A Pilot Study of Biomarkers in Obstructive Sleep Apnea

Not Applicable

Completed

Conditions: Obstructive Sleep Apnea

Interventions: Procedure: Lumbar Puncture (Standard-of-Care)

Registration Number: NCT02325687

Lead Sponsor: Hospital for Special Surgery, New York

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

Inclusion Criteria

Patients between the ages of 50 and 84
Treated and Untreated OSA Patients: Known OSA, diagnosed by polysomnography
Treated OSA Patients: Known CPAP prescription, dose used nightly, and compliance status
Controls: No suspicion for OSA, based on STOP-BANG screening score (<3)
Any patient presenting for knee replacement surgery with prior consent for spinal or combined spinal-epidural anesthesia

Exclusion Criteria

Presence of dementia
Presence of cognitive disease
Presence of depression, anxiety, or other mood disorder(s)
Recent oral steroid therapy (within prior 6 months)
Requirement of stress-dose steroids pre-operatively
Autoimmune disease
Neurologic disease
Controls: Suspected OSA, either disclosed by patient, or by clinical suspicion based on STOP-BANG questionnaire (score ≥ 3)
Chronic renal disease
Chronic liver disease
Traumatic spinal or spinal-epidural placement (i.e., blood-contaminated CSF)
Alcohol abuse - defined as being diagnosed with alcohol abuse or consuming more than 2 drinks per night, on average
Use of NSAIDs within 7 days prior to surgery
Chronic benzodiazepine use (for more than one month)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treated OSA (CPAP-compliant)	Lumbar Puncture (Standard-of-Care)	Treated OSA patients will have previously been diagnosed with OSA, and are currently CPAP-compliant. CPAP compliance is defined by daily use of a CPAP machine for at least 4 hours. We will determine if patients are CPAP-compliant by looking at their medical records and pre-operative assessments, as well as directly verifying compliance with the patient. Intervention: Lumbar Puncture (Standard-of-Care)
Untreated OSA (non-CPAP-compliant)	Lumbar Puncture (Standard-of-Care)	Patients in the untreated OSA group will have previously been diagnosed with OSA, but for some reason do not use a CPAP machine every night. We will determine if patients are CPAP-compliant by looking at their medical records and pre-operative assessments, as well as directly verifying compliance with the patient. Intervention: Lumbar Puncture (Standard-of-Care)
Control (No suspicion of OSA)	Lumbar Puncture (Standard-of-Care)	Patients in the control group will not have previously been diagnosed with OSA, and are currently not at high risk. We will determine overall risk for OSA using the STOP-BANG questionnaire. Patients with a STOP-BANG score \<3 are considered to have minimal risk for OSA and will be included in the control group. Intervention: Lumbar Puncture (Standard-of-Care)

Primary Outcome Measures

Name	Time	Method
Serum IL-6 (Interleukin 6) Levels	Intraoperatively - Pre-Incision	The primary outcome, the levels of cytokine IL-6 in serum of OSA-treated, OSA-untreated and control patients presenting for knee replacement surgery with planned spinal or combined spinal-epidural anesthesia.

Secondary Outcome Measures

Name	Time	Method
Length of Stay in the Recovery Unit	Throughout stay in the recovery unit, or an average of 1-2 days.	Levels of blood oxygen saturation throughout the length of stay in the recovery unit will be measured via arterial blood gas levels, found in the patient's electronic medical record
Serum and CSF (Cerebrospinal Fluid) Levels of the Cytokines TNF-alpha (Tumor Necrosis Factor) , IL-6, IL-8, IL-10 (Interleukin)	Intraoperatively - Pre-Incision	Biological samples were collected, but not analyzed for the presence and levels of particular cytokines (TNF-alpha, IL-6, IL-8, IL-10) and neurotrophins (BDNF(brain-derived neurotrophic factor), β-NGF (nerve growth factor)) due to the integrity of the samples.
Number of Participants With Respiratory, Cardiac, and/or CNS (Central Nervous System) Complications	Throughout hospital stay, or an average of 1 week.	We will look at the incidence of respiratory complications (hypoxia; need for respiratory intervention), cardiac complications (MI/ACS or arrhythmias) and CNS (central nervous system) complications (delirium, TIA or CVA). Parameters will be scored for presence or absence over the entire length of stay.
Serum and CSF Levels of the Neurotrophins BDNF, IFN-gamma (Interferon Gamma)	Intraoperatively - Pre-Incision	CSF (cerebrospinal fluid) was planned to be screened for the differential expression of proteins.The samples have been collected, but the assays have not been performed due to the integrity of the samples.
Incidence of Intraoperative Obstructive Respiratory Events	Throughout hospital stay, or an average of 1 week.	Incidences of intraoperative obstructive respiratory events will be collected perioperatively in the operating room by the anesthesiologist
Levels of Blood Oxygen Saturation	Throughout stay in the recovery unit, or an average of 1-2 days.	Levels of blood oxygen saturation will be measured via arterial blood gas levels. These will be drawn as standard-of-care.