Trajectory of Neuroinflammatory Markers in Cerebrospinal Fluid Prior to and After Thoracic Aortic Surgery

Study Overview
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Brief Summary
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Observational prospective pilot study to analyze the trajectory of neuroinflammatory protein expression in cerebrospinal fluid (CSF) in relation to systemic compartment in patients undergoing thoracic aortic surgery. The aim of this study is to identify and unravel the biochemical (neuroinflammatory) pathways involved in postoperative delirium. Patient undergoing thoracic aortic surgery will have an external lumbar drain (ELD) in situ on the day before surgery. This ELD remains in place during and three days after surgery to reduce the risk on periprocedural spinal cord ischemia. Paired measurements of CSF and blood will be analyzed.

Detailed Description
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Major (cardiovascular) surgery is frequently associated with cerebral dysfunction postoperatively. Major surgical procedures account for substantial systemic inflammatory activation. Interestingly, animal models have shown that surgery rather than anaesthetics trigger a neurocognitive decline. An increase of pro-inflammatory cytokines and activation of immune cells mediate this post operative cognitive decline. There is growing support that systemic inflammation can activate the innate immune system of the brain leading to inflammation in the brain ('neuroinflammation'). This neuroinflammation is suggested to play a pivotal role in postoperative delirium and postoperative cognitive decline due to surgery-related systemic inflammation. However little evidence is available on the extend of the neuroinflammation and which biochemical pathways are dysregulated in the brain after surgery. Thoracic aortic surgery offers the unique opportunity to study the trajectory of protein expression in CSF prior to and after surgery in a non-invasive matter. It is standard of care that an external lumbar drain (ELD) is placed the day prior to surgery and this ELD will remain in place during three postoperative days. To advance the understanding of the impact of major surgery to the brain, the investigators wish to study the trajectory of protein expression prior to and after thoracic aortic surgery.

Official Title
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Trajectory of Neuroinflammatory Markers in Cerebrospinal Fluid Prior to and After Thoracic Aortic Surgery: the TURBO Study

Conditions
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Postoperative Delirium, Postoperative Cognitive Dysfunction, Thoracic Aortic Aneurysm

Intervention / Treatment
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* Diagnostic Test: Trajectory of neuroinflammatory proteins in CSF and blood


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Competent patients ≥ 18 years Patients who will undergo thoracic aortic surgery and will therefore receive an external lumbar drain as a standard of care procedure. Exclusion Criteria: Patients with meningitis/encephalitis/brain abscess within the last 6 months Patients with other neurological conditions: brain injury (acute stroke, brain trauma or cerebral haemorrhage) within the last 3 months, known brain tumours, neurodegenerative disease or known pre-existing cognitive impairment (to a degree that would be compatible with mild cognitive impairment or more). Brain or spinal surgery within the last 3 months Active infection <2 weeks before surgery Patients who object against storage of their body material for scientific reasons

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Thoracic aortic surgery patients<br> | Diagnostic Test: Trajectory of neuroinflammatory proteins in CSF and blood<br>* Kinetics of neuroinflammatory markers in CSF and blood<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trajectory of the concentration of a panel of inflammatory proteins in CSF | Changes in CSF cytokine concentrations will be determined (including IL6, IL8, IL10, MCP-1, IL1RA and CX3CL1) between timepoints described below. | 9 timepoints: Baseline (immediately before surgery); Start extracorporeal circulation; Stop extracorporeal circulation (ECC); 2 hours (h) after stop ECC; 4h after stop ECC; 6h after stop ECC; 24h after baseline; 48h after baseline; 72h after baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trajectory of the concentration of a panel of inflammatory proteins in plasma | Changes in plasma cytokine concentrations will be determined (including IL6, IL8, IL10, MCP-1, IL1RA and CX3CL1) between timepoints described below. | 9 timepoints: Baseline to 72 hours after surgery | 
| Trajectory of blood-CSF barrier disruption based on CSF/Plasma albumine ratio | CSF/Plasma albumine ratios will be measured for all timepoints where paired CSF/plasma samples are present | 9 timepoints: Baseline to 72 hours after surgery | 
| Occurence of postoperative delirium | Yes or No | 14-day incidence of delirium | 
| Trajectory of brain injury markers in CSF | Changes in brain injury markers will be determined (including NFL, S100B, GFAP, UCHL1, NSE) | 9 timepoints: Baseline to 72 hours after surgery | 
| Trajectory of brain injury markers in plasma | Changes in brain injury markers will be determined (including S100B, GFAP, UCHL1, NSE) | 9 timepoints: Baseline to 72 hours after surgery | 
| Changes in ex vivo cytokine production after whole blood stimulation | TNF-a,IL6, IL10 | 5 timepoints: Baseline to 48 hours after surgery | 
| Changes in mHLA-DR expression | monocytic HLA-DR expression assessed by flowcytometry | 5 timepoints: Baseline to 48 hours after surgery |