Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery

Heart Defects, Congenital Clinical Trial

Official title:

Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04997291
• Other study ID #: 2020-02-0075
• Status: Recruiting
• Phase: Phase 1
• Start date: April 9, 2021
• Est. completion date: January 2022

Study information

• Verified date: August 2021
• Source: University of Texas at Austin
• Contact: Daniel Stromberg, MD
• Phone: 512-324-3357
• Email: dstromberg[@]austin.utexas.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: January 2022
• Est. primary completion date: October 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 1 Year

Eligibility

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

Related Conditions & MeSH terms

• Congenital Abnormalities
• Heart Defects, Congenital

Intervention

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).

Locations

Country	Name	City	State
United States	Dell Children's Medical Center of Central Texas	Austin	Texas

Sponsors (2)

Lead Sponsor	Collaborator
University of Texas at Austin	Dell Children's Medical Center of Central Texas

Country where clinical trial is conducted

United States, 

References & Publications (46)

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* Note: There are 46 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Peak Plasma Concentration (Cmax)		24 hours
Primary	Area under the plasma concentration vs time curve (AUC)		24 hours
Primary	Minimum plasma concentration (Cmin)		24 hours
Primary	Time to resolution of organ failure	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.	14 days
Secondary	Myocardial Injury	determined by elevated serum cardiac troponin	7 days
Secondary	Oxidative Stress	measured by lipoperoxidation (serum F2 isoprostane)	3 days
Secondary	Inflammatory activation (IL-6 and IL-10)		3 days
Secondary	Neurologic IR injury	measured by serum activin A concentration	3 days
Secondary	ICU Length of Stay		60 days
Secondary	Hospital Length of Stay		60 days
Secondary	Tei Index (via echocardiogram)	the sum of the isovolumic contraction and relaxation times divided by the ejection time	60 days
Secondary	Ventricular ejection fraction (via echocardiogram)	the volumetric fraction of fluid ejected from a chamber with each contraction	60 days
Secondary	Tissue doppler E/E' ratio (via echocardiogram)	calculated as E wave divided by e' velocities	60 days
Secondary	Composite outcome for neonatal cardiac surgery	(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]	60 days