Respiratory and Autonomic Plasticity Following Intermittent Hypoxia

Sleep Apnea Syndromes Clinical Trial

— RAP-IH  

Official title:

Respiratory and Autonomic Plasticity Following Intermittent Hypoxia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00860743
• Other study ID #: PULM-014-08F
• Secondary ID: GRANT00507547
• Status: Completed
• Phase: Early Phase 1
• First received: March 10, 2009
• Last updated: September 29, 2017
• Start date: September 2009
• Est. completion date: September 2013

Study information

• Verified date: September 2017
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: September 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hypoxia
• Sleep Apnea Syndromes

Intervention

Drug:
• Antioxidant cocktail
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.

Locations

Country	Name	City	State
United States	John D. Dingell VA Medical Center, Detroit	Detroit	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

References & Publications (2)

Mateika JH, Syed Z. Intermittent hypoxia, respiratory plasticity and sleep apnea in humans: present knowledge and future investigations. Respir Physiol Neurobiol. 2013 Sep 15;188(3):289-300. doi: 10.1016/j.resp.2013.04.010. Epub 2013 Apr 12. Review. — View Citation

Syed Z, Lin HS, Mateika JH. The impact of arousal state, sex, and sleep apnea on the magnitude of progressive augmentation and ventilatory long-term facilitation. J Appl Physiol (1985). 2013 Jan 1;114(1):52-65. doi: 10.1152/japplphysiol.00985.2012. Epub 2 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ventilation (Aim 1)	Ventilation was measured before and after exposure to intermittent hypoxia in males and females. Ventilation was measured using a pneumotachograph, which is a flow measuring device.	Within the same experimental session
Primary	Heart Rate Variability (Aim 2)	Heart rate variability (HRV) was measured before and after exposure to intermittent hypoxia following administration of a placebo or antioxidant cocktail. Heart rate variability refers to beat-to-beat alterations in heart rate. Under resting conditions, the electrocardiogram of healthy individuals reveals periodic variation in R-R intervals. To measure HRV, R-R interval data are presented in a graph, in which the y-axis plots the R-R intervals (ms2), and the x-axis the total number of beats. Spectral analysis of the graph transforms the signal from time to frequency on the x-axis (Hz), by representing the signal as a combination of sine and cosine waves, with different amplitudes and frequencies. The approach uses Fourier transforms. The heart rate spectrum contains a high frequency (0.15-0.4 Hz) component, which is synchronous with respiration and a low frequency (0.04 to 0.15 Hz) component that appears to be mediated by both the vagus and cardiac sympathetic nerves.	Within the same experimental session