Alzheimers Disease, Post Operative Cognitive Dysfunction, Postoperative Delirium
Conditions
Keywords
isoflurane, propofol, total intravenous anesthesia, inhaled anesthetic, volatile anesthetic, anesthesia, delirium, Post Operative Cognitive Dysfunction, Alzheimer's Disease, Mild Cognitive Impairment
Brief summary
This study will examine the hypothesis that changes in the cognition (i.e. thinking and memory) after anesthesia and surgery are correlated with changes in markers of Alzheimers Disease in the fluid around the brain and spinal cord (i.e. cerebrospinal fluid, or CSF), and/or changes in brain connectivity. The investigators will also examine whether different types of anesthesia have different effects on these CSF markers of Alzheimers disease, or different effects on thinking and memory after anesthesia and surgery, or differential effects on the correlation between cognitive changes and CSF marker changes.
Interventions
DRUGGeneral anesthesia with isoflurane
Sponsors
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Surgical patients 60 years of age or older * Surgery scheduled to last at least 2 hours (including time for anesthesia induction, etc) * English speaking ability. * Ability to give informed consent
Exclusion criteria
* Inmate of a correctional facility (i.e. prisoners). * Pregnancy * Documented or suspected family or personal history of malignant hyperthermia. * Patient unable to receive either propofol or isoflurane due to allergy or other specific contraindication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Perioperative Change in Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change | Baseline to 6 weeks | Spearman correlation was used here as the CSF markers follow a skewed distribution. Spearman correlation describes the strength of the monotonic relationship between two measures and is bounded between -1 and 1. Negative values indicate an inverse relationship while positive values mean that the variables move in tandem. |
| Correlation Between Perioperative Change in Ratios of Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change | Baseline to 6 weeks | Spearman correlation was used here as the ratio of CSF markers follow a skewed distribution. Spearman correlation describes the strength of the monotonic relationship between two measures and is bounded between -1 and 1. Negative values indicate an inverse relationship while positive values mean that the variables move in tandem. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Continuous Cognitive Index Score Change Difference Between Anesthetic Agent Groups | Baseline to 6 weeks | To characterize cognitive function over time, while minimizing potential redundancy in the cognitive measures, a factor analysis was performed on the 10 cognitive test scores from baseline. To quantify overall cognitive function, a baseline cognitive index was first calculated as the mean of the preoperative domain scores. The cognitive index score has a mean of zero, thus any positive score is above the mean, any negative score is below the mean. A continuous change score was then calculated by subtracting the baseline from the 6-week cognitive index. A negative change score indicating decline and a positive score indicating improvement. The resulting outcome measure is unbounded with a standard deviation of 0.31 in the full surgical cohort. |
| Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group | Baseline to 6 weeks | CSF Markers of Alzheimer's Disease over time in the subjects treated with propofol versus those treated with isoflurane. |
| Change in Ratio of CSF Markers of Alzheimers Disease by Anesthetic Agent Group | baseline to 6-weeks | Change in ratio of CSF Markers of Alzheimer's Disease over time in the subjects treated with propofol versus those treated with isoflurane. |
| Perioperative CSF Tau/Abeta Ratio Change | Baseline to 24 hours | The perioperative change in the CSF tau/Abeta ratio from the start of anesthesia/surgery to 24 hours later. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| General Anesthesia With Isoflurane Surgical patients randomized to receive inhalational anesthesia with isoflurane during surgery | 55 |
| Total Intravenous Anesthesia With Propofol Surgical patients randomized to receive iintravenous anesthesia with propofol during surgery | 55 |
| Non-Surgical Controls Cohort of community dwelling healthy controls for tertiary comparison | 46 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 2 | 0 |
| Overall Study | Physician Decision | 2 | 1 | 0 |
| Overall Study | Surgery Cancelled | 3 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 10 | 5 |
Baseline characteristics
| Characteristic | Total | Non-Surgical Controls | Total Intravenous Anesthesia With Propofol | General Anesthesia With Isoflurane |
|---|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 6.8 | 69.6 years STANDARD_DEVIATION 7.6 | 69.7 years STANDARD_DEVIATION 6.9 | 68.6 years STANDARD_DEVIATION 6.1 |
| Baseline CSF levels Abeta | 347 pg/ml | 330.5 pg/ml | 352 pg/ml | 369 pg/ml |
| Baseline CSF levels P-Tau | 25 pg/ml | 21.0 pg/ml | 28 pg/ml | 26 pg/ml |
| Baseline CSF levels Tau | 49 pg/ml | 58.5 pg/ml | 50 pg/ml | 47 pg/ml |
| Baseline CSF ratio levels P-Tau/Abeta Ratio | 0.07 ratio | 0.06 ratio | 0.08 ratio | 0.08 ratio |
| Baseline CSF ratio levels Tau/Abeta Ratio | 0.14 ratio | 0.16 ratio | 0.14 ratio | 0.13 ratio |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 9 Participants | 8 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 135 Participants | 36 Participants | 47 Participants | 52 Participants |
| Region of Enrollment United States | 156 participants | 46 participants | 55 participants | 55 participants |
| Sex: Female, Male Female | 59 Participants | 18 Participants | 24 Participants | 17 Participants |
| Sex: Female, Male Male | 97 Participants | 28 Participants | 31 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 72 | 2 / 68 | 0 / 51 |
| other Total, other adverse events | 2 / 72 | 8 / 68 | 7 / 51 |
| serious Total, serious adverse events | 0 / 72 | 0 / 68 | 0 / 51 |
Outcome results
Primary
Correlation Between Perioperative Change in Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change
Spearman correlation was used here as the CSF markers follow a skewed distribution. Spearman correlation describes the strength of the monotonic relationship between two measures and is bounded between -1 and 1. Negative values indicate an inverse relationship while positive values mean that the variables move in tandem.
Time frame: Baseline to 6 weeks
Population: Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Combined Surgical Cohort | Correlation Between Perioperative Change in Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change | Tau | -1.21 pg/ml |
| Combined Surgical Cohort | Correlation Between Perioperative Change in Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change | Abeta | -5.09 pg/ml |
| Combined Surgical Cohort | Correlation Between Perioperative Change in Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change | P-Tau | -0.44 pg/ml |
Comparison: Correlation between 6-week change in Tau and continuous cognitive index95% CI: [-0.23, 0.18]
Comparison: Correlation between 6-week change in Abeta and continuous cognitive index95% CI: [-0.29, 0.13]
Comparison: Correlation between 6-week change in P-Tau and continuous cognitive index95% CI: [-0.08, 0.32]
Primary
Correlation Between Perioperative Change in Ratios of Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change
Spearman correlation was used here as the ratio of CSF markers follow a skewed distribution. Spearman correlation describes the strength of the monotonic relationship between two measures and is bounded between -1 and 1. Negative values indicate an inverse relationship while positive values mean that the variables move in tandem.
Time frame: Baseline to 6 weeks
Population: Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Combined Surgical Cohort | Correlation Between Perioperative Change in Ratios of Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change | Tau/Abeta Ratio | 0.001 ratio |
| Combined Surgical Cohort | Correlation Between Perioperative Change in Ratios of Cerebrospinal Fluid (CSF) Markers of Alzheimers Disease and Perioperative Cognitive Change | P-Tau/Abeta Ratio | 0.002 ratio |
Comparison: Correlation between 6-week change in Tau/Abeta ratio and continuous cognitive index95% CI: [-0.19, 0.22]
Comparison: Correlation between 6-week change in P-Tau/Abeta ratio and continuous cognitive index95% CI: [-0.05, 0.34]
Secondary
Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group
CSF Markers of Alzheimer's Disease over time in the subjects treated with propofol versus those treated with isoflurane.
Time frame: Baseline to 6 weeks
Population: Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Combined Surgical Cohort | Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group | Tau | -0.80 pg/ml |
| Combined Surgical Cohort | Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group | Abeta | -2.10 pg/ml |
| Combined Surgical Cohort | Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group | P-Tau | -2.25 pg/ml |
| General Anesthesia With Isoflurane | Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group | Tau | -1.67 pg/ml |
| General Anesthesia With Isoflurane | Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group | Abeta | -9.50 pg/ml |
| General Anesthesia With Isoflurane | Change in CSF Markers of Alzheimers Disease by Anesthetic Agent Group | P-Tau | 1.10 pg/ml |
Comparison: Difference in 6-week Tau Change between anesthetic groupsp-value: 0.532Wilcoxon (Mann-Whitney)
Comparison: Difference in 6-week Abeta Change between anesthetic groupsp-value: 0.565Wilcoxon (Mann-Whitney)
Comparison: Difference in 6-week P-Tau Change between anesthetic groupsp-value: 0.11Wilcoxon (Mann-Whitney)
Secondary
Change in Ratio of CSF Markers of Alzheimers Disease by Anesthetic Agent Group
Change in ratio of CSF Markers of Alzheimer's Disease over time in the subjects treated with propofol versus those treated with isoflurane.
Time frame: baseline to 6-weeks
Population: Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Combined Surgical Cohort | Change in Ratio of CSF Markers of Alzheimers Disease by Anesthetic Agent Group | Tau/Abeta Ratio | 0.00 ratio |
| Combined Surgical Cohort | Change in Ratio of CSF Markers of Alzheimers Disease by Anesthetic Agent Group | P-Tau/Abeta Ratio | -0.00 ratio |
| General Anesthesia With Isoflurane | Change in Ratio of CSF Markers of Alzheimers Disease by Anesthetic Agent Group | Tau/Abeta Ratio | -0.00 ratio |
| General Anesthesia With Isoflurane | Change in Ratio of CSF Markers of Alzheimers Disease by Anesthetic Agent Group | P-Tau/Abeta Ratio | 0.01 ratio |
Comparison: Difference in 6-week Tau/Abeta ratio Change between anesthetic groupsp-value: 0.439Wilcoxon (Mann-Whitney)
Comparison: Difference in 6-week P-Tau/Abeta Change between anesthetic groupsp-value: 0.082Wilcoxon (Mann-Whitney)
Secondary
Continuous Cognitive Index Score Change Difference Between Anesthetic Agent Groups
To characterize cognitive function over time, while minimizing potential redundancy in the cognitive measures, a factor analysis was performed on the 10 cognitive test scores from baseline. To quantify overall cognitive function, a baseline cognitive index was first calculated as the mean of the preoperative domain scores. The cognitive index score has a mean of zero, thus any positive score is above the mean, any negative score is below the mean. A continuous change score was then calculated by subtracting the baseline from the 6-week cognitive index. A negative change score indicating decline and a positive score indicating improvement. The resulting outcome measure is unbounded with a standard deviation of 0.31 in the full surgical cohort.
Time frame: Baseline to 6 weeks
Population: Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Surgical Cohort | Continuous Cognitive Index Score Change Difference Between Anesthetic Agent Groups | 0.019 units on a scale | Standard Error 0.05 |
| General Anesthesia With Isoflurane | Continuous Cognitive Index Score Change Difference Between Anesthetic Agent Groups | 0.061 units on a scale | Standard Error 0.04 |
p-value: 0.36t-test, 2 sided
Secondary
Perioperative CSF Tau/Abeta Ratio Change
The perioperative change in the CSF tau/Abeta ratio from the start of anesthesia/surgery to 24 hours later.
Time frame: Baseline to 24 hours
Population: Analysis for the primary and secondary outcome 6 use the combination of both randomized treatment groups. The treatment groups are separated and compared in secondary analysis of outcomes 3-5, and the control group is only used in tertiary analyses. To be included in the outcome analysis patients must have returned for six-week follow-up visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Surgical Cohort | Perioperative CSF Tau/Abeta Ratio Change | -0.001 ratio |
p-value: 0.801Wilcoxon Signed Rank