Effects of Oxygen Treatment on Mechanisms Involved in Ischemia-reperfusion Injury: A Pilot Study in Healthy Volunteers

NCT02286544 | Completed Phase 1

• 2 other identifiers: DNR-2014/252-312014-002282-30
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

Oxygen treatment is widely used in acutely ill patients. In particular, oxygen treatment is routinely used in acute coronary syndrome (ACS) patients with suspected acute myocardial infarction and variably recommended in ACS-guidelines, despite very limited data supporting a beneficial effect. Immediate re-opening of the acutely occluded infarct-related bloodvessel via primary percutaneous coronary intervention (PCI) is the treatment of choice to limit ischemic injury in the setting of ST-elevation ACS (STE-ACS). However, the sudden re-initiation of blood flow achieved with primary PCI can give rise to further damage, so-called reperfusion injury. Ischemia and reperfusion associated myocardial injury (IR-injury) involves a wide range of pathological processes. Vascular leakage, activation of cell death programs, transcriptional reprogramming, no reflow phenomenon and innate and adaptive immune activation all contribute to tissue damage, thereby determining the infarct size. The effect of oxygen treatment on these pathological processes, on the extent of IR-injury and the final infarct size in STE-ACS patients has not previously been studied. ACS is characterized by a systemic inflammation with typical elevations of soluble inflammatory markers as well as changes in white blood cells. The inflammatory reaction might be considered helpful in restoring myocardial tissue structure and function, but on the other hand it might worsen IR-injury by activating various pathological processes. In human experimental studies, Salmonella typhi vaccine has been used to create a standardized model of systemic inflammation and when administered to healthy volunteers the vaccination has not been associated with any adverse events. In an ongoing register randomized multicentre clinical trial, the DETO2X (Determination of role of oxygen in suspected acute myocardial infarction) study, the effect of oxygen on morbidity and mortality in ACS patients is being investigated. In a substudy of the DETO2X-trial, the investigators have planned to evaluate the effect of oxygen treatment on IR-injury in STE-ACS as assessed by biomarkers reflecting various aspects of the pathological processes involved. The presented study is an experimental pilot study performed in healthy volunteers with a Salmonella typhi vaccine-induced inflammation with the purpose of studying effects of oxygen treatment on biological systems involved in the pathogenesis of IR- injury.

Conditions

Myocardial Infarction; Inflammation; Acute Coronary Syndrome (ACS); Reperfusion Injury

Keywords

Myocardial Infarction; Oxygen; Inflammation; Acute coronary syndrome (ACS); ST-segment elevation myocardial infarction (STEMI); Reperfusion injury (IR-injury); Biomarkers; Normoxemia; Salmonella typhi; Vaccine-induced inflammation; Soluble markers of apoptosis; Leukocyte subset distribution; Matrix metalloproteinase (MMP); Biological Markers

Outcome Measures

Primary Outcomes (1)

• Plasma concentration levels over time of biomarkers of oxidative stress, apoptosis, inflammation and platelet aggregation

  Venous blood samples will be collected at 3, 6 and 8 hours after baseline and plasmaconcentration analyzed for Interleukin (IL)-6 \[pg/mL\], CRP \[mg/L\], Isoprostane \[pg/mL\], Soluble TNF receptor 1 \[pg/mL\], Soluble TNF receptor 2 \[pg/mL\], Soluble Fas \[pg/mL\], Soluble Fas ligand (pg/mL\], MMP-2 \[ng/mL\], TIMP-2 \[ng/mL\], Soluble P-selectin \[ng/mL\], Platelet factor (PF)-4 \[ng/mL\], Beta-thromboglobulin \[ng/mL\].

  Within 8hours from baseline

Study Arms (3)

Salmonella typhi vaccine

ACTIVE COMPARATOR

0.5 mL Salmonella typhi vaccine

Biological: Salmonella typhi vaccine (Typhim Vi®)

Salmonella typhi vaccine + oxygen

EXPERIMENTAL

0.5 mL Salmonella typhi vaccine + 6l/min oxygen

Biological: Salmonella typhi vaccine (Typhim Vi®); Drug: Oxygen (Oxymask®)

S. typhi vaccine + oxygen + Atorvastatin

EXPERIMENTAL

0.5 mL Salmonella typhi vaccine + 6l/min oxygen + 80mg Atorvastatin

Biological: Salmonella typhi vaccine (Typhim Vi®); Drug: Oxygen (Oxymask®); Drug: Atorvastatin

Interventions

Salmonella typhi vaccine (Typhim Vi®) BIOLOGICAL

A peripheral venous catheter will be inserted. This catheter will be used to collect blood sample during the study day. In addition, peripheral oxygen saturation will be measured by pulse oximetry. After baseline venous blood samples have been collected, all study participants will receive 0.5 mL of the Salmonella typhi vaccine as an intramuscular injection (Typhim Vi®, Sanofi Pasteur MSD, injection solution 25 microgram/0.5 mL) Venous blood samples will be collected at 3, 6 and 8 hours after baseline. After the 8-hour blood sampling, the peripheral venous catheter will be removed and the study day ended.

S. typhi vaccine + oxygen + Atorvastatin; Salmonella typhi vaccine; Salmonella typhi vaccine + oxygen

Oxygen (Oxymask®) DRUG

As in arm 1. Half an hour after vaccination is administered, oxygen treatment will be initiated at 6 L/min via Oxymask® and continued for 6 hours. During oxygen treatment peripheral oxygen saturation will be measured by pulsoximetry. Venous blood samples will be collected at 3, 6 and 8 hours after baseline. After the 8-hour blood sampling, the peripheral venous catheter will be removed and the study day ended.

S. typhi vaccine + oxygen + Atorvastatin; Salmonella typhi vaccine + oxygen

Atorvastatin DRUG

As in arm 1. Half an hour after vaccination is administered, oxygen treatment will be initiated at 6 L/min via Oxymask® and continued for 6 hours. During oxygen treatment peripheral oxygen saturation will be measured by pulsoximetry. A single dose of Atorvastatin 80 mg will be given immediately prior to start of oxygen. Venous blood samples will be collected at 3, 6 and 8 hours after baseline. After the 8-hour blood sampling, the peripheral venous catheter will be removed and the study day ended.

Also known as: Lipitor

S. typhi vaccine + oxygen + Atorvastatin

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-40 years
• Male gender

You may not qualify if:

• Female gender
• Not willing to participate
• Not able to communicate or to understand study instructions
• Participation in another on-going trial
• Any chronic disease
• Current smokers

Sponsors & Collaborators

• Karolinska Institutet: lead
• University Hospital, Linkoeping: collaborator

Study Sites (1)

Linköping University Hospital

Linköping, 58191, Sweden

Location

Related Publications (7)

• Hofmann R, James SK, Svensson L, Witt N, Frick M, Lindahl B, Ostlund O, Ekelund U, Erlinge D, Herlitz J, Jernberg T. DETermination of the role of OXygen in suspected Acute Myocardial Infarction trial. Am Heart J. 2014 Mar;167(3):322-8. doi: 10.1016/j.ahj.2013.09.022. Epub 2013 Dec 19.

  PMID: 24576515 BACKGROUND

• Cabello JB, Burls A, Emparanza JI, Bayliss S, Quinn T. Oxygen therapy for acute myocardial infarction. Cochrane Database Syst Rev. 2013 Aug 21;(8):CD007160. doi: 10.1002/14651858.CD007160.pub3.

  PMID: 23963794 BACKGROUND

• Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007 Sep 13;357(11):1121-35. doi: 10.1056/NEJMra071667. No abstract available.

  PMID: 17855673 BACKGROUND

• Ekstrom M, Eriksson P, Tornvall P. Vaccination, a human model of inflammation, activates systemic inflammation but does not trigger proinflammatory gene expression in adipose tissue. J Intern Med. 2008 Dec;264(6):613-7. doi: 10.1111/j.1365-2796.2008.01998.x. No abstract available.

  PMID: 19017180 BACKGROUND

• Eltzschig HK, Eckle T. Ischemia and reperfusion--from mechanism to translation. Nat Med. 2011 Nov 7;17(11):1391-401. doi: 10.1038/nm.2507.

  PMID: 22064429 BACKGROUND

• Shuvy M, Atar D, Gabriel Steg P, Halvorsen S, Jolly S, Yusuf S, Lotan C. Oxygen therapy in acute coronary syndrome: are the benefits worth the risk? Eur Heart J. 2013 Jun;34(22):1630-5. doi: 10.1093/eurheartj/eht110. Epub 2013 Apr 3.

  PMID: 23554440 BACKGROUND

• Piper HM, Meuter K, Schafer C. Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg. 2003 Feb;75(2):S644-8. doi: 10.1016/s0003-4975(02)04686-6.

  PMID: 12607706 BACKGROUND

MeSH Terms

Conditions

Myocardial Infarction; Inflammation; Acute Coronary Syndrome; Reperfusion Injury; ST Elevation Myocardial Infarction

Interventions

Vi polysaccharide vaccine, typhoid; Oxygen; Atorvastatin

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Postoperative Complications

Intervention Hierarchy (Ancestors)

Chalcogens; Elements; Inorganic Chemicals; Gases; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Study Officials

• Lennart Nilsson, MD, PHD

  Department of Medical and Health Sciences, Linköping University, and Department of Cardiology, University Hospital, 58185 Linköping, Sweden

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PHD

Study Record Dates

• First Submitted: October 27, 2014
• First Posted: November 10, 2014
• Study Start: October 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: December 11, 2017

Record last verified: 2017-12

Locations

SE (1)