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. Convalescence from Fontan surgery: days of intensive care; hours of mechanical ventilation; days of chest tube drainage; direct costs of hospitalization; number of days alive and out of the hospital within 180 days of surgery. [ Time Frame: 180 days ]
2. Hemodynamics following Fontan surgery: CI at postop. hours 1, 8; CVP, peak lactate level, inotropic score, troponin I level and net fluid balance within 24 hours of CICU admit; incidence of tachyarrhythmias during the first 120 hours of CICU admission. [ Time Frame: 5 days ]
3. Renal function following Fontan surgery: Urine output during first 24 hours of postoperative CICU admit; diuretic requirements for the first 120 postoperative hours; maximal change in serum creatinine and creatinine clearance up to 14 days after surgery. [ Time Frame: 2 weeks ]
4. Neurohumoral profile following Fontan surgery: plasma aldosterone, norepinephrine, epinephrine, renin, endothelin-1 and vasopressin levels from preoperative baseline to postoperative CICU hour 1. [ Time Frame: 24 hours ]
5. Adverse events associated with nesiritide, milrinone or placebo use following Fontan surgery. [ Time Frame: Throughout hospitalization ]

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
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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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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, Children's Hospital, Boston
ClinicalTrials.gov Identifier:	NCT00543309 History of Changes
Other Study ID Numbers:	0735070N
First Posted:	October 12, 2007
Last Update Posted:	November 4, 2013
Last Verified:	November 2013

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

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