Respiratory and Autonomic Plasticity Following Intermittent Hypoxia
Condition: Sleep Apnea Syndromes
MeSH terms: Sleep Apnea Syndromes; Hypoxia
Study type: Interventional
Phase: Early Phase 1

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.
    

Intervention name(s): Antioxidant cocktail
Intervention type(s): Drug
Intervention description(s): 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.
Intervention MeSH terms: Antioxidants
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: intermittent hypoxia; ventilatory long-term facilitation; autonomic nervous system plasticity