Dushianthan Ahilanandan, Martin Daniel, Mouncey Paul, Shahid Tasnin, Lampro Lamprini, Johnson Amelia Francis, Goss Victoria, Cazley Angelica, Herbert William, Jones William, Lamond Mark, Neyroud Florence, Salmon Karen, Lentaigne Julian, Minnion Magdalena, Panchal Madhuri, Koster Grielof, Moyses Helen, Postle Anthony D, Feelisch Martin, Grocott Michael P W
General Intensive Care Unit, University Hospital Southampton, Southamnpton, Hampshire, SO16 6YD, UK.
NIHR Biomedical Research Centre, University Hospital Southampton, Southampton, Hampshire, SO16 6YD, UK.
NIHR Open Res. 2024 Jul 8;4:23. doi: 10.3310/nihropenres.13567.2. eCollection 2024.
MecROX is a mechanistic sub-study of the UK-ROX trial which was designed to evaluate the clinical and cost-effectiveness of a conservative approach to oxygen therapy for invasively ventilated adults in intensive care. This is based on the scientific rationale that excess oxygen is harmful. Epithelial cell damage with alveolar surfactant deficiency is characteristic of hyperoxic acute lung injury. Additionally, hyperoxaemia (excess blood oxygen levels) may exacerbate whole-body oxidative stress leading to cell death, autophagy, mitochondrial dysfunction, bioenergetic failure and multi-organ failure resulting in poor clinical outcomes. However, there is a lack of human models evaluating the mechanisms that underpin oxygen-induced organ damage in mechanically ventilated patients.
The aim of the MecROX mechanistic sub-study is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale to the UK-ROX trial findings. The objectives are to quantify surfactant composition, synthesis, and metabolism with markers of oxidative stress and systemic redox disequilibrium (as evidenced by alterations in the 'reactive species interactome') to differentiate between groups of conservative and usual oxygen targets.
After randomisation into the UK-ROX trial, 100 adult participants (50 in the conservative and 50 in usual care group) will be recruited at two trial sites. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3 mg/kg -D -choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been extensively used to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the surfactant synthesis and breakdown (by hydrolysis and oxidation), oxidative stress and redox disequilibrium from sequential plasma and bronchial samples using an array of analytical platforms. We will compare conservative and usual oxygenation groups according to the amount of oxygen administered. Trial registration: ISRCTNISRCTN61929838, 27/03/2023 https://doi.org/10.1186/ISRCTN61929838.
MecROX是英国ROX试验的一项机制性子研究，该试验旨在评估对重症监护中接受有创通气的成年人采用保守氧疗方法的临床效果和成本效益。这基于过量氧气有害的科学原理。高氧急性肺损伤的特征是上皮细胞损伤和肺泡表面活性物质缺乏。此外，高氧血症（血液中氧水平过高）可能会加剧全身氧化应激，导致细胞死亡、自噬、线粒体功能障碍、生物能量衰竭和多器官功能衰竭，从而导致临床预后不良。然而，缺乏评估机械通气患者中氧气诱导器官损伤潜在机制的人体模型。
MecROX机制性子研究的目的是评估肺表面活性物质组成和全身氧化还原状态，为英国ROX试验结果提供机制性和补充性科学依据。目标是用氧化应激和全身氧化还原失衡标志物（如“活性物质相互作用组”的改变所证明）量化表面活性物质组成、合成和代谢，以区分保守氧目标组和常规氧目标组。
在随机分组进入英国ROX试验后，将在两个试验地点招募100名成年参与者（保守治疗组50名，常规治疗组50名）。在输注3mg/kg -D -氯化胆碱后0、48和72小时采集血液和气管内样本。这是胆碱（维生素）的一种非放射性稳定同位素，已被广泛用于研究人体表面活性物质磷脂动力学。本研究将使用一系列分析平台，从连续的血浆和支气管样本中，对表面活性物质的合成和分解（通过水解和氧化）、氧化应激和氧化还原失衡进行机制性评估。我们将根据给予的氧气量比较保守氧疗组和常规氧疗组。试验注册：ISRCTNISRCTN61929838，2023年3月27日https://doi.org/10.1186/ISRCTN61929838 。
