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

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00543309

Enrollment

106

Registered

2007-10-12

Start date

2007-10-31

Completion date

2013-07-31

Last updated

2018-06-25

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Defects, Congenital

Keywords

Fontan Operation, Cardiopulmonary Bypass, Heart Defects, Congenital, Milrinone, Natriuretic peptide, brain

Brief summary

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.

Interventions

DRUGnesiritide

Nesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted

DRUGmilrinone

Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted

DRUGplacebo

Placebo bolus on CPB, then placebo infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame
Days Alive and Out of the Hospital Within 30 Days of Surgery.	30 days

Secondary

Measure	Time frame	Description
Cardiovascular: Arrhythmia	Postoperative day (POD) #0 through 5	arrhythmia lasting \>30 seconds or requiring treatment
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.
Cardiovascular: Peak Lactate Level	Initial 24 hours in CICU	—
Renal Function: Urine Output	first 24 hours CICU admit	Volume of urine in mL/kg per day
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.
Cardiovascular: Cardiac Index	Postoperative hour #1	Cardiac index measured using Fick principle with measured oxygen consumption.
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.
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.

Countries

United States

Participant flow

Recruitment details

Recruitment period: October 2007 - January 2013. Location: Cardiac operating rooms and cardiac intensive care unit (CICU) at Boston Children's Hospital

Participants by arm

Arm	Count
I- 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. nesiritide: Nesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted	35
II- 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. milrinone: Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted	36
III- 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. placebo: Placebo bolus on CPB, then placebo infusion	35
Total	106

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Physician Decision	0	1	0

Baseline characteristics

Characteristic	II- Milrinone	III- Placebo	I- Nesiritide	Total
Age, Continuous	2.6 years	2.7 years	2.7 years	2.7 years
Chromosomal abnormality or syndrome	1 Participants	1 Participants	3 Participants	5 Participants
History of Arrhythmias	5 Participants	2 Participants	9 Participants	16 Participants
Noncardiac congenital anomaly	7 Participants	6 Participants	4 Participants	17 Participants
Prior Cardiac Operations	2 operations	2 operations	2 operations	2 operations
Prior Interventional Cardiac Catheterization	30 Participants	30 Participants	28 Participants	88 Participants
Race/Ethnicity, Customized Race Asian	3 Participants	2 Participants	0 Participants	5 Participants
Race/Ethnicity, Customized Race Black	2 Participants	4 Participants	3 Participants	9 Participants
Race/Ethnicity, Customized Race Hispanic/Latino	7 Participants	5 Participants	3 Participants	15 Participants
Race/Ethnicity, Customized Race More than one race	0 Participants	2 Participants	0 Participants	2 Participants
Race/Ethnicity, Customized Race Other	0 Participants	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Race White	24 Participants	22 Participants	28 Participants	74 Participants
Region of Enrollment United States	36 Participants	35 Participants	35 Participants	106 Participants
Sex: Female, Male Female	17 Participants	12 Participants	15 Participants	44 Participants
Sex: Female, Male Male	19 Participants	23 Participants	20 Participants	62 Participants
Ventricular Morphology Left dominant	10 Participants	12 Participants	15 Participants	37 Participants
Ventricular Morphology Right dominant	25 Participants	22 Participants	20 Participants	67 Participants
Ventricular Morphology Two ventricles	1 Participants	1 Participants	0 Participants	2 Participants
Weight	12.8 kilograms	12.6 kilograms	12.5 kilograms	12.6 kilograms

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	1 / 35	0 / 36	0 / 35
other Total, other adverse events	24 / 35	27 / 36	24 / 35
serious Total, serious adverse events	0 / 35	0 / 36	0 / 35

Outcome results

Primary

Days Alive and Out of the Hospital Within 30 Days of Surgery.

Time frame: 30 days

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Days Alive and Out of the Hospital Within 30 Days of Surgery.	20 days
II- Milrinone	Days Alive and Out of the Hospital Within 30 Days of Surgery.	18 days
III- Placebo	Days Alive and Out of the Hospital Within 30 Days of Surgery.	20 days

Secondary

Cardiovascular: Arrhythmia

arrhythmia lasting \>30 seconds or requiring treatment

Time frame: Postoperative day (POD) #0 through 5

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
I- Nesiritide	Cardiovascular: Arrhythmia	16 Participants
II- Milrinone	Cardiovascular: Arrhythmia	21 Participants
III- Placebo	Cardiovascular: Arrhythmia	13 Participants

Secondary

Cardiovascular: Cardiac Index

Cardiac index measured using Fick principle with measured oxygen consumption.

Time frame: Postoperative hour #8

Population: Study patients for whom cardiac index measurements were available.

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Cardiovascular: Cardiac Index	3.2 L/min/m2
II- Milrinone	Cardiovascular: Cardiac Index	2.9 L/min/m2
III- Placebo	Cardiovascular: Cardiac Index	2.5 L/min/m2

Secondary

Cardiovascular: Cardiac Index

Cardiac index measured using Fick principle with measured oxygen consumption.

Time frame: Postoperative hour #1

Population: Study patients for whom cardiac index measurements were available.

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Cardiovascular: Cardiac Index	3.5 L/min/m2
II- Milrinone	Cardiovascular: Cardiac Index	2.8 L/min/m2
III- Placebo	Cardiovascular: Cardiac Index	2.5 L/min/m2

Secondary

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.

Time frame: Initial 24 hours in CICU

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Cardiovascular: Peak Inotrope Score	5 dose equivalents
II- Milrinone	Cardiovascular: Peak Inotrope Score	5 dose equivalents
III- Placebo	Cardiovascular: Peak Inotrope Score	5 dose equivalents

Secondary

Cardiovascular: Peak Lactate Level

Time frame: Initial 24 hours in CICU

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Cardiovascular: Peak Lactate Level	2.6 mEq/liter
II- Milrinone	Cardiovascular: Peak Lactate Level	3.1 mEq/liter
III- Placebo	Cardiovascular: Peak Lactate Level	3.1 mEq/liter

Secondary

Epinephrine Levels

Plasma epinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.

Time frame: Preoperative baseline to 24 hours after CICU admission

Arm	Measure	Group	Value (MEDIAN)
I- Nesiritide	Epinephrine Levels	Preoperative baseline	0 ng/mL
I- Nesiritide	Epinephrine Levels	1 hour after CICU admit	1.2 ng/mL
I- Nesiritide	Epinephrine Levels	8 hours after CICU admit	0.5 ng/mL
I- Nesiritide	Epinephrine Levels	24 hours after CICU admit	0.2 ng/mL
II- Milrinone	Epinephrine Levels	24 hours after CICU admit	1.5 ng/mL
II- Milrinone	Epinephrine Levels	Preoperative baseline	0 ng/mL
II- Milrinone	Epinephrine Levels	8 hours after CICU admit	0.5 ng/mL
II- Milrinone	Epinephrine Levels	1 hour after CICU admit	2.7 ng/mL
III- Placebo	Epinephrine Levels	24 hours after CICU admit	1.3 ng/mL
III- Placebo	Epinephrine Levels	1 hour after CICU admit	2.1 ng/mL
III- Placebo	Epinephrine Levels	8 hours after CICU admit	1.0 ng/mL
III- Placebo	Epinephrine Levels	Preoperative baseline	0 ng/mL

Secondary

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.

Time frame: Preoperative baseline to 24 hours after CICU admission

Arm	Measure	Group	Value (MEDIAN)
I- Nesiritide	N-terminal Pro-brain Natriuretic Peptide Levels	1 hour after CICU admit	81 fmol/mL
I- Nesiritide	N-terminal Pro-brain Natriuretic Peptide Levels	24 hours after CICU admit	142 fmol/mL
I- Nesiritide	N-terminal Pro-brain Natriuretic Peptide Levels	8 hours after CICU admit	91 fmol/mL
I- Nesiritide	N-terminal Pro-brain Natriuretic Peptide Levels	Preoperative baseline	77 fmol/mL
II- Milrinone	N-terminal Pro-brain Natriuretic Peptide Levels	8 hours after CICU admit	71 fmol/mL
II- Milrinone	N-terminal Pro-brain Natriuretic Peptide Levels	24 hours after CICU admit	136 fmol/mL
II- Milrinone	N-terminal Pro-brain Natriuretic Peptide Levels	1 hour after CICU admit	61 fmol/mL
II- Milrinone	N-terminal Pro-brain Natriuretic Peptide Levels	Preoperative baseline	77 fmol/mL
III- Placebo	N-terminal Pro-brain Natriuretic Peptide Levels	24 hours after CICU admit	109 fmol/mL
III- Placebo	N-terminal Pro-brain Natriuretic Peptide Levels	Preoperative baseline	88 fmol/mL
III- Placebo	N-terminal Pro-brain Natriuretic Peptide Levels	8 hours after CICU admit	88 fmol/mL
III- Placebo	N-terminal Pro-brain Natriuretic Peptide Levels	1 hour after CICU admit	77 fmol/mL

Secondary

Plasma Norepinephrine Levels.

Plasma norepinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.

Time frame: Preoperative baseline to 24 hours after CICU admission

Arm	Measure	Group	Value (MEDIAN)
I- Nesiritide	Plasma Norepinephrine Levels.	Preoperative baseline	0.2 ng/mL
I- Nesiritide	Plasma Norepinephrine Levels.	1 hour after CICU admit	2.0 ng/mL
I- Nesiritide	Plasma Norepinephrine Levels.	8 hours after CICU admit	2.3 ng/mL
I- Nesiritide	Plasma Norepinephrine Levels.	24 hours after CICU admit	1.3 ng/mL
II- Milrinone	Plasma Norepinephrine Levels.	24 hours after CICU admit	1.5 ng/mL
II- Milrinone	Plasma Norepinephrine Levels.	Preoperative baseline	0.4 ng/mL
II- Milrinone	Plasma Norepinephrine Levels.	8 hours after CICU admit	2.4 ng/mL
II- Milrinone	Plasma Norepinephrine Levels.	1 hour after CICU admit	2.1 ng/mL
III- Placebo	Plasma Norepinephrine Levels.	24 hours after CICU admit	1.3 ng/mL
III- Placebo	Plasma Norepinephrine Levels.	1 hour after CICU admit	2.9 ng/mL
III- Placebo	Plasma Norepinephrine Levels.	8 hours after CICU admit	1.3 ng/mL
III- Placebo	Plasma Norepinephrine Levels.	Preoperative baseline	0.5 ng/mL

Secondary

Renal Function: Maximum Change in Serum Creatinine

Time frame: 14 days after surgery

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Renal Function: Maximum Change in Serum Creatinine	0.1 mg/dL
II- Milrinone	Renal Function: Maximum Change in Serum Creatinine	0.2 mg/dL
III- Placebo	Renal Function: Maximum Change in Serum Creatinine	0.2 mg/dL

Secondary

Renal Function: Urine Output

Volume of urine in mL/kg per day

Time frame: first 24 hours CICU admit

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Renal Function: Urine Output	43 mL/kg per day
II- Milrinone	Renal Function: Urine Output	37 mL/kg per day
III- Placebo	Renal Function: Urine Output	34 mL/kg per day

Secondary

Resource Utilization: Chest Tube Days

Days during which one or more chest tubes were in place following the Fontan operation.

Time frame: From Fontan operation until final chest tube removed, assessed during postoperative hospitalization, up to 90 days.

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Resource Utilization: Chest Tube Days	5 days
II- Milrinone	Resource Utilization: Chest Tube Days	5 days
III- Placebo	Resource Utilization: Chest Tube Days	5 days

Secondary

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

Time frame: 180 days

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery	167 days
II- Milrinone	Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery	168 days
III- Placebo	Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery	170 days

Secondary

Resource Utilization: Days of Initial CICU Stay

Days of initial postoperative CICU care following the Fontan operation.

Time frame: From Fontan operation until initial discharge from the CICU, assessed during the postoperative hospitalization, up to 90 days.

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Resource Utilization: Days of Initial CICU Stay	3 days
II- Milrinone	Resource Utilization: Days of Initial CICU Stay	3 days
III- Placebo	Resource Utilization: Days of Initial CICU Stay	2 days

Secondary

Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation

Hours of mechanical ventilation until initial extubation following the Fontan operation.

Time frame: From Fontan operation until initial extubation, assessed during initial CICU stay, up to 30 days.

Arm	Measure	Value (MEDIAN)
I- Nesiritide	Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation	24 hours
II- Milrinone	Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation	23 hours
III- Placebo	Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation	22 hours

Source: ClinicalTrials.gov · Data processed: Mar 7, 2026

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

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Days Alive and Out of the Hospital Within 30 Days of Surgery.

Cardiovascular: Arrhythmia

Cardiovascular: Cardiac Index

Cardiovascular: Cardiac Index

Cardiovascular: Peak Inotrope Score

Cardiovascular: Peak Lactate Level

Epinephrine Levels

N-terminal Pro-brain Natriuretic Peptide Levels

Plasma Norepinephrine Levels.

Renal Function: Maximum Change in Serum Creatinine

Renal Function: Urine Output

Resource Utilization: Chest Tube Days

Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery

Resource Utilization: Days of Initial CICU Stay

Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation