Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery: Proposal for Pilot Investigation

Phase 1

Terminated

• Conditions: Heart Defects, Congenital
• Interventions: Drug: Dexrazoxane

• Registration Number: NCT02519335
• Lead Sponsor: Medical City Children's Hospital

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. Therefore, the investigators are performing a pilot study of 12 children to assess:

1. how Dexrazoxane at 3 different doses is metabolized in the body of a child age 0-6 months during and after congenital heart surgery, and

2. the safety of Dexrazoxane use in the neonatal and young infant population undergoing cardiac surgery.

Detailed Description

Neonates and infants undergoing heart surgery with 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 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 deleterious effects of cardiopulmonary bypass \[CPB\] with cardioplegic arrest of the heart during congenital heart operations greatly influence postoperative morbidity and mortality. Neonates and infants undergoing cardiac surgery experience both a systemic inflammatory response, and myocardial IR injury as cardioplegic arrest is reversed. These processes provoke elaboration of cytokines and activation of the complement cascade, as well as oxygen free radical formation and induction of myocardial apoptosis (1, 2, 3). Frequently, myocardial injury and cardiac dysfunction ensue, leading to low cardiac output syndrome and multi-system organ failure. The irreversible component of these injuries, in addition to the abnormal workloads imposed on the myocardium from the anatomic defects themselves, may have consequences for long-term cardiac function, and may in part explain contractile dysfunction observed late after congenital heart

The investigators propose a pilot pharmacokinetic/safety trial of dexrazoxane in children 0-6 months of age, followed by a randomized, double-blind, clinical trial of dexrazoxane vs placebo during congenital heart surgery. The investigators will evaluate postoperative time to resolution of organ failure, development of low cardiac output syndrome, length of cardiac ICU and hospital stays, and echocardiographic indices of cardiac dysfunction. Results could establish the safety and clinical utility of dexrazoxane in ameliorating ischemia-reperfusion injury during congenital heart surgery.

Study Timeline

• Study Start: 2014-09
• Study First Submitted: 2015-05-14
• Study First Submitted QC: 2015-08-05
• Study First Posted: 2015-08-10
• Status Verified: 2017-03
• Primary Completion: 2017-03
• Study Completion: 2017-03
• Last Update Submitted: 2018-07-24
• Last Update Posted: 2018-07-26

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

• age 6 months and under
• open heart surgery requiring CPB and use of cardioplegia
• parent/guardian consent for study obtained surgery planned Monday to Friday

Exclusion Criteria

• gestational age <36weeks
• known syndrome or genetic abnormality, except Trisomy 21 single ventricle physiology
• concurrent enrollment in another research protocol
• no parental/guardian consent obtained
• ECMO utilization prior to surgery or necessary at the time of ICU admission

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dexrazoxane	Dexrazoxane	Trial subjects will be assigned preoperatively to receive Dexrazoxane at one of three doses: low (200mg/m2/dose), medium (300mg/m2/dose), or high (400mg/m2/dose). Four patients will be assigned to each dosing regimen for a total of 12 patients. The medication will be administered in the operating room 15-30 minutes prior to starting cardiopulmonary bypass (dose #1), after finishing cardiopulmonary bypass (dose #2), and on the morning after surgery in the cardiac intensive care unit (dose #3).

Primary Outcome Measures

Name	Time	Method
Resolution of organ failure	60 days postoperative	measured by number of days to the point of being off invasive mechanical ventilation, renal replacement therapy and inotropic support

Secondary Outcome Measures

Name	Time	Method
Postoperative low cardiac output syndrome	60 days	observance of clinical signs or symptoms such as tachycardia, oliguria, poor perfusion and cardiac arrest.

Trial Locations

Locations (1)

Medical City Children's Hospital; 🇺🇸 Dallas, Texas, United States