# Oxidative stress, redox status and surfactant metabolism in mechanically ventilated patients receiving different approaches to oxygen therapy (MecROX): An observational study protocol for mechanistic evaluation

## TL;DR

This study investigates how excess oxygen affects lung surfactant and oxidative stress in ICU patients on ventilators to understand the mechanisms of oxygen-induced harm.

## Contribution

The study introduces a novel mechanistic evaluation of surfactant metabolism and redox status in mechanically ventilated patients receiving different oxygen therapies.

## Key findings

- Excess oxygen may damage surfactant-producing cells and increase surfactant breakdown.
- Oxidative stress from high oxygen levels could lead to systemic cell damage and organ failure.
- The study will compare surfactant and redox markers between conservative and usual oxygen therapy groups.

## Abstract

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
in-vivo 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
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.

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
methyl-D
9-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
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 according to the amount of oxygen administered.

Trial registration: ISRCTN

ISRCTN61929838, 27/03/2023
https://doi.org/10.1186/ISRCTN61929838.

Although oxygen is necessary, excess oxygen can be harmful especially to those requiring artificial ventilation. 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). The UK-ROX trial will not be able to assess how exactly 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 the lungs. Usually, lungs are kept open by a detergent-like material within them called "surfactant" so they can function properly. Too much oxygen can kill the cells that make surfactant or increase the breakdown of surfactant. Too much oxygen can also cause powerful chemical reactions (called oxidative stress) that can damage cells all around the body, causing organs to malfunction and worsen the patient’s condition.

One hundred patients from the UK-ROX trial will be recruited to determine whether surfactant and oxidative stress play a role in oxygen-induced lung damage. We will take blood and lung fluid samples from these participants three times during the study. Patients on a breathing machine will usually receive sedation as part of their treatment, so they are unlikely to be able to consent to participate in the study. 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 for their consent at the earliest opportunity when they regain consciousness.  Patient and public members helped design this study. 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.