title: Sildenafil exposure and hemodynamic effect after Fontan surgery.
abstract: OBJECTIVE
  Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery.
  
  
  METHODS
  Prospective dose-escalation trial.
  
  
  METHODS
  Single-center pediatric catheterization laboratory.
  
  
  METHODS
  Nine children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: median (range) age and weight, 5.2 years (2.5-9.4 yr) and 16.3 kg (9.5-28.1 kg). Five children (55%) were boys, and six of nine (67%) had a systemic right ventricle.
  
  
  METHODS
  Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.25, 0.35, or 0.45 mg/kg over 20 min).
  
  
  RESULTS
  Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic variables measured by cardiac catheterization and echocardiography. Maximum sildenafil concentrations ranged from 124 to 646 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type-5 inhibition in eight of nine children and 90% inhibition in seven of seven children with doses more than or equal to 0.35 mg/kg. Sildenafil improved stroke volume (+22%, p = 0.05) and cardiac output (+10%, p = 0.01) with no significant change in heart rate in eight of nine children. Sildenafil also lowered systemic (-16%, p = 0.01) and pulmonary vascular resistance index in all nine children (median baseline pulmonary vascular resistance index 2.4 [range, 1.3-3.7]; decreased to 1.9 [0.8-2.7] Wood Units × m; p = 0.01) with no dose-response effect. Pulmonary arterial pressures decreased (-10%, p = 0.02) and pulmonary blood flow increased (9%, p = 0.02). There was no change in myocardial performance index and no adverse events.
  
  
  CONCLUSIONS
  After Fontan surgery, sildenafil infusion acutely improves cardiopulmonary hemodynamics, increasing cardiac index. For the range of doses studied, exposure was within the acute safety range reported in adult subjects.
authors.affiliation: 1Department of Pediatrics, Duke University Medical Center, Durham, NC. 2Duke Clinical Research Institute, Durham, NC. 3Department of Pediatrics, University of North Carolina, Chapel Hill, NC.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Tunks
authors.forename: Piers C A
authors.initials: PC
authors.lastname: Barker
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Fleming
authors.forename: Matthew
authors.initials: M
authors.lastname: Laughon
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Li
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Hill
mesh_terms: D062186:Arterial Pressure / Q000187:drug effects; D006328:Cardiac Catheterization; D002648:Child; D002675:Child, Preschool; D004452:Echocardiography; D005260:Female; D018729:Fontan Procedure; D006330:Heart Defects, Congenital / Q000601:surgery; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D058986:Phosphodiesterase 5 Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011182:Postoperative Care; D011446:Prospective Studies; D011651:Pulmonary Artery / Q000502:physiology; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013318:Stroke Volume / Q000187:drug effects; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate