Early Use of Vasopressin in Post-Fontan Management (VAMP)

June 20, 2020 updated by: Amee Bigelow, Medical College of Wisconsin

Use of Arginine Vasopressin in Early Postoperative Management After Fontan Palliation

This is an investigator initiated, prospective, single-center, double-blinded, randomized, placebo-controlled trial of post-operative low dose vasopressin infusions as an early treatment of low systemic perfusion in pediatric patients following Fontan palliation.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The treatments for preventing and managing low cardiac output syndrome after congenital heart surgery with cardiopulmonary bypass include manipulations of vascular volume and infusions of phosphodiesterase inhibitors (milrinone) and catecholamines (epinephrine and norepinephrine) for inotropic and vasoactive effects, all of which have associated risks which can contribute to morbidity and mortality. Vasopressin, a vasoactive drug with efficacy in septic shock, has also been utilized to improve postoperative hemodynamics after cardiac surgery in children. It is a common institutional practice to use vasopressin in this patient population, but usually after escalation through two or three other vasoactive drugs. There have been several studies in pediatrics and adults which suggest that vasopressin is not inferior to other vasoconstrictor therapies, and advantageous when looking at specific end points. The investigators propose to randomize the use of vasopressin to use at an earlier point in our typical post-operative medication strategy. The proposed study is a double blinded, randomized, placebo control study of vasopressin infusion immediately after the completion Fontan operation. The goal is to identify a vasoactive treatment strategy that improves hemodynamics with lower catecholamine infusion burden, reduces volume of fluid resuscitation, and reduces in-hospital resource utilization.

Neonatal and pediatric interventions associated with congenital heart disease (CHD) continue to produce improved outcomes. There are no established guidelines for managing patients after congenital heart surgery due to lesion-specific unique challenges in the post-operative period. Volume resuscitation and catecholamine infusions are the traditional treatment methods to maintain adequate perfusion. However, these two treatment modalities are associated with increased risk of worsening lung function and prolonged ventilator support with aggressive fluid resuscitation, increased myocardial oxygen demand, and precipitation of arrhythmias. Given the multifactorial etiology of postoperative low cardiac output syndrome, it is often unclear which catecholamine infusion is optimal to improve circulatory function. Vasopressin, an alternative vasoactive therapy commonly utilized in shock, has been utilized to improve postoperative hemodynamics in neonatal and pediatric patient populations and has recently gained more attention.

The use of arginine vasopressin infusion in infants and children after cardiac surgery was first reported in 1999 in a case series of 11 patients with vasodilatory shock in the postoperative period. This case series reported initiation of vasopressin for hypotension refractory to traditional treatment methods and reported a significant rise in hemodynamics with improved blood pressure in all patients as well as weaning inotropic support in 10/11 patients. Since this study there have been conflicting reports regarding vasopressin levels and the use of vasopressin to improve hemodynamics. Results from a study published in 2008 evaluated vasopressin levels in 39 patients with CHD in the pre and post-operative periods and concluded that children do not have deficient levels of vasopressin following surgery with cardiopulmonary bypass (CPB). In addition, lower levels were not associated with hypotension. A larger study in 2010 of 121 patients who had congenital heart surgery with CPB described results suggestive of clinically important hypotension associated with low vasopressin levels. Several other publications have reported improved blood pressure and decreased catecholamine usage in patients with CHD. Two of these reports have focused on vasopressin use in infants with single ventricle physiology. In all of these reported case series the vasopressin infusion has been initiated in the post-operative period as a rescue therapy. None of the studies have advocated for initiation of vasopressin immediately post-operatively and prior to a time period of hemodynamic instability, except for one retrospective chart review by Alten et al. This study from 2012 initiated vasopressin in the operating room after CPB in 19 neonates undergoing either an arterial switch for d-transposition of the great arteries or the Norwood palliation procedure for hypoplastic left heart syndrome. In this study, all neonates in whom vasopressin was initiated in the operating room received significantly lower amounts of volume replacement and catecholamine support in the immediate post-operative period. They also described lower heart rate, lower incidence of arrhythmias, shorter duration of mechanical ventilation and shorter intensive care unit stay when compared to lesion-matched control group. More recently in 2016, a single center retrospectively reviewed their experience with vasopressin and patients undergoing Fontan operations over a 10 year period and it's effects on chest tube output. They determined that patients receiving vasopressin perioperatively had less chest tube output and shorter duration of chest tube drainage in addition to shorter hospital length of stay and improved fluid balance as compared to historical controls.

There is a gap in the literature describing improved outcomes with a specific targeted vasoactive and inotropic therapy regimen to use in the post-operative Fontan procedure patients. This proposed novel study will further provide evidence for outcome based post-operative medical interventions. The proposed study is a double blinded, randomized control study of vasopressin infusion versus placebo in the first 24-hours after Fontan completion. The aim of this study is to evaluate the impact of vasopressin on the early postoperative course in a relatively homogenous population, with specific attention to catecholamine use, hemodynamics, pleural drainage, extracardiac organ function (kidney and liver) and length of stay. Furthermore, the investigators plan to evaluate vasopressin levels between the two groups.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Children's Hospital of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 weeks to 18 years (ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Planned completion of Fontan palliation
  • English or Spanish speaking
  • Completion of Informed Consent

Exclusion Criteria:

  • Previous failed attempts at Fontan completion with subsequent takedown
  • Planned concomitant atrioventricular valvuloplasty or neoaortic valve or arch reconstruction at the time of Fontan completion
  • History of renal failure requiring renal replacement therapy
  • Absence of informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: QUADRUPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Vasopressin, Arginine
Patients randomized to this arm will receive a continuous arginine vasopressin in normal saline carrier infusion immediately following the modified ultrafiltration (MUF) period of their cardiac surgery.
Drug: Vasopressin, Arginine
Subjects will be started on a blinded continuous infusion of study drug/placebo in the OR, immediately following the completion of the MUF at 0.3 mU/kg/min. All caregivers will be blinded to the arm assignment. The infusion will run for 20 hours, at which time it will be weaned off at 0.1 mU/hr, over 3 hours.During the active study period, the care team will treat subjects per SOC, using any preferred medication to correct low cardiac output; there is no restriction on using open-label vasopressin during the active study treatment period.
Other Names:
  • Arginine Vasopressin
PLACEBO_COMPARATOR: Placebo
Patients randomized to this arm will receive a continuous normal saline carrier infusion immediately following the modified ultrafiltration (MUF) period of their cardiac surgery.
Drug: Placebo
Subjects will be started on a blinded continuous infusion of study drug/placebo in the OR, immediately following the completion of the MUF at 0.3 mU/kg/min. All caregivers will be blinded to the arm assignment. The infusion will run for 20 hours, at which time it will be weaned off at 0.1 mU/hr, over 3 hours.During the active study period, the care team will treat subjects per SOC, using any preferred medication to correct low cardiac output; there is no restriction on using open-label vasopressin during the active study treatment period.
Other Names:
  • Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hemodynamics as Characterized by Vasoactive Inotrope Score (VIS)
Time Frame: 48 hours post-operative
The vasoactive inotrope score (VIS) is a linear sum of vasoactive and inotrope durg infusion doses. It is usually reported as dimensionless but is sometimes reported as normalized to dopamine mcg/kg/min equivalents. The score starts at 0 and has no defined upper limit, with a commonly observed range 0-50. It is used as a measure of the intensity of hemodynamic support, with higher scores indicating more vasoactive drug support for patients. The relationship of VIS to other patient outcomes is not consistent. It will be calculated hourly for all subjects and compared between groups over the entire observation timeframe.
48 hours post-operative
Hemodynamics as Characterized by Mean Arterial Pressure
Time Frame: 24 hours post-operative
Organ perfusion pressure measured as Mean Arterial Pressure (MAP). It will be measured hourly for 24 postoperative hours for all subjects and compared between the two study groups over the whole time of observation as the main between-group effect in panel regression.
24 hours post-operative
Hemodynamics as Characterized by Transpulmonary Pressure Gradient
Time Frame: 24 hours post-operative
The transpulmonary pressure gradient (TPG), defined as the difference between mean pulmonary arterial pressure (Ppa) and left/common atrial (common atrial) pressure (Pla) will be measured hourly for 24 postoperative hours for all subjects and compared between the two study groups over the whole time of observation as the main between-group effect in panel regression.
24 hours post-operative

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Renal Dysfunction as Characterized by Change in Cystatin Level
Time Frame: from baseline pre-cardiopulmonary bypass to 24 hours post-operative
Cystatin levels will be measured at baseline (immediately before cardiopulmonary bypass) 24 hours postoperative. The change (postoperative minus baseline) in cystatin level will be compared between groups.
from baseline pre-cardiopulmonary bypass to 24 hours post-operative
Liver Dysfunction as Characterized by Transaminase Levels
Time Frame: 48 hours post-operative
Transaminase levels (alanine and aspartate, measured in IU/L ) will be tracked for all patients and changes will be compared between study groups.
48 hours post-operative

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Resource Utilization Measured by Length of Stay (LOS)
Time Frame: from time of operation until hospital discharge
Length of stay (LOS) measured in postoperative hours compared between groups
from time of operation until hospital discharge

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Medical College of Wisconsin

Investigators

  • Principal Investigator: George Hoffman, MD, Medical College Of Wisconsin

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 6, 2017

Primary Completion (ACTUAL)

November 1, 2018

Study Completion (ACTUAL)

January 28, 2019

Study Registration Dates

First Submitted

February 28, 2017

First Submitted That Met QC Criteria

March 16, 2017

First Posted (ACTUAL)

March 23, 2017

Study Record Updates

Last Update Posted (ACTUAL)

July 7, 2020

Last Update Submitted That Met QC Criteria

June 20, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRBNet 885148

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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