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

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.

Study Overview

• Status: Terminated
• Conditions: Heart Defects, Congenital
• Intervention / Treatment: Drug: nesiritide; Drug: milrinone; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: nesiritide; Nesiritide bolus 2 mcg/kg on CPB, then infusion of 0.015 mcg/kg/min. infusion dose may be adjusted; Other Names: Natrecor
Active Comparator: 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.	Drug: milrinone; Milrinone 50 mcg/kg bolus on CPB, the infusion of 0.5 mcg/kg/min. Infusion rate may be adjusted; Other Names: Primacor
Placebo Comparator: 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.	Drug: placebo; Placebo bolus on CPB, then placebo infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: John M Costello
• Collaborators: American Heart Association
• Investigators: Principal Investigator: John M Costello, MD MPH, Boston Children's Hospital

Publications and helpful links

General Publications

• Costello JM, Dunbar-Masterson C, Allan CK, Gauvreau K, Newburger JW, McGowan FX Jr, Wessel DL, Mayer JE Jr, Salvin JW, Dionne RE, Laussen PC. Impact of empiric nesiritide or milrinone infusion on early postoperative recovery after Fontan surgery: a randomized, double-blind, placebo-controlled trial. Circ Heart Fail. 2014 Jul;7(4):596-604. doi: 10.1161/CIRCHEARTFAILURE.113.001312. Epub 2014 Jun 6.

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): January 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: October 10, 2007
• First Submitted That Met QC Criteria: October 10, 2007
• First Posted (Estimate): October 12, 2007

Study Record Updates

• Last Update Posted (Actual): June 25, 2018
• Last Update Submitted That Met QC Criteria: May 25, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Heart Defects, Congenital; Cardiopulmonary Bypass; Milrinone; Fontan Operation; Natriuretic peptide, brain
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiovascular Abnormalities; Congenital Abnormalities; Heart Defects, Congenital; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Natriuretic Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Milrinone; Natriuretic Peptide, Brain
• Other Study ID Numbers: 0735070N

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: email the PI for data requests.