Acute Lung Injury, Oxygen Toxicity, Pulmonary Injury
Conditions
Brief summary
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.
Interventions
DRUGLiquid oxygen
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.
DRUGmedical air
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.
Sponsors
Belfast Health and Social Care Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1\. Healthy non-smoking subjects less than 45 years of age and BMI \< 29 kg/m²
Exclusion criteria
1. Age \< 18 years 2. On concomitant medications including over the counter medications excluding oral contraception and paracetamol 3. Previous adverse reactions to LPS, lignocaine or sedative agents 4. Pregnant or Breast-Feeding 5. Participation in a clinical trial of an investigational medicinal product within 30 days 6. Consent declined 7. History of asthma or other respiratory conditions 8. Smoking/ e cigarette use 9. Marijuana use or other inhaled products with or without nicotine in the last 3 months 10. Alcohol abuse, as defined by the Alcohol Use Disorders Identification Test (AUDIT) 11. Subjects with history of prior conventional cigarette (\> 100 cigarettes lifetime and smoking within 6 months) or electronic cigarette use.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bronchoalveolar lavage Interleukin-8 (IL-8) concentration | 6 hours post-intervention | To determine the effects of hyperoxia on alveolar inflammatory response |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 6 hours post-intervention | To determine the effects of hyperoxia on alveolar protease and antiprotease activity |
| Bronchoalveolar lavage white cell differential counts (total cell count, neutrophils, macrophages and lymphocytes) | 6 hours post-intervention | To determine the effects of hyperoxia on alveolar cell populations |
| Plasma cytokines including but not limited to IL-8, tumour necrosis factor alpha, IL-1 beta and IL-6 | 6 and 24 hours post-intervention | To determine the effects of hyperoxia on plasma inflammatory response biomarkers |
| Bronchoalveolar lavage soluble programmed cell death receptor (SP-D) | 6 hours post-intervention | To determine the effects of hyperoxia on alveolar epithelial and endothelial function |
| Bronchoalveolar lavage total protein | 6 hours post-intervention | To determine the effects of hyperoxia on alveolar epithelial and endothelial function |
| Bronchoalveolar lavage cytokines including but not limited to tumour necrosis factor alpha, IL-1 beta and IL-6 | 6 hours post-intervention | To determine the effects of hyperoxia on alveolar inflammatory response biomarkers |
| Bronchoalveolar lavage 4-hydroxy-2-nonenal (4-HNE) | 6 hours post-intervention | To determine the effects of hyperoxia on oxidative stress |
| Bronchoalveolar lavage oxidised low density lipoprotein (oxLDL) | 6 hours post-intervention | To determine the effects of hyperoxia on oxidative stress |
| Plasma advanced glycation end products (AGE) | 6 and 24 hours post-intervention | To determine the effects of hyperoxia on oxidative stress |
| Plasma oxidised low density lipoprotein (oxLDL) | 6 and 24 hours post-intervention | To determine the effects of hyperoxia on oxidative stress |
| Plasma 4-hydroxy-2-nonenal (4-HNE) | 6 and 24 hours post-intervention | To determine the effects of hyperoxia on oxidative stress |
| Bronchoalveolar lavage receptor for advanced glycation end-products (RAGE) | 6 hours post-intervention | To determine the effects of hyperoxia on alveolar epithelial and endothelial function |
Countries
United Kingdom
Contacts
Primary ContactDanny McAuley, MD
Backup ContactDermot Linden, PhD
Outcome results
None listed