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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Heart Defects, Congenital	Drug: nesiritide; Drug: milrinone; Drug: placebo	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	106 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Impact of Empiric Nesiritide or Milrinone Infusion on Early Postoperative Recovery Following Fontan Surgery: a Randomized, Double-blind, Placebo-controlled Clinical Trial
Study Start Date :	October 2007
Actual Primary Completion Date :	January 2013
Actual Study Completion Date :	July 2013

Arms and Interventions

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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 Name: 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 Name: 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

Outcome Measures

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Primary Outcome Measures :

1. Days Alive and Out of the Hospital Within 30 Days of Surgery. [ Time Frame: 30 days ]

Secondary Outcome Measures :

1. Cardiovascular: Cardiac Index [ Time Frame: Postoperative hour #1 ]
   Cardiac index measured using Fick principle with measured oxygen consumption.
2. Cardiovascular: Cardiac Index [ Time Frame: Postoperative hour #8 ]
   Cardiac index measured using Fick principle with measured oxygen consumption.
3. Cardiovascular: Arrhythmia [ Time Frame: Postoperative day (POD) #0 through 5 ]
   arrhythmia lasting >30 seconds or requiring treatment
4. Cardiovascular: Peak Inotrope Score [ Time Frame: 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.

5. Cardiovascular: Peak Lactate Level [ Time Frame: Initial 24 hours in CICU ]
6. Renal Function: Urine Output [ Time Frame: first 24 hours CICU admit ]
   Volume of urine in mL/kg per day
7. Renal Function: Maximum Change in Serum Creatinine [ Time Frame: 14 days after surgery ]
8. Resource Utilization: Hours of Mechanical Ventilation Until Initial Extubation [ Time Frame: 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.
9. Resource Utilization: Days of Initial CICU Stay [ Time Frame: 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.
10. Resource Utilization: Chest Tube Days [ Time Frame: 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.
11. Resource Utilization: Days Alive and Out of Hospital Within 180 Days of Surgery [ Time Frame: 180 days ]
    Days the patient was alive and out of hospital within the 180 days after Fontan surgery
12. Plasma Norepinephrine Levels. [ Time Frame: Preoperative baseline to 24 hours after CICU admission ]
    Plasma norepinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.
13. Epinephrine Levels [ Time Frame: Preoperative baseline to 24 hours after CICU admission ]
    Plasma epinephrine levels measured at preoperative baseline and postoperative CICU hour 1, 8, 24.
14. N-terminal Pro-brain Natriuretic Peptide Levels [ Time Frame: 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.

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Older Adult
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Locations

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

Sponsors and Collaborators

John M Costello

American Heart Association

Investigators

Principal Investigator:	John M Costello, MD MPH	Boston Children’s Hospital

More Information

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Publications of Results:

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.

Responsible Party:	John M Costello, Associate in Cardiology, Boston Children’s Hospital
ClinicalTrials.gov Identifier:	NCT00543309 History of Changes
Other Study ID Numbers:	0735070N
First Posted:	October 12, 2007
Results First Posted:	June 22, 2018
Last Update Posted:	June 22, 2018
Last Verified:	May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided
Plan Description:	email the PI for data requests.

Keywords provided by John M Costello, Boston Children’s Hospital:

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

Additional relevant MeSH terms:

Heart Defects, Congenital; Congenital Abnormalities; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Natriuretic Peptide, Brain; Milrinone; Natriuretic Agents; Physiological Effects of Drugs	Cardiotonic Agents; Platelet Aggregation Inhibitors; Vasodilator Agents; Phosphodiesterase 3 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Protective Agents