Clinical trial NCT02519335: Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery: Proposal for Pilot Investigation
Official title: Use of the Cardioprotectant Dexrazoxane During Congenital Heart Surgery: Proposal for Pilot Investigation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Heart Defects, Congenital
Keywords: cardiopulmonary bypass
ischemia reperfusion injury
Lead sponsor: Medical City Children's Hospital
Sponsor class: OTHER
Collaborators: name: Mylan Pharmaceuticals Inc
First posted: 2015-08-10
Enrollment: 12
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Resolution of organ failure
timeFrame: 60 days postoperative
Secondary outcomes:
measure: Postoperative low cardiac output syndrome
timeFrame: 60 days
Other outcomes:
measure: Myocardial injury
timeFrame: 60 days
measure: Oxidative stress
timeFrame: 60 days
measure: Inflammatory activation (IL-6 and IL-10)
timeFrame: 60 days
measure: Myocardial dysfunction (via echocardiogram)
timeFrame: 60 days
measure: Neurologic injury (activin A)
timeFrame: 60 days
measure: ICU and hospital length of stay
timeFrame: 60 days
Locations:
city: Dallas
country: United States
facility: Medical City Children's Hospital
state: Texas
Study officials:
affiliation: Medical City Children's Hospital
name: Daniel Stromberg, MD
role: PRINCIPAL_INVESTIGATOR
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