Treatment of Sleep Apnea in Patients With Cervical Spinal Cord Injury

Patients with cervical spinal cord injury demonstrate central sleep disordered breathing
manifesting as central sleep apnea or a periodic breathing pattern. Understanding the causes
of central sleep apnea may be critically important to understanding upper airway obstruction
in susceptible individuals, given the critical role of ventilatory motor output in
maintaining upper airway patency as evidenced by upper airway narrowing or occlusion at the
nadir of ventilator drive during periodic breathing. This study is likely to identify
therapeutic strategies that could be tested in large clinical trials, with the ultimate goal
of improving quality of life among patients with cervical SCI who also experience central
sleep disordered breathing.

To this end the research proposal is aimed as follows:

Specific Aim 1: Test the hypothesis that patients with cervical SCI will demonstrate greater
magnitude of long-term facilitation (LTF) following episodic hypoxia during sleep, compared
to patients with thoracic Spinal cord injury. This aim will be accomplished by measuring the
effect of acute episodic hypoxic ventilation and upper airway mechanics in both groups.

Specific Aim 2: Test the hypothesis that dampening peripheral chemoreceptor activity in
patients with cervical SCI and central sleep disordered breathing (SDB) with supplemental
oxygen will reduce central respiratory events and decrease respiratory variability during
sleep. The aim will be accomplished by providing supplemental oxygen to participants with
cervical SCI and central SDB.

Specific Aim 3: Test the hypothesis that administration of trazodone, in patients with
cervical spinal cord injury and central SDB will decrease respiratory related arousals and
central apnea index, and the propensity to develop central apnea, compared to placebo. To
accomplish this aim, the investigators will test the acute effect of trazodone on
respiratory related arousals and central sleep apnea, and the chronic effect on central
apnea indices and the CO2 reserve.

The investigators will study subjects with SCI at T6 or above who are not on artificial
ventilation. To characterize the sleep and breathing state of each subject, polysomnography
and upper airway collapsibility will be measured at baseline. Then the following experiments
will be conducted: an episodic hypoxia protocol vs normoxia will be used to determine
whether cervical SCI will demonstrate greater magnitude of LTF. Experiments will be
conducted to see whether dampening peripheral chemoreceptor activity in cervical SCI by
giving supplemental oxygen will reduce the central respiratory events and reduce the
breathing variability during sleep. A cross over experiment will be done to see whether
administration of trazodone in patients with cervical SCI and central SDB decreases
respiratory-related arousals and central apnea. The participant will be given the
drug/placebo for one week then cross over after a 1 week wash out period to placebo.

Inclusion Criteria:

1. healthy adults between the ages of 18 - 65

2. chronic spinal cord injury patients (T6 and above), > 3 months since injury and not
on mechanical ventilation, and have not received mechanical ventilation via
tracheostomy in the past.

Exclusion Criteria:

1. subjects ≤ 17 yrs old

2. Pregnant and lactating females

3. demyelinating SCI

4. history of cardiac disease including heart failure, peripheral vascular disease or
stroke

5. history of head trauma that resulted in neurological symptoms or loss of
consciousness

6. advanced COPD, liver disease and chronic kidney disease

7. severe obstructive or parenchymal respiratory defect by PFTs

8. extreme obesity defined for this protocol as BMI >35 kg/m2 (to avoid the effect of
morbid obesity on ventilation.