Respiratory and Autonomic Plasticity Following Intermittent Hypoxia

Respiratory and Autonomic Plasticity Following Intermittent Hypoxia

Sponsors

Lead Sponsor: VA Office of Research and Development

Source VA Office of Research and Development
Brief Summary

The prevalence of obstructive sleep apnea is high in the Veteran population. If not treated promptly, sleep apnea may result in daytime fatigue which may lead to increased prevalence of accidents while driving or in the workplace. Recent large scale epidemiological studies have shown that the prevalence of excessive daytime sleepiness increases in individuals who suffer from obstructive sleep apnea. Obstructive sleep apnea may also result in the development of hypertension and other cardiovascular disorders. Previous findings have shown that subjects with sleep apnea have a greater risk for developing coronary vascular disease compared to individuals that do not suffer from sleep apnea Thus, a significant amount of evidence suggests that sleep apnea is a major health concern in the Veteran population. Consequently, determining the mechanisms that may impact on the severity of sleep apnea and increase the prevalence of cardiovascular incidents associated with this disorder is important, as is discovering novel treatments.

Detailed Description

Approximately 8 % of the Veteran population in the United States suffers from sleep apnea. Consequences of untreated sleep apnea include increased daytime fatigue, hypertension and stroke. Thus, sleep apnea is a major health concern. One of the primary hallmarks of sleep apnea is exposure to intermittent hypoxia (IH) which occurs as a consequence of central or obstructive apneas. Exposure to IH may lead to neural plasticity (i.e. a change in system performance based on prior experience) of the respiratory and autonomic nervous system. One adaptation that has been shown to manifest itself in animals following exposure to IH is long-term facilitation (LTF) of ventilation and sympathetic nervous system activity (SNSA). This phenomenon is characterized by a gradual increase in respiratory motor activity and SNSA during successive periods of normoxia that separate hypoxic episodes and by activity that persists above baseline levels for up to 90 minutes following exposure to IH. Although LTF of minute ventilation has been well established in animals it has not been observed consistently in healthy humans or in individuals with obstructive sleep apnea. Similarly, although a few studies have shown that exposure to IH leads to increases in SNSA in healthy individuals the magnitude of the response has varied significantly. Findings from animal studies suggest that the manifestation of LTF in humans might in part be dependent on a variety of factors, including prior exposure to IH, arousal state (wake vs. sleep) and gender. Thus, the initial aim of our proposal will establish whether LTF can be induced in healthy humans and individuals with obstructive sleep apnea and whether the magnitude of the response is dependent on those factors mentioned above. Moreover, the initial aim will explore whether the presence of LTF of minute ventilation promotes or mitigates apnea severity. Animal studies have also indicated that LTF of respiratory and autonomic activity may in part be induced by increases in oxidative stress. Thus, the second objective of our proposal will explore whether administration of an antioxidant cocktail impacts respiratory and autonomic nervous system plasticity during wakefulness and sleep following IH. Likewise, the second aim will explore whether administration of an antioxidant cocktail alters apnea severity following exposure to IH. Establishing whether LTF of minute ventilation exists in individuals with sleep apnea is important since activation of this phenomenon could impact on apnea severity across the night. Similarly, LTF of SNSA activity and possibly long-term depression (LTD) of parasympathetic nervous system activity (PNSA) could ultimately lead to persistent increases in blood pressure and heart rate. Furthermore, given that exposure to IH may lead to long-term plasticity of respiratory and autonomic activity that are physiologically detrimental, exploring mechanisms that ultimately lead to treatments that may mitigate or prevent the manifestation of this phenomenon are important.

Overall Status Completed
Start Date September 2009
Completion Date September 2013
Primary Completion Date September 2013
Phase Early Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Ventilation (Aim 1) Within the same experimental session
Heart Rate Variability (Aim 2) Within the same experimental session
Enrollment 63
Condition
Intervention

Intervention Type: Drug

Intervention Name: Antioxidant cocktail

Description: 120 mg of Coenzyme Q10 (orally), 800 mg of Superoxide Dismutase (orally), 400 IU of Vitamin E (orally) before exposure to intermittent hypoxia. Two doses of 1 g of Vitamin C in 50 cc of saline IV (in the vein) before and after exposure to intermittent hypoxia.

Arm Group Label: ANTIOXIDANT COCKTAIL

Eligibility

Criteria:

Inclusion Criteria:

Characteristics of OSA subject population:

- Body mass index < 30 kg/m2.

- 20 to 40 years old.

- Newly diagnosed never-treated mild to moderate sleep apnea (i.e. 50 > apnea/hypopnea index >10 events per hour - average nocturnal oxygen saturation > 90%).

- Not pregnant.

- Free of any other known medical conditions.

- Not taking any medication.

- Non-smokers with normal lung function.

- Minimal alcohol consumption (i.e. no more than the equivalent of a glass of wine/day).

Characteristics of control group population:

- Body mass index < 30 kg/m2.

- 20 to 40 years old.

- Apnea/hypopnea index < 5 events per hour.

- Not pregnant.

- Free of any known medical conditions.

- Not taking any medication.

- Non-smokers with normal lung function.

- Minimal alcohol consumption (i.e. no more than the equivalent of a glass of wine/day).

Exclusion Criteria:

- Anything not in inclusion criteria.

Gender: All

Minimum Age: 20 Years

Maximum Age: 40 Years

Healthy Volunteers: Accepts Healthy Volunteers

Overall Official
Last Name Role Affiliation
Jason H Mateika, PhD MS BS Principal Investigator John D. Dingell VA Medical Center, Detroit
Location
Facility: John D. Dingell VA Medical Center, Detroit
Location Countries

United States

Verification Date

September 2017

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Arm 1

Type: No Intervention

Description: We plan to study 10 males and 10 females with moderate obstructive sleep apnea (OSA), and 10 healthy males and 10 healthy females. The males and the females will be matched based on age, race, sex and body mass index. The OSA and control participants will be exposed to intermittent hypoxia and "sham" intermittent hypoxia during wakefulness and sleep.

Label: ANTIOXIDANT COCKTAIL

Type: Experimental

Description: We plan to study 10 male participants with moderate obstructive sleep apnea (OSA) and 10 male control participants matched for age, race and body mass index. The OSA and control participants will be exposed to intermittent hypoxia during wakefulness and sleep following administration of an antioxidant or a placebo cocktail that will be presented in a randomized fashion.

Acronym RAP-IH
Study Design Info

Allocation: Randomized

Intervention Model: Factorial Assignment

Primary Purpose: Basic Science

Masking: Double (Participant, Investigator)

Source: ClinicalTrials.gov