The Neuro-epigenetics Biomarkers of Postoperative Delirium in Elderly Patients Undergoing Hip/Knee Replacement

Study Overview
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Brief Summary
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Introduction: Postoperative delirium (POD), an acute, transient, fluctuating disturbance in attention, cognition, and level of consciousness, is a common (15-53%) postoperative complication, and it is associated with longer hospital stays, worse functional outcomes, higher healthcare costs, and increased mortality. However, at the current time, effective prevention and treatment are not only hampered by lack of knowledge about the neuropathogenesis of POD but also by a lack of biomarkers that could predict individual risk and assess diagnosis and severity of POD. Recent studies have focused on inflammatory markers (IL-1, IL-6, IL-8, IL-10, CRP), Alzheimer's disease-related factors (Tau, Aβ40/42), and nerve injury factors (S100β, NSE), but failed to establishing causality between these markers and POD. Furthermore, these results were contradictory. Previous study of the investigators found that the dysregulation of preoperative microRNA (miR)-146a and miR-181c in cerebrospinal fluid (CSF) and serum was associated with the development and severity of POD. Therefore, the investigators hypothesized these neurimmiRs and other neuro-epigenetics biomarkers might participate in the neuropathogenesis of POD. Purpose: Aims to search for neuro-epigenetics biomarkers to predict and diagnose POD.

Detailed Description
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Method: Study design: This study is a prospective investigation that searches for neuro-epigenetics biomarkers to predict and diagnose POD. Inclusion criteria / Exclusion Criteria Inclusion criteria: Eligible patients were at least 65 years old and were scheduled to have hip/knee replacement. Exclusion Criteria: a past medical history of neurological or clinically evident neurovascular disease (e.g., Alzheimer's disease, other forms of dementia, stroke); Patients diagnosed with malignant or benign tumors; Mini-Mental State Examination (MMSE) scores of 26 or less; American Society of Anesthesiologists (ASA) score [a global score that assesses the physical status of patients before surgery, ranging from 1 (normal health) to 5 (moribund)] greater than 3; a history of alcohol abuse and drug dependence; inability to read or severe visual or auditory deficits; unwillingness to comply with the protocol or procedures.

Official Title
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The Neuro-epigenetics Biomarkers of Postoperative Delirium in Elderly Patients Undergoing Hip/Knee Replacement

Conditions
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Postoperative Delirium

Intervention / Treatment
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* Procedure: hip/knee replacement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eligible patients were at least 65 years old and were scheduled to have hip/knee replacement. Exclusion Criteria: a past medical history of neurological or clinically evident neurovascular disease (e.g., Alzheimer's disease, other forms of dementia, stroke); patients diagnosed with malignant or benign tumors; Mini-Mental State Examination (MMSE) scores of 26 or less; American Society of Anesthesiologists (ASA) score greater than 3; a history of alcohol abuse and drug dependence; inability to read or severe visual or auditory deficits; unwillingness to comply with the protocol or procedures.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 100 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 |
| --- | --- |
| Delirium group<br>Group of patients with postoperative delirium | Procedure: hip/knee replacement<br>* hip/knee replacement<br>|
| Non delirium group<br>Group of patients without postoperative delirium | Procedure: hip/knee replacement<br>* hip/knee replacement<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cell-free DNA, cell-free RNA and exosomal RNA level in blood and urine | Cell-free DNA, cell-free RNA and exosomal RNA level in blood and urine of the participants were measured by DNA sequencing or RNA sequencing before surgery. | just before surgery | 
| genome-specific difference between POD and non-POD patients | Compare the exon sequence in blood samples of the participants, as assessed by whole exome sequencing. | just before surgery | 
| candidate cell-free DNA, cell-free RNA and exosomal RNA level in blood and urine | Candidate cell-free DNA, cell-free RNA and exosomal RNA identified in the first outcome were quantified by PCR or RT-PCR on post operative day 1. | post operative day 1 | 
| candidate cell-free DNA, cell-free RNA and exosomal RNA level in blood and urine | Candidate cell-free DNA, cell-free RNA and exosomal RNA were quantified by PCR or RT-PCR on post operative day 3. | post operative day 3 | 
| candidate cell-free DNA, cell-free RNA and exosomal RNA level in blood and urine | Candidate cell-free DNA, cell-free RNA and exosomal RNA were quantified by PCR or RT-PCR on post operative day 7 or the day after delirium disappeared. | post operative day 7 or the day after delirium disappeared | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delirium assessment - 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) | positive or negative | before surgery (from 1 week before to the day before) | 
| Delirium assessment - 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) | positive or negative | post operative day 1 | 
| Delirium severity assessment - Delirium Severity based on 3D-CAM (3D-CAM-S) | ranging from 0 to 7 points | post operative day 1 | 
| Delirium subtype assessment - Richmond Agitation-Sedation Scale (RASS) | ranging from -5 to +4 points | post operative day 1 | 
| Delirium assessment - 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) | positive or negative | post operative day 3 | 
| Delirium severity assessment - Delirium Severity based on 3D-CAM (3D-CAM-S) | ranging from 0 to 7 points | post operative day 3 | 
| Delirium subtype assessment - Richmond Agitation-Sedation Scale (RASS) | ranging from -5 to +4 points | post operative day 3 | 
| Delirium assessment - 3-minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) | positive or negative | post operative day 7 or the day after delirium disappeared | 
| Delirium severity assessment - Delirium Severity based on 3D-CAM (3D-CAM-S) | ranging from 0 to 7 points | post operative day 7 or the day after delirium disappeared | 
| Delirium subtype assessment - Richmond Agitation-Sedation Scale (RASS) | ranging from -5 to +4 points | post operative day 7 or the day after delirium disappeared |