Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest

Overview

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.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: July 2021

Detailed Description

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.

Interventions

  • Device: Cardiopulmonary bypass machine
    • Routinely used cardiopulmonary bypass machine (standard of care) will be used to initiate circulatory arrest

Arms, Groups and Cohorts

  • Active Comparator: Deep Hypothermia
    • Initiation of circulatory arrest using the cardiopulmonary bypass machine at temperature ≤20 degrees Celsius
  • Active Comparator: Low Hypothermia
    • Initiation of circulatory arrest using the cardiopulmonary bypass machine at temperature 20.1 – 24.0 degrees Celsius
  • Active Comparator: Moderate Hypothermia
    • Initiation of circulatory arrest using the cardiopulmonary bypass machine at temperature 24.1 – 28 degrees Celsius

Clinical Trial Outcome Measures

Primary Measures

  • Change in short-term cognition as measured by continuous cognitive score
    • Time Frame: From baseline to 4 weeks post-operatively
    • 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.

Secondary Measures

  • Change in SUMO 2/3 levels
    • Time Frame: 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
    • Time Frame: From baseline to 1 year post-operatively
    • 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.
  • Incidence of delirium
    • Time Frame: Up to post-operative day 3
    • Confusion Assessment Method (CAM)
  • Change in neurological function as measured by NIHSS
    • Time Frame: Assessed at baseline, post-op day 4, 4 weeks
  • Change in neuronal metabolism
    • Time Frame: From baseline to 4 weeks
    • Magnetic resonance spectra (metabolic peaks) of myoinositol, creatine, choline and N-acetyl aspartate
  • Change in resting-state functional connectivity
    • Time Frame: From baseline to 4 weeks post-operatively
    • 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.
  • Change in Duke Activity Status Index score
    • Time Frame: From baseline to 4 weeks postoperatively
  • Change in depression score
    • Time Frame: From baseline to 4 weeks postoperatively
    • Measured by the Center for Epidemiological Studies Depression Scale (CES-D).
  • Change in anxiety score
    • Time Frame: From baseline to 4 weeks postoperatively
    • Measured by State Trait Anxiety Inventory (STA-I).
  • Change in SF-36 score
    • Time Frame: From baseline to 1 year postoperatively
  • Change in employment status
    • Time Frame: From baseline to 1 year postoperatively

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Duke University
  • Collaborator
    • Emory Healthcare
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Joseph P Mathew, MD, MHSc, MBA, Principal Investigator, Duke University Health System

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