The Effect of Melatonin on Sleep and Ventilatory Control in Obstructive Sleep Apnea
Condition: Obstructive Sleep Apnea
MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive
Study type: Interventional

Summary: 
      Our hypothesis is that oxidative stress induced during repeated apneas in obstructive sleep
      apnea (OSA) patients alters the neural control of breathing which destabilizes ventilatory
      control and exacerbates OSA. Thus antioxidant treatment has the potential to reduce OSA
      severity. Melatonin is a hormone which regulates sleep patterns, but it is also a potent
      antioxidant. Melatonin production is suppressed when the eyes register light so people with
      healthy sleep exhibit a peak in blood serum levels around 2am which then decreases towards
      morning. OSA patients exhibit lower melatonin levels with a later peak around 6am which then
      extends later into the day. This abnormal pattern is thought to compound difficulty falling
      asleep and daytime mental fatigue. Therefore the potential benefits of melatonin treatment in
      OSA patients are two-fold: most importantly via its antioxidant actions melatonin may reduce
      chemoreflex sensitivity, stabilize ventilatory control and reduce OSA severity; by
      normalizing sleep phase melatonin may also allow patients to fall asleep easier and wake more
      refreshed.
    

Detailed description: 
      OSA is a common sleep disorder characterized by repeated collapse of the upper airway during
      sleep causing bouts of hypercapnia and hypoxia, typically followed by arousal,
      hyperventilation and a subsequent apnea. The resultant swings in blood gases and fragmented
      sleep have been associated with major neurocognitive and cardiovascular sequelae. Although
      the commonly cited statistics are that 4% of middle aged US men and 2% of US women have
      symptomatic OSA, these figures may be underestimates. However despite its prevalence and well
      recognized consequences, treatment of OSA remains unacceptable due to poor adherence to and
      variable efficacy of existing therapies, leading many to advocate for further research into
      underlying mechanisms to identify new therapeutic targets.

      During sleep ventilatory control is dominated by the level of CO2 and O2 in the blood.
      Arterial CO2 has the greatest influence, with increasing CO2 stimulating an increase in
      ventilatory drive and vice versa. Ventilatory drive not only determines the level of activity
      of the thoracic pump muscles, but also the upper airway dilator muscles. Consequently the
      upper airway is susceptible to collapse when CO2, and therefore neural drive to the upper
      airway muscles, is low. Loop gain is an engineering method used to measure the stability of
      the negative feedback chemoreflex control system, calculated as the ratio of the ventilatory
      response to the disturbance which elicited the response. Higher LG equals less stable
      control, as a disproportionately large ventilatory response will result in a greater degree
      of hypocapnia and subsequent reduction in ventilatory drive. Thus high LG contributes to
      propagating apneas. Supporting this is evidence that OSA patients have higher LG than non-OSA
      and LG correlates with the apnea hypopnea index (AHI). Additionally, treatments such as
      supplemental oxygen and acetazolamide which reduce LG significantly reduce AHI. However these
      treatments essentially counteract high LG, rather than treating the cause of high LG.

      LG includes "plant" (respiratory apparatus) and "controller" (chemoreflex) gain components.
      OSA patients exhibit abnormalities in chemoreflex control which increase the sensitivity to
      blood gases and thus increase controller and LG. These abnormalities normalize with
      continuous positive airway pressure (CPAP) treatment, indicating they are induced by OSA
      itself. Intermittent hypoxia, as occurs during repeated apneas, induces lasting changes in
      the neural control of breathing which induces the same abnormalities and increased controller
      gain as is seen in OSA. Therefore it is thought that the IH experienced in OSA contributes to
      worsening of OSA by inducing changes to the neural control of breathing which increase
      controller and LG. The cellular changes induced by IH are dependent on the formation of
      reactive oxygen species (ROS) and both animal and human studies have shown antioxidant
      treatment prior to IH experimentally blocks these neural changes. Thus antioxidants may be a
      suitable alternative treatment in OSA, by treating the actual cause of high LG. Indeed there
      have been two published studies showing vitamins and N-acetyl-cysteine reduced AHI in OSA
      patients.

      Melatonin is a hormone produced in the pineal gland of the brain which is most well-known for
      its critical role in regulating sleep and the circadian clock. However it is also a potent
      antioxidant which not only acts as a direct free radical scavenger, but it also stimulates
      synthesis of other antioxidants. Unlike most antioxidants it also crosses all cell membranes
      easily, allowing it to cross the blood brain barrier and also enter intracellular
      compartments such as mitochondria where ROS production is highest. Owing to the fact that
      most antioxidants become reactive species themselves once they have been oxidized, many
      antioxidants become toxic and cause disease with prolonged high doses. For this reason most
      antioxidants are unsuitable as a long-term treatment option in OSA. However melatonin does
      not have this problem because as it is oxidized it converts into multiple different
      metabolites all of which have various antioxidant functions. This adds to its efficacy as it
      neutralizes an extremely wide range of radical species. Consequently melatonin is non-toxic
      at even extremely high doses and extended use. Indeed melatonin has been found effective in
      treating multiple diseases in humans associated with ROS and oxidative stress, such as
      diabetes, chronic obstructive pulmonary disease and multiple sclerosis. Of particular
      interest is that OSA is intimately associated with metabolic disorder, with the two
      conditions having compounding negative consequences on cardiovascular disease, and melatonin
      has been shown to improve hypertension, oxidative stress and blood lipid profiles in
      metabolic disorder. For these reasons, we propose that melatonin may be a safe long term
      treatment option in OSA patients that are unable to tolerate CPAP, which may block the neural
      changes induced by IH, thereby reducing controller and LG and therefore reducing AHI.
      Additionally, melatonin treatment may have added benefits associated with preventing ROS
      induced morbidities of both OSA and metabolic disorder.

      Melatonin production is inhibited by light and normally peaks around 2am. However OSA exhibit
      much lower levels of melatonin with a lower peak at around 6am. OSA is associated with
      chronic systemic oxidative stress and endogenous levels of melatonin play a critical role in
      regulation of total antioxidant status. Therefore this abnormal pattern of melatonin
      production in OSA likely contributes to exacerbation of oxidative stress and also to sleep
      and cognitive deficits in OSA, as this would delay the circadian sleep phase, making it
      difficult for patients to fall asleep and adding to mental fatigue during the morning.
      Therefore, in addition to its antioxidant activity, melatonin treatment in OSA may have
      additional benefits via normalizing sleep phase. Thus the primary focus of this study will be
      to investigate the effects of melatonin treatment in OSA on waking chemoreflex control and
      ventilatory stability as assessed via LG and AHI during sleep, but we also intend to assess
      if there are additional sleep and cardiovascular benefits of melatonin treatment, by
      assessing melatonin blood serum phase resetting effects, sleep quality, blood pressure and
      electrocardiogram (ECG).
    

Intervention name(s): Melatonin; Placebo
Intervention type(s): Dietary Supplement; Other
Intervention MeSH terms: Melatonin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: loop gain; chemoreflex control; melatonin; antioxidant; obstructive sleep apnea; ventilatory control