Effects of hyperoxia on pulmonary inflammation and organ injury in a human in vivo model (HIPI): a randomised controlled trial

Abstract

Introduction It is uncertain whether hyperoxia contributes to adverse intensive care unit outcomes. Potential harm is likely mediated by oxidative stress driving pulmonary and systemic inflammation. Methods We conducted a randomised, double-blind, placebo-controlled trial to test the hypothesis that hyperoxia modifies pulmonary and systemic inflammation following inhaled lipopolysaccharide (LPS) challenge. Healthy adult volunteers were randomised (1:1) to receive hyperoxia administered via high-flow nasal oxygen (FiO 2 1.0, 60 L/min) or synthetic medical air for 6 hours. Bronchoalveolar lavage (BAL) was performed at 6 hours following inhalation of 50 µg of LPS. Blood was collected at baseline, 6 hours and 24 hours. The primary outcome was BAL interleukin-8 (IL-8). Secondary outcome measures included markers of pulmonary and systemic inflammation. Untargeted metabolomic and lipidomic profiling of BAL fluid and plasma was performed by liquid chromatography–mass spectrometry to investigate oxidative stress. Transcriptomic analysis was also performed on whole blood. Results Between January 2023 and March 2024, twenty-two participants were recruited and completed all study procedures. BAL IL-8 did not differ between groups at 6 hours (hyperoxia 375.7 pg/mL (IQR 351.1–467.7) vs placebo 331.9 pg/mL (IQR 251.6–459), p=0.33). No between-group differences were observed in BAL cytokines or markers of systemic inflammation. Hyperoxia was associated with an approximately fourfold increase in BAL reduced glutathione (unadjusted p=0.02). Hyperoxia was associated with distinct transcriptional responses at 24 hours with 175 differentially expressed genes (padj <0.05), including upregulation of genes related to extracellular matrix remodelling, platelet activation and endothelial repair. Discussion In a human inhaled LPS challenge model, 6 hours of hyperoxia did not increase markers of pulmonary or systemic inflammation. Trial registration number NCT05414370 .