Hyperoxia Induced Pulmonary Inflammation and Organ Injury: a Human in Vivo Model

Oxygen is the most commonly administered therapy in critical illness. Accumulating evidence suggests that patients often achieve supra-physiological levels of oxygenation in the critical care environment. Furthermore, hyperoxia related complications following cardiac arrest, myocardial infarction and stroke have also been reported. The underlying mechanisms of hyperoxia mediated injury remain poorly understood and there are currently no human in vivo studies exploring the relationship between hyperoxia and direct pulmonary injury and inflammation as well as distant organ injury. The current trial is a mechanistic study designed to evaluate the effects of prolonged administration of high-flow oxygen (hyperoxia) on pulmonary and systemic inflammation. The study is a randomised, double-blind, placebo-controlled trial of high-flow nasal oxygen therapy versus matching placebo (synthetic medical air). We will also incorporate a model of acute lung injury induced by inhaled endotoxin (LPS) in healthy human volunteers. Healthy volunteers will undergo bronchoalveolar lavage (BAL) at 6 hours post-intervention to enable measurement of pulmonary and systemic markers of inflammation, oxidative stress and cellular injury.

Liquid medical oxygen will be administered for 6 hours using high-flow nasal cannula delivery system with an Fi02 of 100% and flow rate of 60 litres per minute.

Synthetic medical air will be administered for 6 hours using high-flow nasal cannula delivery system with a flow rate of 60 litres per minute.

Bronchoalveolar lavage cytokines including but not limited to tumour necrosis factor alpha, IL-1 beta and IL-6

Bronchoalveolar lavage proteases and anti-proteases including but not limited to Matrix Metalloproteinases (MMP-2, MMP-8, MMP-9 and MMP-11), Tissue Inhibitors of Metalloproteinase (TIMPs 1-2) and neutrophil elastase

Bronchoalveolar lavage white cell differential counts (total cell count, neutrophils, macrophages and lymphocytes)

Inclusion Criteria: 1. Healthy non-smoking subjects less than 45 years of age and BMI < 29 kg/m² Exclusion Criteria: Age < 18 years On concomitant medications including over the counter medications excluding oral contraception and paracetamol Previous adverse reactions to LPS, lignocaine or sedative agents Pregnant or Breast-Feeding Participation in a clinical trial of an investigational medicinal product within 30 days Consent declined History of asthma or other respiratory conditions Smoking/ e cigarette use Marijuana use or other inhaled products with or without nicotine in the last 3 months Alcohol abuse, as defined by the Alcohol Use Disorders Identification Test (AUDIT) Subjects with history of prior conventional cigarette (> 100 cigarettes lifetime and smoking within 6 months) or electronic cigarette use.