Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest

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 Overview

• Status: Completed
• Conditions: Cognition Disorders
• Intervention / Treatment: Device: Cardiopulmonary bypass machine

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.

• Study Type: Interventional
• Enrollment (Actual): 273
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Emory Saint Joseph's Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center
  • Texas
    • Plano, Texas, United States, 75093
      • Baylor Scott & White Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: University of Pennsylvania; National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); Baylor Scott and White Health; Emory Healthcare
• Investigators: Principal Investigator: Joseph P Mathew, MD, MHSc, MBA, Duke Health

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2016
• Primary Completion (Actual): January 1, 2022
• Study Completion (Actual): February 1, 2023

Study Registration Dates

• First Submitted: July 6, 2016
• First Submitted That Met QC Criteria: July 12, 2016
• First Posted (Estimate): July 15, 2016

Study Record Updates

• Last Update Posted (Actual): February 24, 2023
• Last Update Submitted That Met QC Criteria: February 23, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Functional Magnetic Resonance Imaging; Postoperative Cognitive Decline; Deep Hypothermic Circulatory Arrest; Cardiovascular Surgical Procedures; Small Ubiquitin-Related Modifier Proteins
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Body Temperature Changes; Cognition Disorders; Hypothermia
• Other Study ID Numbers: Pro00064962; 1R01HL130443-01A1 (U.S. NIH Grant/Contract)

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