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

Phase 2

Terminated

Conditions: Heart Defects, Congenital

Interventions: Drug: milrinone
Drug: placebo
Drug: nesiritide

Registration Number: NCT00543309

Lead Sponsor: John M Costello

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 106

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
II- Milrinone	milrinone	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.
III- placebo	placebo	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.
I- nesiritide	nesiritide	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.

Primary Outcome Measures

Name	Time	Method
Days Alive and Out of the Hospital Within 30 Days of Surgery.	30 days

Secondary Outcome Measures

Name	Time	Method
Cardiovascular: Cardiac Index	Postoperative hour #8	Cardiac index measured using Fick principle with measured oxygen consumption.
Cardiovascular: Peak Lactate Level	Initial 24 hours in CICU
Cardiovascular: Arrhythmia	Postoperative day (POD) #0 through 5	arrhythmia lasting \>30 seconds or requiring treatment
Renal Function: Urine Output	first 24 hours CICU admit	Volume of urine in mL/kg per day
Cardiovascular: Peak Inotrope Score	Initial 24 hours in CICU	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.
Renal Function: Maximum Change in Serum Creatinine	14 days after surgery
Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation	From Fontan operation until initial extubation, assessed during initial CICU stay, up to 30 days.	Hours of mechanical ventilation until initial extubation following the Fontan operation.
Resource Utilization: Days of Initial CICU Stay	From Fontan operation until initial discharge from the CICU, assessed during the postoperative hospitalization, up to 90 days.	Days of initial postoperative CICU care following the Fontan operation.
Resource Utilization: Chest Tube Days	From Fontan operation until final chest tube removed, assessed during postoperative hospitalization, up to 90 days.	Days during which one or more chest tubes were in place following the Fontan operation.
Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery	180 days	Days the patient was alive and out of hospital within the 180 days after Fontan surgery
Plasma Norepinephrine Levels.	Preoperative baseline to 24 hours after CICU admission	Plasma norepinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.
Epinephrine Levels	Preoperative baseline to 24 hours after CICU admission	Plasma epinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.
N-terminal Pro-brain Natriuretic Peptide Levels	Preoperative baseline to 24 hours after CICU admission	N-terminal pro-brain natriuretic peptide levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.