Preventing Brain Injury in Infants With Congenital Heart Disease

Pilot Study of Topiramate Prophylaxis in Infants Undergoing Surgery for Congenital Heart Disease

Newborn babies with congenital heart disease often require surgery in the first month of life. The risks of brain damage from congenital heart disease and from the various corrective surgeries are high because of poor levels of oxygen reaching the brain. Topiramate is an anti-convulsant medication that protects brain cells from damage due to low amounts of oxygen in animal studies. The investigators hypothesize that giving topiramate to babies with congenital heart disease before and after surgery will decrease the amount of brain damage caused by the heart disease and/or the surgery to correct the heart disease.

Study Overview

• Status: Completed
• Conditions: Cyanotic Congenital Heart Disease
• Intervention / Treatment: Drug: Topiramate; Other: No medication, but routine heart surgery

Detailed Description

Infants with cyanotic congenital heart disease undergoing surgery in the neonatal period have a high rate of brain injury resulting in seizures, stroke, cerebral palsy, and neurodevelopmental delays. Neuroimaging abnormalities are found in 30% to 60% of cases and neurodevelopmental impairments occur in more than half of these children. The mechanisms of brain injury in these children are not fully understood. Experimental animal models have shown that the abundant release of glutamate in the brain during hypoxic-ischemic insult results in brain injury. Blocking glutamate receptors by administration of the anticonvulsant topiramate has been shown to prevent such injury in animal studies. This study is an open pilot trial of peri-operative topiramate administration to infants with cyanotic congenital heart disease to test the feasibility of this approach and generate preliminary data about markers of brain injury (serum S100B levels and urine metabolomics) and neurodevelopment at 18 months of age. If the approach is feasible and the preliminary data are encouraging a larger efficacy trial will be designed. Although topiramate has been used in neonates and infants to treat seizures and in a pilot study in term infants with hypoxic-ischemic encephalopathy, this is the first study of its effects on markers of brain injury and neurologic outcomes in infants with cyanotic congenital heart disease.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • UC Davis Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 2 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age less than 2 months
• Cyanotic congenital heart disease requiring surgery

Exclusion Criteria:

• Genetic syndromes with high risk of neurodevelopmental delay
• Gestational age less than 35 weeks at birth
• Multiple organ failure or multiple organ anomalies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Topiramate	Drug: Topiramate; Topiramate 5 mg/kg by mouth (or by feeding tube) once a day for one week before and one week after heart surgery.
Active Comparator: Control; These infants will undergo surgery, but will not receive topiramate	Other: No medication, but routine heart surgery; No medication, but routine heart surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in Plasma S100B	Baseline plasma S100B levels will be determined prior to surgery (at enrollment) with repeat levels at the two timepoints after surgery. Main outcome will be change from baseline.	1 week before surgery, 1 day and 1 week after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mullen Scales of Early Learning	This broad assessment of neurodevelopment includes five scales: Gross Motor, Visual Reception, Fine Motor, Expressive Language, and Receptive Language, with further testing if needed to explore deficits.	18 months of age
Changes from baseline in urine metabolomics	Urine specimens obtained at enrollment and at the two time points after surgery will be assessed for a broad range of metabolites (complex molecules). Changes from baseline will be evaluated.	1 week before surgery, 1 day and 1 week after surgery

Collaborators and Investigators

• Sponsor: University of California, Davis
• Investigators: Principal Investigator: Mark A Underwood, MD, University of California, Davis

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): July 28, 2017
• Study Completion (Actual): July 28, 2017

Study Registration Dates

• First Submitted: August 5, 2011
• First Submitted That Met QC Criteria: August 29, 2011
• First Posted (Estimate): August 31, 2011

Study Record Updates

• Last Update Posted (Actual): February 8, 2019
• Last Update Submitted That Met QC Criteria: February 7, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: stroke; brain injury; cerebral palsy; seizures
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Hypoglycemic Agents; Physiological Effects of Drugs; Anticonvulsants; Topiramate
• Other Study ID Numbers: 216534