Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest

Study Overview
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Brief Summary
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In this study the investigator will randomize 273 subjects to deep (<20°C), low (20.1°C-24°C), or moderate (24.1°C-28°C) hypothermia during aortic arch surgery with circulatory arrest. The primary purpose of this study is to determine the effect of deep vs low vs moderate hypothermia on neurocognitive function, brain functional connectivity, and leukocyte SUMOylation patterns after surgical circulatory arrest in participants.

Detailed Description
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Purpose of the Study: Determine the effect of deep vs low vs moderate hypothermia on neurocognitive function, brain functional connectivity, and leukocyte SUMOylation patterns after surgical circulatory arrest. Hypothesis: Deep hypothermia is superior to moderate hypothermia in reducing postoperative cognitive decline and preserving brain functional connectivity and that low hypothermia is non-inferior to deep hypothermia. Design and Procedures: 273 informed and consenting patients who are scheduled for elective proximal aortic reconstructive surgery (ascending aorta + aortic valve or root) with concomitant proximal hemi- or total arch replacement via median sternotomy will be randomized to deep (<20°C), low (20.1°C-24°C), or moderate (24.1°C-28°C) hypothermia during circulatory arrest. Cognitive testing using a standard battery will occur preoperatively (baseline), at 4 weeks, and at 1 year after surgery. Neuroimaging procedures before surgery, and at 4 weeks and 1 year after surgery will consist of high-resolution anatomic, resting-state fMRI (rs-fMRI) and magnetic resonance spectroscopy (MRS) sequences. To characterize leukocyte activation, whole blood will be drawn at 5 time points: at baseline (prior to surgery), before circulatory arrest, 10 minutes after reperfusion, 10 minutes after CPB, and 4 hours after CPB.

Official Title
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Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest

Conditions
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Cognition Disorders

Intervention / Treatment
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* Device: Cardiopulmonary bypass machine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are scheduled for elective proximal aortic reconstructive surgery (ascending aorta + aortic valve or root) with concomitant proximal hemi- or total arch replacement via median sternotomy Exclusion Criteria: < 18 years of age History of symptomatic cerebrovascular disease, eg, prior stroke with residual deficit Alcoholism (> 2 drinks/day) Psychiatric illness (any clinical diagnoses requiring therapy) Drug abuse (any illicit drug use in the past 3 months) Hepatic insufficiency (liver function tests > 1.5 times the upper limit of normal) Severe pulmonary insufficiency (requiring home oxygen therapy) Renal failure (serum creatinine > 2.0 mg/dL) Claustrophobic fear Unable to read and thus unable to complete the cognitive testing Pregnant women Patients who score < 24 on a baseline Mini Mental State Examination (MMSE) or ≥ 27 on the baseline Center for Epidemiological Studies Depression (CES-D) scale Patients who have pre-existing unsafe implants for 3 Tesla magnetic resonance imaging (MRI). Patients who have received chemotherapy in the last 12 months. Patients with COVID-19 diagnosis within the past 12 months

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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Deep Hypothermia<br>Initiation of circulatory arrest using the cardiopulmonary bypass machine at temperature ≤20 degrees Celsius | Device: Cardiopulmonary bypass machine<br>* Routinely used cardiopulmonary bypass machine (standard of care) will be used to initiate circulatory arrest<br>|
| Active Comparator: Low Hypothermia<br>Initiation of circulatory arrest using the cardiopulmonary bypass machine at temperature 20.1 - 24.0 degrees Celsius | Device: Cardiopulmonary bypass machine<br>* Routinely used cardiopulmonary bypass machine (standard of care) will be used to initiate circulatory arrest<br>|
| Active Comparator: Moderate Hypothermia<br>Initiation of circulatory arrest using the cardiopulmonary bypass machine at temperature 24.1 - 28 degrees Celsius | Device: Cardiopulmonary bypass machine<br>* Routinely used cardiopulmonary bypass machine (standard of care) will be used to initiate circulatory arrest<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in short-term cognition as measured by continuous cognitive score | To characterize cognitive function over time while minimizing potential redundancy in the cognitive measures, a factor analysis will be performed on the cognitive test scores from baseline. A continuous change score will be calculated by subtracting the baseline cognitive index (the mean of the domain scores from factor analysis) from the follow-up cognitive index at 4 weeks. | From baseline to 4 weeks post-operatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in SUMO 2/3 levels |  | Pre-incision, before circulatory arrest, 10 minutes after reperfusion, 10 minutes after cardiopulmonary bypass, 4 hrs after cardiopulmonary bypass | 
| Change in long-term cognition as measured by continuous cognitive score | To characterize cognitive function over time while minimizing potential redundancy in the cognitive measures, a factor analysis will be performed on the cognitive test scores from baseline. A continuous change score will be calculated by subtracting the baseline cognitive index (the mean of the domain scores from factor analysis) from the follow-up cognitive index at 1 year. | From baseline to 1 year post-operatively | 
| Incidence of delirium | Confusion Assessment Method (CAM) | Up to post-operative day 3 | 
| Change in neurological function as measured by NIHSS |  | Assessed at baseline, post-op day 4, 4 weeks | 
| Change in neuronal metabolism | Magnetic resonance spectra (metabolic peaks) of myoinositol, creatine, choline and N-acetyl aspartate | From baseline to 4 weeks | 
| Change in resting-state functional connectivity | For the rs-fMRI data, the analyses of primary interest will be the spontaneous, low-frequency fluctuations in the blood oxygen level dependent (BOLD) data of the Default Mode, Salience, and Executive Control Networks. | From baseline to 4 weeks post-operatively | 
| Change in Duke Activity Status Index score |  | From baseline to 4 weeks postoperatively | 
| Change in depression score | Measured by the Center for Epidemiological Studies Depression Scale (CES-D). | From baseline to 4 weeks postoperatively | 
| Change in anxiety score | Measured by State Trait Anxiety Inventory (STA-I). | From baseline to 4 weeks postoperatively | 
| Change in SF-36 score |  | From baseline to 1 year postoperatively | 
| Change in employment status |  | From baseline to 1 year postoperatively | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postoperative Cognitive Decline, Deep Hypothermic Circulatory Arrest, Cardiovascular Surgical Procedures, Functional Magnetic Resonance Imaging, Small Ubiquitin-Related Modifier Proteins