Obstructive Sleep Apnea and Arousal Threshold in Patients With Post-traumatic Stress Disorder
Obstructive Sleep Apnea and Arousal Threshold in Patients With Post-traumatic Stress Disorder
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.
Inclusion Criteria:

 -  Normal sleep study aside from elevated AHI

 -  Prior home sleep test (HST) or polysomnogram with results consistent with mild,
 moderate, or severe sleep apnea. If a sleep study has not been performed in the past,
 the participant will be offered an HST and included if OSA is confirmed on HST.

 -  PTSD as diagnosed by psychiatrist, psychologist, or other licensed mental health
 professional

 Exclusion Criteria:

 -  Any known cardiac (apart from treated hypertension), symptomatic pulmonary (including
 asthma), renal, neurologic (including epilepsy), neuromuscular, or hepatic disease.

 -  Pregnant women.

 -  History of hypersensitivity to Afrin, Lidocaine, or Trazodone

 -  History of bleeding diathesis and/or gastrointestinal bleeding.

 -  Daily use of any sedative medications that may affect sleep or breathing, including
 benzodiazepines, opioids, or hypnotics.

 -  A psychiatric disorder, other than mild depression or PTSD; e.g. schizophrenia,
 bipolar disorder, major depression, panic or anxiety disorders.

 -  Substantial cigarette (>5/day), alcohol (>3oz/day) or use of illicit drugs.

 -  More than 10 cups of beverages with caffeine (coffee, tea, soda/pop) per day.

 -  Subjects with oxyhemoglobin desaturations to <70% on the initial PSG (Aim 1) will be
 excluded from participation in Aim 2.

 -  Current, everyday use of continuous positive airway pressure therapy.