ewan.goligher@utoronto.ca. 3. Toronto General Hospital Research Institute, 585 University Ave., 11-PMB Room 192, Toronto, ON, M5G 2N2, Canada. ewan.goligher@utoronto.ca. 4. APHP Hôpital Pitié-Salpêtrière, Institut de Cardiologie, Institute of Cardio-metabolism and Nutrition, and Service de Médecine Intensive-réanimation, UMRS_1166-ICAN, INSERM, Sorbonne Université, Paris, France. 5. Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA. 6. Center for Acute Respiratory Failure, New York-Presbyterian Hospital, New York, NY, USA. 7. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada. 8. Department of Medicine, Division of Respirology, University Health Network, Toronto, Canada. 9. Toronto General Hospital Research Institute, 585 University Ave., 11-PMB Room 192, Toronto, ON, M5G 2N2, Canada. 10. Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, Canada. 11. Department of Physiology, University of Toronto, Toronto, Canada. 12. Dipartimento di Anestesia, Rianimazione ed Emergenza Urgenza, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy. 13. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy. 14. Policlinico di Sant'Orsola, Anesthesia and Intensive Care Medicine, Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-Università di Bologna, Bologna, Italy. 15. Keenan Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.
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.
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.
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