Obstructive Sleep Apnea and Arousal Threshold in Patients With Post-traumatic Stress Disorder

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.