A Pilot Study of Biomarkers in Obstructive Sleep Apnea
Condition: Obstructive Sleep Apnea
MeSH terms: Apnea; Sleep Apnea Syndromes; Sleep Apnea, Obstructive
Study type: Interventional

Summary: 
      Obstructive sleep apnea (OSA) is common and is a risk factor for postoperative complications,
      including respiratory and cardiac events and delirium. Despite this risk, however, there are
      currently no accepted biomarkers that can predict poor outcomes, making it unclear to see
      which patients will have complications after surgery, and who might need prolonged monitoring
      or an extended hospital stay. An improved understanding of the pathophysiology of OSA is
      required to identify potential biomarkers for outcomes after surgery, as well as to develop
      new treatments. The aim of this pilot study is to identify serum and cerebrospinal (CSF)
      biomarkers associated with obstructive sleep apnea (OSA). The presence of cytokines and
      neurotrophins will be determined and quantified in both patients with OSA and in controls.
      The CSF samples will additionally be analyzed by proteomic methods to identify potential
      biomarkers with significantly different levels present in patients with and without OSA. The
      working hypothesis is that OSA patients who are non-CPAP-compliant will have higher levels of
      circulating cytokines and lower levels of circulating neurotrophins in serum and CSF,
      compared to patients who are CPAP-compliant and/or controls.
    

Detailed description: 
      It is being increasingly understood that OSA represents an inflammatory state, with multiple
      studies showing increased levels of circulating cytokines, possibly providing the link
      between OSA and cardiovascular/pulmonary morbidity. In support of this, use of CPAP therapy
      is associated with a reduction in the levels of circulating cytokines in patients with OSA.
      Despite these data, to our knowledge, there are no studies that specifically examine the
      association between the presence of cytokines and surgical complications. The present
      investigation may be helpful for future studies looking at this relationship.Inflammation has
      recently been emphasized as a component of the CNS manifestations of OSA as well, including
      generalized cognitive deficits and post-operative delirium. It is possible that intermittent
      hypoxia leads to CNS inflammation/activation of microglia (as has been shown in in vitro
      studies), which, together with blood-brain barrier (BBB) breakdown (recently shown to be
      involved in OSA), results in elevated circulating peripheral levels of cytokines.
      Alternatively (or additionally), there could be direct peripheral activation of systemic
      macrophages as a consequence of sleep deprivation and the cortisol/stress response to this
      condition. In any event, to date, there are no studies exploring the presence or levels of
      cytokines in the CSF of patients with OSA. In addition to the release of inflammatory
      cytokines, activation of microglia causes the release of neuroprotective neurotrophins.
      Alterations in levels of several neurotrophins have been implicated in multiple CNS diseases.
      For example, in Parkinson's disease, there is a known elevation in cytokines with reduced
      circulating levels of CSF neurotrophins (BDNF and NGF) and this balance has been posited to
      underlie some of the symptoms and progression of the disease. BDNF has recently been shown to
      protect against the development of Alzheimer's disease and dementia, as well as to increase
      with caloric restriction and physical activity.

      Considering OSA is associated with obesity, it is possible that low BDNF may (at least in
      part) mediate some of the cognitive deficits seen in OSA. Additionally, low BDNF is
      associated with postoperative delirium in clinical studies. Currently, the role of
      neurotrophins in OSA remains underinvestigated. Of all the known neurotrophins, only BDNF has
      been studied in OSA patients, and the results are conflicting, with some studies suggesting
      reduced levels of serum BDNF and others showing no differences compared to control patients.
      This may in part be due to the detection methods employed or small sample sizes, and to date,
      no one has investigated CSF levels of neurotrophins in this patient population. Here we
      hypothesize that the detrimental effects of circulating cytokines in OSA may be balanced in
      some patients by beneficial effects exerted by neurotrophins, and that this differential
      balance may represent: 1) a tool for identifying which patients are at risk for
      post-operative complications in future studies, i.e., a useful biomarker for stratifying
      operative risk; 2) a new understanding of the pathophysiology of OSA; and 3) a role for
      neuroprotective strategies in the management of OSA.
    

Intervention name(s): Lumbar Puncture (Standard-of-Care)
Intervention type(s): Procedure
Intervention description(s): All study patients will have previously consented to undergo either spinal or spinal-epidural anesthesia. Patients will undergo their planned spinal or combined spinal-epidural placement in the OR. At the time of confirmation of placement of the spinal needle (positive CSF flow), 5 mL CSF will be collected and stored. CSF will be drawn using a standard 25g or 27g needle commonly used for anesthesia. The volume of CSF removed will be replaced with 4 cc local anesthetic (1.5% mepivacaine for spinal anesthesia).
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Obstructive Sleep Apnea; Arthroplasty, Replacement, Knee; Cerebrospinal Fluid; Inflammation; TNF-alpha; Interleukin-6 (IL-6); Interleukin-8 (IL-8); Interleukin-10 (IL-10); Cytokines; Neurotrophins; BDNF; Beta-NGF; Proteomic Analysis