A Pilot Study of Biomarkers in Obstructive Sleep Apnea

NCT ID: NCT02325687

Last Updated: 2020-04-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2016-11-30

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.

Conditions

Obstructive Sleep Apnea

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Treated OSA (CPAP-compliant)

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)

Group Type: EXPERIMENTAL

Lumbar Puncture (Standard-of-Care)

Intervention Type: PROCEDURE

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).

Untreated OSA (non-CPAP-compliant)

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)

Group Type: EXPERIMENTAL

Lumbar Puncture (Standard-of-Care)

Intervention Type: PROCEDURE

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).

Control (No suspicion of OSA)

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)

Group Type: EXPERIMENTAL

Lumbar Puncture (Standard-of-Care)

Intervention Type: PROCEDURE

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).

Interventions

Lumbar Puncture (Standard-of-Care)

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).

Intervention Type: PROCEDURE

Eligibility Criteria

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)

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 84 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospital for Special Surgery, New York

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kethy M Jules-Elysee, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital for Special Surgery, New York

Locations

Hospital for Special Surgery

New York, New York, United States

Countries

United States

References

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Reference Type: BACKGROUND

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Other Identifiers

2014-100

Identifier Type: -

Identifier Source: org_study_id