Inflammatory Mediators in Obstructive Sleep Apnoea Syndrome; Mechanisms of Production and the Effect of Long Term Antioxidants Administration

Obstructive Sleep Apnea Syndrome (OSAS) is associated with elevated plasma levels of IL-6 and TNF-α, which cannot be accounted for by obesity (Vgontzas et al Sleep Med Rev 2005;9:211-24, Ciftci et al Cytokine 2004;28:87-91].

Obstructive apneas-hypopneas are accompanied by strenuous diaphragmatic contractions before the ensuing arousals and re-establishment of airway patency. We have shown that strenuous diaphragmatic contractions induced by resistive loading lead to elevated plasma levels of IL-6, TNF-α, and IL-1β (Vassi-lakopoulos et al AJRCCM 2002;166:1572-8) with concomitant up-regulation of the cytokines within the diaphragmatic myofibers (Vassilakopoulos et al AJRCCM 2004;170:154-61).

OSAS patients exhibit frequent episodes of hypoxemia during the night. Loaded breathing is a form exercise for the respiratory muscles, and both acute and chronic hypoxia lead to an augmented plasma IL-6 response to exercise compared to normoxia (Lundby et al Eur J Appl Physiol 2004;91:88-93).

In OSAS, monocytes have oxidative stress (Dyugovskaya et al AJRCCM 2002;165:934-9) and produce more cytokines (TNF-α) in vitro (Minoguchi et al Chest 204;126:1473-9).

Hypothesis #1: plasma levels of IL-6 and TNF-α are increased during the night in OSAS patients secondary to the intermittent strenuous diaphragmatic contractions and the episodes of hypoxia-reoxygenation associated with the obstructive apneas-hypopneas.

Hypothesis #2: monocytes from sleep apnea patients, exhibit augmented intracellular expression of IL-6 and TNF-α during the night.

Hypothesis #3: Oxidative stress is a stimulus for cytokine upregulation in OSAS.

Study Overview

• Status: Unknown
• Conditions: Obstructive Sleep Apnea Syndrome
• Intervention / Treatment: Device: n-CPAP; Device: Oxygen supplementation; Drug: Vitamin A, Vitamin C, Vitamin E, Allopurinol, N-Acetylcysteine

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Greece
  • Attiki
    • Athens, Attiki, Greece
      • Recruiting
      • Department of Critical Care Evangelismos General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Obstructive Sleep Apnea Syndrome diagnosis

Exclusion Criteria:

• narcolepsy or idiopathic hypersomnia
• chronic obstructive disease,
• neuromuscular or endocrinological disease,
• autoimmune systemic disease,
• psychological disorders,
• use of non steroids antinflammatory drugs,
• use of cortisone drugs,
• recent or concomitant systemic infections
• upper or lower airway infections

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OSAS patients; This arm includes the OSAS diagnosed cohort that has been planned to undergo four polysomnographic studies. One standard, one with oxygen supplementation, one with n-CPAP device and one post antioxidants administration	Device: n-CPAP; administration of continuous positive airway pressure through a nasal device; Device: Oxygen supplementation; Oxygen supplementation (3L) through nasal spectacles; Drug: Vitamin A, Vitamin C, Vitamin E, Allopurinol, N-Acetylcysteine; Vitamin A 50,000 IU, Vitamin C 1000 mg , Vitamin E 200 mg, Allopurinol 600 mg, N-Acetylcysteine 2 g. Duration is set for 60 days
No Intervention: Control Group; This group is scheduled to undergo a plain polysomnographic study, whilst plasma cytokine levels will be measured. It will comprise of healthy, non-OSAS volunteers.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IL-6 Area under the curve	The primary outcome measure ( IL-6 Area under the curve) is evaluated at the end of each polysonographic study. We anticipate each subject to have completed all three sudies within one month and receive the antioxidant supplementation for an additional 60 day period. In total three months	three months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TNF-a area under the curve	The secondary outcome measure ( TNF-a Area under the curve) is evaluated at the end of each polysonographic study. we anticipate each subject to have completed all three sudies within one month and receive the antioxidant supplementation for an additional 60 day period. In total three months	three months

Collaborators and Investigators

• Sponsor: University of Athens
• Investigators: Principal Investigator: Theodoros Vassilakopoulos, MD, PhD, Associate Professor in Critical Care, University of Athens

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Anticipated): October 1, 2010
• Study Completion (Anticipated): October 1, 2010

Study Registration Dates

• First Submitted: August 20, 2010
• First Submitted That Met QC Criteria: August 24, 2010
• First Posted (Estimate): August 25, 2010

Study Record Updates

• Last Update Posted (Estimate): August 25, 2010
• Last Update Submitted That Met QC Criteria: August 24, 2010
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Keywords: Antioxidants; Oxidative Stress; IL6; OSAS; Sleep Apnoea; TNFα
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Disease; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Syndrome; Apnea; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Micronutrients; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Gout Suppressants; Expectorants; Vitamin E; Vitamins; Acetylcysteine; N-monoacetylcystine; Allopurinol; Vitamin A
• Other Study ID Numbers: 439