Heart Disease
Conditions
Keywords
Hypoplastic left heart syndrome, Hypoplastic right heart syndrome, Superior cavopulmonary anastomosis, Total cavopulmonary anastomosis, Children with single ventricle anatomy
Brief summary
Patients with single ventricle anatomy undergo staged surgical palliation. The result is an in series circulation with pulmonary blood flow and cardiac output directly related to pulmonary vascular resistance. While surgical outcomes have improved, the physiology of the single ventricle palliation results in continued long term attrition. Elevated pulmonary vascular resistance and impaired systemic ventricular function are important risk factors for failure of single ventricle palliation. Sildenafil is a pulmonary vasodilator and has been shown to improve cardiac contractility in the pressure overloaded right ventricle. The investigators will assess the safety, pharmacokinetics and hemodynamic efficacy of sildenafil in single ventricle patients following stage II and III surgical palliation.
Interventions
DRUGSildenafil by injection
Sildenafil 0.125mg/kg injection over 20min
Sponsors
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 120 Months
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 3 months; ≤120 months. 2. History of congenital heart disease with severe hypoplasia of a right or left ventricle. 3. Undergoing cardiac catheterization as part of standard clinical care. 4. Availability and willingness of the parent/legally authorized representative to provide written informed consent.
Exclusion criteria
1. History of serious adverse event related to sildenafil administration. 2. History of sildenafil exposure within 48 hours of the study. 3. Presence of pulmonary venous obstruction. 4. Treatment with organic nitrates or alpha blockade therapy. 5. Contraindication to cardiac catheterization as determined by the attending cardiologist and including: 1. Significant hemodynamic instability. 2. Sepsis. 3. Need for Extra-Corporeal Membrane Oxygenation (ECMO) support. 4. Venous occlusion precluding adequate access. 5. Recent systemic illness. 6. Renal failure defined as serum creatinine \> 2 times higher than the upper limit of normal. 7. Liver dysfunction defined as alanine aminotransferase or aspartate aminotransferase \> 3 times higher than the upper limit of normal. 8. Thrombocytopenia defined as a platelet count \< 50 000 cells/µL. 9. Leukopenia defined as white blood cells \< 2500 cells/µL.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Sildenafil Plasma Concentration | 5 minutes after completion of sildenafil infusion | Assessment of peak sildenafil plasma concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hemodynamic Safety and Efficacy | 10 minutes after completion of sildenafil infusion | Assessment of pulmonary vascular resistance |
Countries
United States
Participant flow
Recruitment details
Patients recruited upon presentation for elective Pre-stage II or stage III catheterization. The first patient was recruited on 4/14/2011 and the final patient was enrolled on 11/29/2012
Pre-assignment details
Enrolled subjects were excluded from trial participation if they demonstrated baseline hemodynamics suggesting that they would not tolerate sildenafil infusion (e.g. baseline hypotension)
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Pharmacokinetic and hemodynamic evaluation following sildenafil administration
Sildenafil by injection : Sildenafil 0.45mg/kg by injection over 20min
Sildenafil by injection : Sildenafil 0.25mg/kg injection over 20min
Sildenafil by injection : Sildenafil 0.35mg/kg by injection over 20min
Sildenafil by injection : Sildenafil 0.125mg/kg injection over 20min | 21 |
| Total | 21 |
Baseline characteristics
| Characteristic | Sildenafil |
|---|---|
| Age, Categorical <=18 years | 21 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age Continuous | 3.4 years STANDARD_DEVIATION 2.6 |
| Region of Enrollment United States | 21 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 3 | 0 / 5 | 0 / 8 | 0 / 5 |
| serious Total, serious adverse events | 0 / 3 | 0 / 5 | 0 / 8 | 0 / 5 |
Outcome results
Primary
Maximum Sildenafil Plasma Concentration
Assessment of peak sildenafil plasma concentration.
Time frame: 5 minutes after completion of sildenafil infusion
Population: 3 patients were enrolled in this group but in 1 participant, an inadequate plasma sample volume prevented accurate determination of sildenafil concentration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Peak Sildenafil Level (ng/mL) for Dose = 0.125mg/kg | Maximum Sildenafil Plasma Concentration | 181 ng/mL | Standard Deviation 126 |
| Peak Sildenafil Level (ng/mL) for Dose = 0.35mg/kg | Maximum Sildenafil Plasma Concentration | 515 ng/mL | Standard Deviation 98 |
| Peak Sildenafil Level (ng/mL) for Dose = 0.45mg/kg | Maximum Sildenafil Plasma Concentration | 545 ng/mL | Standard Deviation 185 |
| Peak Sildenafil Level (ng/mL) for Dose = 0.25mg/kg | Maximum Sildenafil Plasma Concentration | 202 ng/mL | Standard Deviation 92 |
Secondary
Hemodynamic Safety and Efficacy
Assessment of pulmonary vascular resistance
Time frame: 10 minutes after completion of sildenafil infusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peak Sildenafil Level (ng/mL) for Dose = 0.125mg/kg | Hemodynamic Safety and Efficacy | 2.3 Wood units * m^2 |
| Peak Sildenafil Level (ng/mL) for Dose = 0.35mg/kg | Hemodynamic Safety and Efficacy | 1.6 Wood units * m^2 |