Early Use of Vasopressin in Post-Fontan Management
Condition: Circulatory Perfusion Disorder; Congenital Heart Disease; Single-ventricle
MeSH terms: Heart Diseases; Heart Defects, Congenital; Univentricular Heart
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

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.
    

Intervention name(s): Vasopressin, Arginine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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 intervention name(s): Arginine Vasopressin; Normal Saline
Intervention MeSH terms: Vasopressins; Arginine Vasopressin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Fontan Palliation Surgery; Post-Operative Care