Cardiopulmonary Bypass, Heart Defects, Congenital
Conditions
Keywords
Nesiritide, Natriuretic Peptide, Brain, Heart Defects, Congenital, Cardiopulmonary Bypass, Diuretics
Brief summary
The purpose of this study is to determine the effects of nesiritide on urine output and hemodynamics following cardiopulmonary bypass in infants. Safety and pharmacokinetic data will also be obtained.
Detailed description
Nesiritide, a recombinant human B-type natriuretic peptide, has vasodilatory, lusitropic and diuretic properties in healthy humans, and improves hemodynamics and symptoms in adults with decompensated congestive heart failure. Several retrospective case series suggest that nesiritide has beneficial effects on hemodynamics and urine output in adults and children following cardiac surgery. The purpose of this prospective, randomized, double-blind, crossover study is to evaluate the effects of a continuous infusion of nesiritide on postoperative hemodynamics and urine output in infants with congenital heart disease who undergo cardiac surgery requiring cardiopulmonary bypass (CPB). Patients less than 1 year of age following cardiac surgery will be eligible for the study if they have received two conventional diuretics (furosemide and chlorothiazide) for at least 12 hours, yet are not effectively achieving a negative fluid balance, thus prohibiting sternal closure or tracheal extubation. Patients will be randomized to receive either a 10-hour infusion of nesiritide, a two hour washout period, followed by a 10-hour infusion of placebo, or this study drug sequence in reverse order. During the 24-hour study period, serial cardiac output measurements and BNP levels will be obtained, vital signs and intracardiac filling pressures will be recorded, and urine output will be measured.
Interventions
DRUGnesiritide
nesiritide 0.015 mcg/kg/hour x 10 hours
DRUGPlacebo
0.9% sodium chloride infusion
Sponsors
Boston Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 1 Years
Healthy volunteers
No
Inclusion criteria
* \> 48 hours after cardiac surgery requiring cardiopulmonary bypass * \< 1 year of age * Receiving chlorothiazide and furosemide for \> 12 hours * Urine output \< 4 cc/kg/hour, or fluid intake \> output for 2 consecutive days * Receiving mechanical ventilation * Presence of body wall edema on CXR, defined as a radiologic index of \> 2 * Plan for \> 24 hrs further diuresis before chest closure or extubation
Exclusion criteria
* Age \> 365 days at the time of enrollment * Corrected estimated gestational age \< 35 weeks at the time of enrollment * Serum creatinine \> 2.0 mg/dL at the time of enrollment * Significant hemodynamic instability at the time of enrollment * Lack of dedicated intravenous access for nesiritide infusion * Lack of arterial line for continuous blood pressure monitoring * Lack of a Foley catheter for continuous urine collection * Enrollment in another research study such that the outcomes of either study may be confounded by participation in this study, or such that the amount of blood drawn for research purposes becomes excessive.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urine Output | 5 hours | Urine output measured in cc/kg/hour during the last 5 hours of the study drug infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Hypotension and Bradycardia | 48 hours | Hypotension (mean arterial blood pressure \< 40 mmHg for \> 30 minutes) that is refractory to volume administration, increased inotropic/vasopressor support, and weaning of other vasodilators (e.g., milrinone) or sedatives Bradycardia, defined as 1) a decrease in heart rate of more than 30 beats/minute from baseline following the initiation of study drug infusion that 2) results in new requirement for temporary atrial pacing or other treatment specifically to increase heart rate and 3) is not readily explainable by other conditions. |
| Urine Output | 10 hours | — |
| Cardiac Index | Baseline (hour 0) and 6 hours after onset of study drug infusion | Cardiac index is based on the cardiac output, which is the amount of blood the left ventricle ejects into the systemic circulation in one minute, measured in liters per minute (l/min). Cardiac output is indexed to a patient's body size by dividing by the body surface area (m\^2) to yield the cardiac index. Cardiac index was calculated in patients with an SVC catheter (previously placed for clinical indications) using the Fick principle using measured oxygen consumption (VO2), hemoglobin levels, and the difference between arterial and superior vena cava oxygen saturation. Oxygen consumption was measured using a real-time gas exchange technique with the Deltatrack II gas sensor. |
Countries
United States
Participant flow
Recruitment details
Recruitment: April 2006- June 2007. Location: Cardiac ICU in a large children's hospital.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Because all participants were randomized to receive all interventions, baseline measurements are combined rather that reported by Arm/Group. | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | All Study Participants | — |
|---|---|---|
| Age, Continuous | 6 days | — |
| Prematurity | 2 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 9 participants | — |
| Sex: Female, Male Female | 3 Participants | — |
| Sex: Female, Male Male | 6 Participants | — |
| Weight | 3.5 Kg | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
Urine Output
Urine output measured in cc/kg/hour during the last 5 hours of the study drug infusion
Time frame: 5 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Urine Output | 2.9 cc/kg/hr |
| Nesiritide | Urine Output | 3.1 cc/kg/hr |
Secondary
Cardiac Index
Cardiac index is based on the cardiac output, which is the amount of blood the left ventricle ejects into the systemic circulation in one minute, measured in liters per minute (l/min). Cardiac output is indexed to a patient's body size by dividing by the body surface area (m\^2) to yield the cardiac index. Cardiac index was calculated in patients with an SVC catheter (previously placed for clinical indications) using the Fick principle using measured oxygen consumption (VO2), hemoglobin levels, and the difference between arterial and superior vena cava oxygen saturation. Oxygen consumption was measured using a real-time gas exchange technique with the Deltatrack II gas sensor.
Time frame: Baseline (hour 0) and 6 hours after onset of study drug infusion
Population: Cardiac index was only able to be measured for 4 of the 9 subjects enrolled in the trial.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Cardiac Index | baseline | 1.83 L/min/m^2 |
| Placebo | Cardiac Index | 6 hours after onset of drug infusion | 1.95 L/min/m^2 |
| Nesiritide | Cardiac Index | baseline | 1.90 L/min/m^2 |
| Nesiritide | Cardiac Index | 6 hours after onset of drug infusion | 2.15 L/min/m^2 |
Secondary
Number of Participants With Hypotension and Bradycardia
Hypotension (mean arterial blood pressure \< 40 mmHg for \> 30 minutes) that is refractory to volume administration, increased inotropic/vasopressor support, and weaning of other vasodilators (e.g., milrinone) or sedatives Bradycardia, defined as 1) a decrease in heart rate of more than 30 beats/minute from baseline following the initiation of study drug infusion that 2) results in new requirement for temporary atrial pacing or other treatment specifically to increase heart rate and 3) is not readily explainable by other conditions.
Time frame: 48 hours
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Hypotension and Bradycardia | hypotension | 0 Participants |
| Placebo | Number of Participants With Hypotension and Bradycardia | bradycardia | 0 Participants |
| Nesiritide | Number of Participants With Hypotension and Bradycardia | hypotension | 0 Participants |
| Nesiritide | Number of Participants With Hypotension and Bradycardia | bradycardia | 0 Participants |
Secondary
Urine Output
Time frame: 10 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Urine Output | 3.4 cc/kg/hr |
| Nesiritide | Urine Output | 4.2 cc/kg/hr |