Evaluation of plasma biomarkers to understand the biology and heterogeneity of treatment effect in lower tidal volume ventilation facilitated by extracorporeal CO2 removal in acute hypoxemic respiratory failure: a secondary analysis of the REST trial
Boyle, Andrew J Reddy, Kiran Conlon, John Auzinger, Georg Bannard-Smith, Jonathan Barrett, Nicholas A Camporota, Luigi Gillies, Michael A Jackson, Colette McDowell, Clíona
Boyle, Andrew J
Reddy, Kiran
Conlon, John
Auzinger, Georg
Bannard-Smith, Jonathan
Barrett, Nicholas A
Camporota, Luigi
Gillies, Michael A
Jackson, Colette
McDowell, Clíona
Affiliation
Queen's University Belfast; Royal Victoria Hospital; Cleveland Clinic London; King's College London; Manchester Royal Infirmary; University of Manchester; Guy's & St Thomas' NHS Foundation Trust; Royal Infirmary of Edinburgh; Northern Ireland Clinical Trials Unit; Imperial College London; University Hospitals Birmingham NHS Foundation Trust; University of Warwick; Aneurin Bevan University Health Board; University of Liverpool
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Publication date
2025-03-27
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Abstract
Objectives: In patients with acute hypoxemic respiratory failure (AHRF), the use of lower tidal volume ventilation facilitated by veno-venous extracorporeal CO2 removal (vv-ECCO2R) does not improve clinical outcomes. The primary objective of this analysis was to evaluate for differences in indices of systemic inflammation and ventilator-induced lung injury between patients treated with lower tidal volume ventilation facilitated by vv-ECCO2R and standard care. Secondary objectives included an evaluation for heterogeneity of treatment effect.
Design: Substudy of a randomized clinical trial.
Setting: Nine U.K. ICUs.
Patients: Moderate-to-severe AHRF (Pao2: Fio2 < 150mmHg [20ka]).
Intervention: Plasma samples obtained at baseline and day 3.
Measurements and main results: The primary outcome was day 3 C-reactive protein (CRP). Clinical outcomes included 90-day mortality and ventilator-free days (VFD) until day 28. Exploratory analyses included an evaluation of plasma indices of lung injury, inflammation, and heterogeneity of treatment effect (HTE). Seventy-nine patients were enrolled, and 69 patients had paired plasma samples taken at baseline and day 3. There was no difference in day 3 plasma CRP (intervention 138.6 [70.4, 189.4] vs. standard care 113.0 [62.7, 233.8] mg/L; p = 0.72). Between baseline and day 3, there was a greater increase in plasma interleukin-18 in patients that received intervention compared with those that received standard care (Δ 337.7 [-128.9, 738.9] vs. 6.4 [-457.2, 6.4] pg/mL p = 0.05). In patients with high interleukin-18, allocation to intervention was associated with increased VFDs (p = 0.03). Similarly in patients with a hyperinflammatory phenotype, the intervention was independently associated with increased VFDs (p < 0.01) and decreased 90-day mortality (p = 0.01).
Conclusions: In patients with moderate-to-severe AHRF, lower tidal volume ventilation, facilitated by vv-ECCO2R, was not associated with a difference in day 3 plasma CRP, but was associated with an increase in plasma interleukin-18 between baseline and day 3. Baseline plasma interleukin-18 and inflammatory phenotypes may identify subgroups of patients with moderate-to-severe AHRF that benefit from lower tidal volume ventilation facilitated by vv-ECCO2R.
Citation
Boyle AJ, Reddy K, Conlon J, Auzinger G, Bannard-Smith J, Barrett NA, Camporota L, Gillies MA, Jackson C, McDowell C, Patel B, Perkins GD, Szakmány T, Tunnicliffe W, Welters ID, McNamee JJ, McAuley DF, O'Kane CM. Evaluation of Plasma Biomarkers to Understand the Biology and Heterogeneity of Treatment Effect in Lower Tidal Volume Ventilation Facilitated by Extracorporeal CO2 Removal in Acute Hypoxemic Respiratory Failure: A Secondary Analysis of the REST Trial. Crit Care Explor. 2025 Mar 27;7(4):e1246. doi: 10.1097/CCE.0000000000001246.
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Article