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Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery

Sponsor
University of Texas at Austin (Other)
Overall Status
Recruiting
CT.gov ID
NCT04997291
Collaborator
Dell Children's Medical Center of Central Texas (Other)
12
Enrollment
1
Location
1
Arm
8.8
Anticipated Duration (Months)
1.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Cardiopulmonary bypass and arrest of the heart during cardiac surgery are necessary to allow the surgeon to perform heart operations. However, these processes can cause injury to the heart which may worsen post-operative outcomes. In fact, the effects of these injuries may continue after surgery, and lead to a long-term decrease in heart function. Neonates and young infants are at particular risk for this occurrence.

While much research has been done in adults looking for medicines that might protect the heart during surgery, few studies have been conducted in neonates and young infants. The investigators are testing Dexrazoxane, which has proven to be cardio-protective in pediatric cancer patients, in the hope that it may lessen cardiac injury during and after congenital heart surgery, and thereby improve outcomes in the neonatal and young infant population.

In order to accomplish this, the investigators must first determine how Dexrazoxane can be safely administered to young children with congenital heart disease.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

Neonates and infants undergoing heart surgery with cardiopulmonary bypass and cardioplegic arrest experience both inflammation and myocardial ischemia-reperfusion [IR] injury. These processes provoke myocardial apoptosis and oxygen free radical formation which result in cardiac injury and dysfunction. Dexrazoxane [DRZ] is a derivative of EDTA that is approved for prevention of anthracycline-related cardiotoxicity. It provides cardioprotection through reduction of toxic reactive oxygen species [ROS], and suppression of apoptosis.

The investigators propose a 12-patient pilot to determine DRZ pharmacokinetics, and to collect additional safety data in the neonatal and infant population. Efficacy of cardioprotection will not be evaluated in this preliminary investigation, though the investigators will determine postoperative time to resolution of organ failure, development of low cardiac output syndrome, length of cardiac ICU and hospital stays, laboratory indices of myocardial injury and systemic inflammation, and echocardiographic cardiac dysfunction for safety purposes, and as a run-in to the larger, randomized, placebo controlled trial. Conducting this pilot could optimize team execution of the study protocol. In addition, results could further establish the safety of DRZ in the neonatal and infant populations.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
12 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery
Actual Study Start Date :
Apr 9, 2021
Anticipated Primary Completion Date :
Oct 1, 2021
Anticipated Study Completion Date :
Jan 1, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Dexrazoxane

Drug: Dexrazoxane
Twelve enrollees will be consecutively assigned to a dosing regimen of 400 mg/m2/dose. The medication will be administered in the operating room 30 minutes prior to starting cardiopulmonary bypass (dose #1), prior to aortic cross clamp removal (dose #2), and on the morning after surgery in the cardiac intensive care unit (dose #3).
Other Names:
  • Zinecard

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Peak Plasma Concentration (Cmax) [24 hours]

    2. Area under the plasma concentration vs time curve (AUC) [24 hours]

    3. Minimum plasma concentration (Cmin) [24 hours]

    4. Time to resolution of organ failure [14 days]

      defined as hours to the point of being off invasive mechanical ventilation, without significant renal dysfunction [cystatin C within normal range for age, and UOP > 1 cc/kg/hr], and off significant inotropic support [defined as milrinone >0.3 mcg/kg/min, dopamine >3 mcg/kg/min, dobutamine >3 mcg/kg/min, any combination of these inotropes, or any epinephrine, norepinephrine, phenylephrine or vasopressin)] with a serum lactate <2 mmol/L. One point will be awarded for each postoperative hour of continued organ dysfunction up to postoperative hour 336 (day 14). A score of 360 will be assigned if organ failure is not resolved by postoperative day 14, or if the patient requires mechanical circulatory support or experiences mortality. This variable has been chosen to allow for recognition of early drug effects, and those which might be delayed beyond the immediate postoperative period.

    Secondary Outcome Measures

    1. Myocardial Injury [7 days]

      determined by elevated serum cardiac troponin

    2. Oxidative Stress [3 days]

      measured by lipoperoxidation (serum F2 isoprostane)

    3. Inflammatory activation (IL-6 and IL-10) [3 days]

    4. Neurologic IR injury [3 days]

      measured by serum activin A concentration

    5. ICU Length of Stay [60 days]

    6. Hospital Length of Stay [60 days]

    7. Tei Index (via echocardiogram) [60 days]

      the sum of the isovolumic contraction and relaxation times divided by the ejection time

    8. Ventricular ejection fraction (via echocardiogram) [60 days]

      the volumetric fraction of fluid ejected from a chamber with each contraction

    9. Tissue doppler E/E' ratio (via echocardiogram) [60 days]

      calculated as E wave divided by e' velocities

    10. Composite outcome for neonatal cardiac surgery [60 days]

      (per Graham, EM, et al) - binary variable defined as death, use of mechanical circulatory support, cardiac arrest requiring chest compressions, hepatic injury [2 times the upper limit of normal for AST or ALT], renal injury [Cr >1.5 mg/dL], or lactic acidosis [an increasing lactate >5 mmol/L in the postoperative period]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    0 Years to 1 Year
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • age ≤ 1 year

    • open heart surgery requiring CPB and use of cardioplegia

    • parent/guardian consent for study obtained

    • surgery planned Monday-Friday

    Exclusion Criteria:

    • gestational age <36 weeks at time of enrollment

    • known syndrome or genetic abnormality, except Trisomy 21

    • single ventricle physiology

    • concurrent enrollment in another research protocol

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Dell Children's Medical Center of Central Texas Austin Texas United States 78723

    Sponsors and Collaborators

    • University of Texas at Austin
    • Dell Children's Medical Center of Central Texas

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Daniel Stromberg, Associate Professor, University of Texas at Austin
    ClinicalTrials.gov Identifier:
    NCT04997291
    Other Study ID Numbers:
    • 2020-02-0075
    First Posted:
    Aug 9, 2021
    Last Update Posted:
    Aug 9, 2021
    Last Verified:
    Aug 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Additional relevant MeSH terms:
    Heart Defects, Congenital
    Congenital Abnormalities
    Dexrazoxane
    Razoxane

    Study Results

    No Results Posted as of Aug 9, 2021