Effects of Perioperative Nesiritide or Milrinone Infusion on Recovery From Fontan Surgery

Study Overview
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Brief Summary
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The staged surgical pathway to treat children with single ventricle heart defects culminates with the Fontan operation. In this procedure, systemic venous return is rerouted directly to the pulmonary arteries, which serves to separate the systemic and pulmonary circulations. Although mortality following the Fontan operation is now uncommon, early postoperative morbidity including prolonged postoperative chest tube drainage and hospitalization remains significant. The efficacy of empiric inotropic, vasodilator and neurohumoral-inhibitory therapies in the perioperative period is unknown and practice varies widely between centers. The investigators will propose a single-center, randomized, double-blind, phase II clinical trial in children undergoing Fontan surgery. The investigators plan to compare the effects of perioperative nesiritide, milrinone and placebo infusions on the early postoperative clinical course and neurohumoral profile. The investigators hypothesize that, when compared to the milrinone and placebo groups, the nesiritide group will have more days alive and out of the hospital within the first 30 days after surgery.

Detailed Description
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The staged surgical pathway to treat children with single ventricle heart defects culminates with the Fontan operation. In this procedure, systemic venous return is rerouted directly to the pulmonary arteries, which serves to separate the systemic and pulmonary circulations. Following this operation, deoxygenated blood flows passively from the body through the lungs without a pumping chamber. Although mortality following the Fontan operation is now uncommon, early postoperative morbidity including prolonged postoperative chest tube drainage and hospitalization remains significant. The efficacy of empiric inotropic, vasodilator and neurohumoral-inhibitory therapies in the perioperative period is unknown and practice varies widely between centers. We propose a single-center, randomized, double-blind, phase II clinical trial in children undergoing Fontan surgery. We plan to compare the effects of perioperative nesiritide, milrinone and placebo infusions on the early postoperative clinical course and neurohumoral profile. The primary aim of the study is to determine whether nesiritide, milrinone or placebo infusion is associated with fewer days alive and out of the hospital within 30 days of surgery. We hypothesize that, when compared to the milrinone and placebo groups, the nesiritide group will have more days alive and out of the hospital within the first 30 days after surgery. Secondary aims are to determine the effects of these infusions on postoperative resource consumption, hemodynamics, arrhythmias, renal function, neurohumoral activation and adverse events. Thirty-nine patients per group (117 total patients) will be enrolled over three years.

Official Title
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Impact of Empiric Nesiritide or Milrinone Infusion on Early Postoperative Recovery Following Fontan Surgery: a Randomized, Double-blind, Placebo-controlled Clinical Trial

Conditions
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Heart Defects, Congenital

Intervention / Treatment
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* Drug: nesiritide
* Drug: milrinone
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing an elective, primary Fontan operation at Children's Hospital Boston. Exclusion Criteria: Revision surgery for failing Fontan circulation. Preoperative serum creatinine > 1.5 mg/dL or chronic dialysis. The attending surgeon, cardiac anesthesiologist, or cardiac intensivist has a compelling indication to initiate either nesiritide or milrinone outside of the confines of the study.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I- nesiritide<br>Patients assigned to the nesiritide group will receive an intravenous loading dose of 2 mcg/kg followed by an infusion of 0.015 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. | Drug: nesiritide<br>* Nesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted<br>* Other names: Natrecor;|
| Active Comparator: II- Milrinone<br>Patients assigned to the milrinone group will receive a bolus of 50 mcg/kg followed by an infusion of 0.5 mcg/kg/min, administered for at least 12 hours after CICU admission and up to five days unless prespecified lack of efficacy criteria are met. | Drug: milrinone<br>* Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted<br>* Other names: Primacor;|
| Placebo Comparator: III- placebo<br>Patients assigned to the placebo group will receive a 0.33 mL/kg bolus of 5% dextrose in water (D5W), followed by an infusion of D5W, administered for at least 12 hours after CICU admission and up to five days, unless prespecified lack of efficacy criteria are met. | Drug: placebo<br>* Placebo bolus on CPB, then placebo infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days Alive and Out of the Hospital Within 30 Days of Surgery. |  | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular: Cardiac Index | Cardiac index measured using Fick principle with measured oxygen consumption. | Postoperative hour #1 | 
| Cardiovascular: Cardiac Index | Cardiac index measured using Fick principle with measured oxygen consumption. | Postoperative hour #8 | 
| Cardiovascular: Arrhythmia | arrhythmia lasting >30 seconds or requiring treatment | Postoperative day (POD) #0 through 5 | 
| Cardiovascular: Peak Inotrope Score | Peak Inotrope Score = Doses of dopamine in mcg/kg/minute + dobutamine in mcg/kg/minute + (epinephrine in mcg/kg/minute x 100). The lowest (best) possible Peak Inotrope Score = 0 dose equivalents. There is no maximum Peak Inotrope Score. | Initial 24 hours in CICU | 
| Cardiovascular: Peak Lactate Level |  | Initial 24 hours in CICU | 
| Renal Function: Urine Output | Volume of urine in mL/kg per day | first 24 hours CICU admit | 
| Renal Function: Maximum Change in Serum Creatinine |  | 14 days after surgery | 
| Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation | Hours of mechanical ventilation until initial extubation following the Fontan operation. | From Fontan operation until initial extubation, assessed during initial CICU stay, up to 30 days. | 
| Resource Utilization: Days of Initial CICU Stay | Days of initial postoperative CICU care following the Fontan operation. | From Fontan operation until initial discharge from the CICU, assessed during the postoperative hospitalization, up to 90 days. | 
| Resource Utilization: Chest Tube Days | Days during which one or more chest tubes were in place following the Fontan operation. | From Fontan operation until final chest tube removed, assessed during postoperative hospitalization, up to 90 days. | 
| Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery | Days the patient was alive and out of hospital within the 180 days after Fontan surgery | 180 days | 
| Plasma Norepinephrine Levels. | Plasma norepinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Preoperative baseline to 24 hours after CICU admission | 
| Epinephrine Levels | Plasma epinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Preoperative baseline to 24 hours after CICU admission | 
| N-terminal Pro-brain Natriuretic Peptide Levels | N-terminal pro-brain natriuretic peptide levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24. | Preoperative baseline to 24 hours after CICU admission | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fontan Operation, Cardiopulmonary Bypass, Heart Defects, Congenital, Milrinone, Natriuretic peptide, brain