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

Effects of Hyperoxia Induced Pulmonary Inflammation and Organ Injury in 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.

Study Overview

• Status: Recruiting
• Conditions: Acute Lung Injury; Oxygen Toxicity; Pulmonary Injury
• Intervention / Treatment: Drug: Liquid oxygen; Drug: medical air

• Study Type: Interventional
• Enrollment (Estimated): 53
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Danny McAuley, MD; Phone Number: +442890 972144; Email: d.f.mcauley@qub.ac.uk
• Study Contact Backup: Name: Dermot Linden, PhD; Phone Number: 07812008626; Email: dlinden02@qub.ac.uk

Study Locations

• United Kingdom
  • Belfast, United Kingdom
    • Recruiting
    • Belfast Health and Social Care Trus
    • Contact: Danny McAuley, MD; Phone Number: +442890 972144; Email: d.f.mcauley@qub.ac.uk
    • Contact: Dermot Linden, PhD; Phone Number: 07812008626; Email: dlinden02@qub.ac.uk
    • Principal Investigator: Danny McAuley, MD
    • Sub-Investigator: Cecilia O'Kane, PhD
    • Sub-Investigator: Dermot Linden, PhD
    • Sub-Investigator: Joe Kidney, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Liquid medical oxygen; Liquid medical oxygen will be administered using high-flow nasal cannula delivery system.	Drug: Liquid 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.; Other Names: Liquid medical oxygen
Placebo Comparator: Synthetic medical air; Synthetic medical air will be administered using high-flow nasal cannula delivery system.	Drug: medical 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.; Other Names: Synthetic medical air

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bronchoalveolar lavage Interleukin-8 (IL-8) concentration	To determine the effects of hyperoxia on alveolar inflammatory response	6 hours post-intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bronchoalveolar lavage cytokines including but not limited to tumour necrosis factor alpha, IL-1 beta and IL-6	To determine the effects of hyperoxia on alveolar inflammatory response biomarkers	6 hours post-intervention
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	To determine the effects of hyperoxia on alveolar protease and antiprotease activity	6 hours post-intervention
Bronchoalveolar lavage white cell differential counts (total cell count, neutrophils, macrophages and lymphocytes)	To determine the effects of hyperoxia on alveolar cell populations	6 hours post-intervention
Plasma cytokines including but not limited to IL-8, tumour necrosis factor alpha, IL-1 beta and IL-6	To determine the effects of hyperoxia on plasma inflammatory response biomarkers	6 and 24 hours post-intervention
Bronchoalveolar lavage soluble programmed cell death receptor (SP-D)	To determine the effects of hyperoxia on alveolar epithelial and endothelial function	6 hours post-intervention
Bronchoalveolar lavage total protein	To determine the effects of hyperoxia on alveolar epithelial and endothelial function	6 hours post-intervention
Bronchoalveolar lavage receptor for advanced glycation end-products (RAGE)	To determine the effects of hyperoxia on alveolar epithelial and endothelial function	6 hours post-intervention
Bronchoalveolar lavage 4-hydroxy-2-nonenal (4-HNE)	To determine the effects of hyperoxia on oxidative stress	6 hours post-intervention
Bronchoalveolar lavage oxidised low density lipoprotein (oxLDL)	To determine the effects of hyperoxia on oxidative stress	6 hours post-intervention
Plasma advanced glycation end products (AGE)	To determine the effects of hyperoxia on oxidative stress	6 and 24 hours post-intervention
Plasma oxidised low density lipoprotein (oxLDL)	To determine the effects of hyperoxia on oxidative stress	6 and 24 hours post-intervention
Plasma 4-hydroxy-2-nonenal (4-HNE)	To determine the effects of hyperoxia on oxidative stress	6 and 24 hours post-intervention

Collaborators and Investigators

• Sponsor: Belfast Health and Social Care Trust
• Investigators: Principal Investigator: Danny McAuley, MD, Queen's University, Belfast

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2022
• Primary Completion (Estimated): December 30, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: May 11, 2022
• First Submitted That Met QC Criteria: June 8, 2022
• First Posted (Actual): June 10, 2022

Study Record Updates

• Last Update Posted (Actual): January 29, 2024
• Last Update Submitted That Met QC Criteria: January 26, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Signs and Symptoms, Respiratory; Thoracic Injuries; Inflammation; Pneumonia; Wounds and Injuries; Acute Lung Injury; Lung Injury; Hyperoxia
• Other Study ID Numbers: 18129MS-AS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No