Title: Oxidative stress, redox status and surfactant metabolism in mechanically ventilated patients receiving different approaches to oxygen therapy.
Funder: Medical Research Council

Abstract: Aims: Intensive Care Patients (ICU) are often given oxygen via artificial ventilation through a breathing machine. Giving too much oxygen is harmful and can damage the lungs. We want to improve outcomes for patients by understanding how excess oxygen causes lung damage. In this study, we aim to determine whether using a lower oxygen target in patients on a breathing machine reduces lung damage. Background: Although oxygen is necessary, excess oxygen can be harmful especially to those requiring artificial ventilation. Usually, lungs are kept open by a detergent-like material in the lungs called "surfactant" so they can work properly. However, too much oxygen can kill the cells that make surfactant or increase surfactant breakdown. This can cause the lung to become damaged and fill with fluid instead of air, causing unnecessary harm. Too much oxygen can also cause powerful chemical reactions (called oxidative stress) that can damage cells around the body, causing major organs to fail. This can lead to the worsening of a patient's condition. Design and method used: A national research study (UK-ROX) is looking to find out whether giving less oxygen to patients in ICU will improve their survival compared to standard care (more oxygen). UK-ROX trial will not be able to assess how exactly the excess oxygen may cause harm. Therefore, this study will run in parallel with UK-ROX to look in more detail at how excess oxygen might affect lungs. We intend to recruit 100 patients from the UK-ROX trial and conduct this detailed sub-study to determine whether surfactant and oxidative stress play a role in excess oxygen induced lung damage. Half of the participants will be recruited from the low oxygen group of UK-ROX and the other half from the standard oxygen group. We will take blood and lung fluid samples from these participants three times during the study. We will take blood from a small catheter already in place as part of their standard ICU treatment. Lung fluid samples will be taken through a small suction tube attached to the breathing tube already in their windpipe. Patients on a breathing machine will usually receive sedation as part of their treatment, so they are unlikely to be able to consent. So, we will approach a nominated person (usually their next of kin) for their opinion on whether they think the patient would want to participate. We will ask patients at the earliest opportunity when they regain consciousness. Patient and public involvement: Patient and public members helped design the UK-ROX trial and this study. These people will actively participate in the oversight of the study, contribute to the production of patient documents, and help dissemination of study findings to the public. How will this research help? The results will help us decide how much oxygen we should give patients on a breathing machine and details of how excess oxygen can damage the lungs. It will also provide essential information to design future studies and treatments to reduce harm from too much oxygen. Possible future treatments may include changes to the amount of oxygen given, medications such as surfactants, antioxidants, or diet (to reduce oxidative stress). Dissemination: Results will be disseminated through media, health charities, publications, and scientific conferences. We will provide evidence for any oxygen-related guidelines for doctors and nurses to provide the best possible care for ICU patients needing oxygen therapy.

Lay abstract: Research question: Does conservative oxygen therapy given during critical illness prevent surfactant deficiency and/or reduce alveolar and systemic oxidative stress? Background: UK-ROX is an NIHR HTA funded multi-centre randomised control trial evaluating the clinical and cost-effectiveness of conservative oxygen therapy (oxygen saturation of 90?2%) versus usual oxygen therapy (defined as local practice by the treating clinicians) in 16,500 mechanically ventilated (MV) patients in intensive care. The UK-ROX trial hypothesis is that exposure to lower concentrations of oxygen in MV patients will be a cost-effective approach to reducing mortality. 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. Hyperoxaemia may also 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 in-vivo human models evaluating the mechanisms that underpin oxygen-induced organ damage in MV patients. Aims and objectives: The aim of this mechanistic study (Mec-ROX) is to assess lung surfactant composition and global systemic redox status to provide a mechanistic and complementary scientific rationale for the UK-ROX study findings from the chosen intervention. The objectives are to quantify in-vivo 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. Methods and justification of study design: After randomisation into the UK-ROX trial, 100 participants with hypoxaemic respiratory failure (50 in the conservative and 50 in usual group) will be recruited from two NHS intensive care units. Blood and endotracheal samples will be taken at 0, 48 and 72 hours following an infusion of 3mg/kg methyl-D9-choline chloride. This is a non-radioactive, stable isotope of choline (vitamin), which has been used extensively to study surfactant phospholipid kinetics in humans. This study will mechanistically evaluate the in-vivo 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 and according to the amount of oxygen administered. Timelines for delivery: The study duration is 30 months. Recruitment: November 2022 for 18 months. The laboratory analysis, follow-up data collection, data analysis and manuscript preparation will be completed over the 12 months from May 2024 to April 2025. Anticipated impact and dissemination: These mechanistic study results provide the much-needed scientific data that underpins hyperoxic lung injury in MV critically ill patients. The linkage between pathophysiology and clinical outcomes will enable refinement of future interventions. The outputs will include conference and national society meeting presentations, publications in peer-reviewed journals, and broadcast in the academic/public media, websites, and press. Relevant findings will be communicated promptly to patient and public groups, policymakers,’ stakeholders and regulatory bodies.

Research activity codes: 5.7 PHYSICAL
Health categories: RESPIRATORY