Sleep Apnea, Obstructive; Post-Traumatic Stress Disorders Clinical Trial
Official title:
Obstructive Sleep Apnea and Arousal Threshold in Patients With Post-traumatic
Obstructive sleep apnea (OSA) has traditionally been attributed only to a collapsible upper airway. However, it is increasingly recognized that multiple additional non-anatomical mechanisms contribute to the disease. Higher rates of OSA in patients with post-traumatic stress disorder (PTSD) than in those without PTSD have been reported however the mechanism behind this increased prevalence has not been investigated. Our hypothesis is that patients with PTSD have a predisposition to OSA due to a lower respiratory arousal threshold (wake up too easily) than patients without PTSD. The goal of this project will be to study and compare the ArTH in patients with PTSD and those without. In addition, we plan to see whether medications can be used to increase the arousal threshold and treat OSA in patients with PTSD.
Obstructive sleep apnea (OSA) is a clinically relevant disease that is associated with
cardiovascular, metabolic, and neurocognitive consequences. OSA is a very common disease; the
Wisconsin Sleep Cohort Study found that OSA affects 2% of women and 4% of men aged 30-60.
However, these data predate the obesity epidemic and use of more modern diagnostic equipment,
such that more recent studies have reported prevalences of moderate to severe OSA as high as
24% in women and 49% in men.
The prevalence of OSA has been found to be particularly high in patients suffering from
post-traumatic stress disorder (PTSD). One study of veterans with combat related PTSD found
that 67.3% of this population was diagnosed with OSA after undergoing polysomnography. This
finding is consistent with those of Mysliwiec et al who found rates of OSA in 63% of
post-deployment soldiers and 51% of active duty soldiers. Despite increased recognition of
this association, there has been little progress in establishing a pathophysiological link
between the two diseases, and no study to our knowledge examining the possibility that PTSD
might drive the development of OSA. Furthermore, individuals with PTSD have been found to
have significantly lower compliance with continuous positive airway pressure (CPAP) therapy
than the general population, with claustrophobia, mask discomfort, and air hunger as the most
commonly cited reasons for non-adherence. Despite this, studies have shown both benefit in
sleep quality and PTSD related nightmares with OSA treatment. Alternative OSA therapies are
therefore particularly important in this group, but will rely on determination of targets
other than those treated by CPAP.
While a propensity towards upper airway collapse, as seen in obesity, has classically been
considered the principle determinate of OSA pathogenesis, more recent work has shown that
non-anatomical variables including the ventilatory arousal threshold (ArTH) are also
important. During wakefulness pharyngeal dilator muscles remain active to maintain airway
patency however during sleep these muscles lose activity in all individuals but in those with
OSA airway collapse occurs and results hypoxia and hypercapnia. Both accumulation of carbon
dioxide and increased negative pressure can cause recruitment of the upper airway dilator
muscles resulting in pharyngeal patency if sleep is maintained. Cortical arousal during apnea
for most individuals represents a protective mechanism as the airway is restored with
resolution of hypoxia and hypercarbia. However individuals with low ArTH (individuals who
wake easily) do not have sufficient time for accumulation of respiratory stimuli, recruitment
of pharyngeal muscles is then unable to occur which results in disruption of sleep. ArTH is
variable amongst individuals and is dependent on the magnitude of negative intrathoracic
pressure tolerated before awakening occurs and is independent from other factors.
A central feature of PTSD is a state of persistent hyperarousal that chronically persists
following a traumatic event. Individuals with PTSD have been found to have important
physiologic changes of the hypothalamic-pituitary axis (HPA) and sympathoadrenal system
including increased levels of sympathetic neurotransmitters such as norepinephrine and
increased activity of α2-adrenergic and glucocortocoid receptors. Both the HPA and
sympathetic nervous system are associated with attention and arousal. Prolonged activation of
these systems has been shown to induce important biochemical changes associated with
disordered sleep. Indeed, studies in norepinephrine deficient knockout mice have demonstrated
that increased stimulus is required to induce cortical arousal in the norepinephrine
deficient mice and results in higher acoustic ArTH when compared to controls. Our hypothesis
is that patients suffering from PTSD will have a lower ArTH when compared to subjects without
PTSD. This work is significant because if lower ArTH is associated with PTSD these patients
may benefit from therapies that raise the ArTH.
Prior studies have indicated that trazodone, a serotonin reuptake inhibitor commonly used for
insomnia and occasionally for depression, may raise the arousal threshold without suppressing
upper airway muscle activity. This medication therefore presents a potentially attractive
alternative treatment to CPAP therapy for patients with OSA related to a low arousal
threshold.
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