Discovery for Biomarkers and Risk Factors for Postoperative Delirium in Elderly Patients With Spine Surgery

Introduction: With the increase of the elderly population, the number of elderly patients undergoing surgery is increasing, and postoperative delirium is 11-51% depending on the type of surgery. In recent cohort studies have shown that delirium might reduce cognitive function and develop dementia.

Since delirium is difficult to treat, the key to treatment is prevention, and about 40% is prevented when prophylactic intervention is applied. However, delirium is difficult to diagnose and difficult to predict, therefore, biomarkers are needed to diagnose and prevention.

Exosome and brain efficiency test(electroencephalogram, and pulse wave test) have the potential of simple biomarkers that can diagnose postoperative delirium and predict cognitive decline.

Purpose: The purpose of this study is to investigate the risk factors affecting delirium in the elderly who have spinal surgery and to search for biomarkers of delirium for early detection and prevention of delirium.

Study Overview

• Status: Recruiting
• Conditions: Spinal Disease
• Intervention / Treatment: Procedure: Spine surgery

Detailed Description

Method:

1. Study design: This study is a prospective investigation that identifies risk factors for postoperative delirium and searches for predictive biomarkers of delirium.

2. Inclusion criteria / Exclusion Criteria

   1. Inclusion criteria

      • Elderly patients over 70
      • Eligible Surgeries: lumbar spine fusion surgery, posterior cervical spine fusion surgery, or anterior cervical spine fusion surgery

   2. Exclusion Criteria

      • Patients with cognitive decline according to MMSE-DS outcome criterion
      • Patients diagnosed with malignant or benign tumors
      • If surgery is scheduled within 2 hours(micro surgery)
      • In case of difficulty in communication
      • History of brain neurological diseases (brain hemorrhage, stroke, dementia, Parkinson's, cognitive impairment diagnosis, etc.)
      • Patients diagnosed with alcoholism or drug addiction
      • Patients with surgical complications (post-operative bleeding, high fever over 39 degrees, etc.)
      • Patients undergoing re-operation due to surgery-related complications

3. Outcome

   1. Primary outcome: Urinary and Blood exosome, stool
   2. Secondary outcome: brain function test(electroencephalogram, pulse wave test, and cognitive test)

4. Measurement

   1. Delirium: Confusion Assessment Method(CAM), Korean-Delirium Rating Scale-R-98(K-DRS-R-98), Korean Nusing Delirium Scale(Nu-DESC)
   2. Cognitive function test: Mini-Mental State Examination-Dementia Screening(MMSE-DS), Montreal Cognitive Assessment(MoCA), Telephone interview for Cognitive Status(TICS)
   3. Depression: Geriatric Depression Scale Short Form Version (GDSSF-K)
   4. Activity Daily of Living: K-ADL, K-IADL
   5. Frail: Korean version of the FRAIL scale
   6. Nutrition: Mini Nutritional Assessment-Short Form
   7. patient-reported outcomes ; PROMIS-29

• Study Type: Observational
• Enrollment (Anticipated): 600

Contacts and Locations

• Study Contact: Name: Bon-Nyeo Koo, MD, PhD; Phone Number: 82-2-2228-2422; Email: koobn@yuhs.ac

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Recruiting
    • Severance Hospital, Yonsei University Health System
    • Contact: Bon-Nyeo Koo, MD, PhD; Phone Number: 82-2-2228-2422; Email: koobn@yuhs.ac

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years to 100 years (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Tertiary hospital, single institution

Description

Inclusion Criteria:

1. Elderly patients over 70
2. Eligible Surgeries: lumbar spine fusion surgery, posterior cervical spine fusion surgery, or anterior cervical spine fusion surgery

Exclusion Criteria:

1. Patients with cognitive decline according to MMSE-DS outcome criterion
2. Patients diagnosed with malignant or benign tumors
3. If surgery is scheduled within 2 hours(micro surgery)
4. In case of difficulty in communication
5. History of brain neurological diseases (brain hemorrhage, stroke, dementia, Parkinson's, cognitive impairment diagnosis, etc.)
6. Patients diagnosed with alcoholism or drug addiction
7. Patients with surgical complications (post-operative bleeding, high fever over 39 degrees, etc.)
8. Patients undergoing re-operation due to surgery-related complications

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Delirium group; Group of patients with postoperative delirium	Procedure: Spine surgery; Eligible Surgeries: lumbar spine fusion surgery, posterior cervical spine fusion surgery, or anterior cervical spine fusion surgery
Non delirium group; Group of patients without postoperative delirium	Procedure: Spine surgery; Eligible Surgeries: lumbar spine fusion surgery, posterior cervical spine fusion surgery, or anterior cervical spine fusion surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exosomes in Urine: Differences in Gene Expression	- Gene expression and expression comparison in exosomes The gene expression difference is determined using the SAM tool and DEseq2, and the Gene Ontology (GO) Database (www.geneontology.org) and the KEGG database (www.genome.jp/kegg) are used to find the correlation between gene functions. In the case of miRNA, there will be a regulatory function of the coding gene, so for this purpose, an integrative analysis is performed to identify the mRNA-miRNA interaction	Just before surgery
Exosomes in Urine: Differences in Gene Expression	- Gene expression and expression comparison in exosomes The gene expression difference is determined using the SAM tool and DEseq2, and the Gene Ontology (GO) Database (www.geneontology.org) and the KEGG database (www.genome.jp/kegg) are used to find the correlation between gene functions. In the case of miRNA, there will be a regulatory function of the coding gene, so for this purpose, an integrative analysis is performed to identify the mRNA-miRNA interaction	just before end of surgery
Exosomes in Urine: Differences in Gene Expression	- Gene expression and expression comparison in exosomes The gene expression difference is determined using the SAM tool and DEseq2, and the Gene Ontology (GO) Database (www.geneontology.org) and the KEGG database (www.genome.jp/kegg) are used to find the correlation between gene functions. In the case of miRNA, there will be a regulatory function of the coding gene, so for this purpose, an integrative analysis is performed to identify the mRNA-miRNA interaction	Post operative day 1 (6 AM)
Exosomes in Urine: Differences in Gene Expression	- Gene expression and expression comparison in exosomes The gene expression difference is determined using the SAM tool and DEseq2, and the Gene Ontology (GO) Database (www.geneontology.org) and the KEGG database (www.genome.jp/kegg) are used to find the correlation between gene functions. In the case of miRNA, there will be a regulatory function of the coding gene, so for this purpose, an integrative analysis is performed to identify the mRNA-miRNA interaction	Post operative day 1 (6 PM)
Exosomes in Urine: Differences in Gene Expression	- Gene expression and expression comparison in exosomes The gene expression difference is determined using the SAM tool and DEseq2, and the Gene Ontology (GO) Database (www.geneontology.org) and the KEGG database (www.genome.jp/kegg) are used to find the correlation between gene functions. In the case of miRNA, there will be a regulatory function of the coding gene, so for this purpose, an integrative analysis is performed to identify the mRNA-miRNA interaction	immediately after onset of delirium
Exosomes in Urine: Differences in Gene Expression	- Gene expression and expression comparison in exosomes The gene expression difference is determined using the SAM tool and DEseq2, and the Gene Ontology (GO) Database (www.geneontology.org) and the KEGG database (www.genome.jp/kegg) are used to find the correlation between gene functions. In the case of miRNA, there will be a regulatory function of the coding gene, so for this purpose, an integrative analysis is performed to identify the mRNA-miRNA interaction	7 days after surgery, within hospitalization period
Exosomes in Blood: Differences in Gene Expression	- Gene expression and expression comparison in exosomes The gene expression difference is determined using the SAM tool and DEseq2, and the Gene Ontology (GO) Database (www.geneontology.org) and the KEGG database (www.genome.jp/kegg) are used to find the correlation between gene functions. In the case of miRNA, there will be a regulatory function of the coding gene, so for this purpose, an integrative analysis is performed to identify the mRNA-miRNA interaction	Just before surgery
Exosomes in Blood: Differences in Gene Expression	- Gene expression and expression comparison in exosomes The gene expression difference is determined using the SAM tool and DEseq2, and the Gene Ontology (GO) Database (www.geneontology.org) and the KEGG database (www.genome.jp/kegg) are used to find the correlation between gene functions. In the case of miRNA, there will be a regulatory function of the coding gene, so for this purpose, an integrative analysis is performed to identify the mRNA-miRNA interaction	just before end of surgery
Fecal microbiota		just before surgery, on the day of discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain efficiency test(EEG)	- EEG test for brain efficiency Peak-MEF(intermediate rhythm of background EEG spectrum), Peak-Freq, Peak_power, Theta frequency band (4 or more and less than 8) of the left (Fp1) EEG power value (log scale), Left (Fp1) EEG alpha frequency band (8 or more and less than 12) Power value (log scale), Left (Fp1) EEG slow beta band (more than 12 and less than 15) power value (log scale), Left (Fp1) EEG mid-beta frequency band (more than 15 and less than 20) power value (log scale), Fast beta frequency band of the left (Fp1) brain waves (more than 20 and less than 30) power value (log scale), Gamma frequency band (30 or more and 50 or less) power value (log scale) of left (Fp1) brain waves, Peak amplitude of 125 Hz auditory stimulated brain potential (ERP); Left and right average of P2 (maximum) peak value difference based on N1 (minimum) peak. Peak amplitude mean of left (Fp1) auditory induced brain potentials (ERPs), Left and right EEG cross-correlation coefficient.	Before surgery (from 2 weeks before to the day before)
Brain efficiency test(pulse wave test)	- pulse wave test for brain efficiency HF (High Frequency) frequency band of heart rate variability (RRV) (0.15 or more and 0.4Hz or less), LF (Low Frequency) frequency band of heart rate variability (RRV) (0.04 or more and less than 0.15 Hz) absolute power, Relative percentage of LF to (LF + HF), Total power of heart rate variability (RRV), Heart rate variability (RRV) histogram; the histogram distribution area divided by the maximum value	Before surgery (from 2 weeks before to the day before)
Cognitive test -MMSE		Before surgery (from 2 weeks before to the day before)
Cognitive test -MOCA		Before surgery (from 2 weeks before to the day before)
Cognitive test -TICS		Before surgery (from 2 weeks before to the day before)
Brain efficiency test(EEG)	- EEG test for brain efficiency Peak-MEF(intermediate rhythm of background EEG spectrum), Peak-Freq, Peak_power, Theta frequency band (4 or more and less than 8) of the left (Fp1) EEG power value (log scale), Left (Fp1) EEG alpha frequency band (8 or more and less than 12) Power value (log scale), Left (Fp1) EEG slow beta band (more than 12 and less than 15) power value (log scale), Left (Fp1) EEG mid-beta frequency band (more than 15 and less than 20) power value (log scale), Fast beta frequency band of the left (Fp1) brain waves (more than 20 and less than 30) power value (log scale), Gamma frequency band (30 or more and 50 or less) power value (log scale) of left (Fp1) brain waves, Peak amplitude of 125 Hz auditory stimulated brain potential (ERP); Left and right average of P2 (maximum) peak value difference based on N1 (minimum) peak. Peak amplitude mean of left (Fp1) auditory induced brain potentials (ERPs), Left and right EEG cross-correlation coefficient.	7 days after surgery, within hospitalization period
Brain efficiency test(pulse wave test)	- pulse wave test for brain efficiency HF (High Frequency) frequency band of heart rate variability (RRV) (0.15 or more and 0.4Hz or less), LF (Low Frequency) frequency band of heart rate variability (RRV) (0.04 or more and less than 0.15 Hz) absolute power, Relative percentage of LF to (LF + HF), Total power of heart rate variability (RRV), Heart rate variability (RRV) histogram; the histogram distribution area divided by the maximum value	7 days after surgery, within hospitalization period
Cognitive test -MMSE		7 days after surgery, within hospitalization period
Cognitive test -MOCA		7 days after surgery, within hospitalization period
Cognitive test -TICS		7 days after surgery, within hospitalization period
Brain efficiency test(EEG)	- EEG test for brain efficiency Peak-MEF(intermediate rhythm of background EEG spectrum), Peak-Freq, Peak_power, Theta frequency band (4 or more and less than 8) of the left (Fp1) EEG power value (log scale), Left (Fp1) EEG alpha frequency band (8 or more and less than 12) Power value (log scale), Left (Fp1) EEG slow beta band (more than 12 and less than 15) power value (log scale), Left (Fp1) EEG mid-beta frequency band (more than 15 and less than 20) power value (log scale), Fast beta frequency band of the left (Fp1) brain waves (more than 20 and less than 30) power value (log scale), Gamma frequency band (30 or more and 50 or less) power value (log scale) of left (Fp1) brain waves, Peak amplitude of 125 Hz auditory stimulated brain potential (ERP); Left and right average of P2 (maximum) peak value difference based on N1 (minimum) peak. Peak amplitude mean of left (Fp1) auditory induced brain potentials (ERPs), Left and right EEG cross-correlation coefficient.	1 month after surgery
Brain efficiency test(pulse wave test)	- pulse wave test for brain efficiency HF (High Frequency) frequency band of heart rate variability (RRV) (0.15 or more and 0.4Hz or less), LF (Low Frequency) frequency band of heart rate variability (RRV) (0.04 or more and less than 0.15 Hz) absolute power, Relative percentage of LF to (LF + HF), Total power of heart rate variability (RRV), Heart rate variability (RRV) histogram; the histogram distribution area divided by the maximum value	1 month after surgery
Cognitive test -MMSE		1 month after surgery
Cognitive test -MOCA		1 month after surgery
Cognitive test -TICS		1 month after surgery
Brain efficiency test(EEG)	- EEG test for brain efficiency Peak-MEF(intermediate rhythm of background EEG spectrum), Peak-Freq, Peak_power, Theta frequency band (4 or more and less than 8) of the left (Fp1) EEG power value (log scale), Left (Fp1) EEG alpha frequency band (8 or more and less than 12) Power value (log scale), Left (Fp1) EEG slow beta band (more than 12 and less than 15) power value (log scale), Left (Fp1) EEG mid-beta frequency band (more than 15 and less than 20) power value (log scale), Fast beta frequency band of the left (Fp1) brain waves (more than 20 and less than 30) power value (log scale), Gamma frequency band (30 or more and 50 or less) power value (log scale) of left (Fp1) brain waves, Peak amplitude of 125 Hz auditory stimulated brain potential (ERP); Left and right average of P2 (maximum) peak value difference based on N1 (minimum) peak. Peak amplitude mean of left (Fp1) auditory induced brain potentials (ERPs), Left and right EEG cross-correlation coefficient.	1 year after surgery
Brain efficiency test(pulse wave test)	- pulse wave test for brain efficiency HF (High Frequency) frequency band of heart rate variability (RRV) (0.15 or more and 0.4Hz or less), LF (Low Frequency) frequency band of heart rate variability (RRV) (0.04 or more and less than 0.15 Hz) absolute power, Relative percentage of LF to (LF + HF), Total power of heart rate variability (RRV), Heart rate variability (RRV) histogram; the histogram distribution area divided by the maximum value	1 year after surgery
Cognitive test -MMSE		1 year after surgery
Cognitive test -MOCA		1 year after surgery
Cognitive test -TICS		1 year after surgery

Collaborators and Investigators

• Sponsor: Yonsei University

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2019
• Primary Completion (Anticipated): October 1, 2021
• Study Completion (Anticipated): October 1, 2021

Study Registration Dates

• First Submitted: September 29, 2019
• First Submitted That Met QC Criteria: October 7, 2019
• First Posted (Actual): October 9, 2019

Study Record Updates

• Last Update Posted (Actual): June 7, 2021
• Last Update Submitted That Met QC Criteria: June 3, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Musculoskeletal Diseases; Bone Diseases; Delirium; Spinal Diseases
• Other Study ID Numbers: 4-2019-0654

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No