Sildenafil exposure and hemodynamic effect after fontan surgery
Objective: Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery. Design: Prospective dose-escalation trial. Setting: Single-center pediatric catheterization laboratory. Patients: 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. Interventions: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.25, 0.35, or 0.45mg/kg over 20min). Measurements and Main Results: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic variables measured by cardiac catheterization and echocardiography. Maximum sildenafil concentrations ranged from 124 to 646ng/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 × m2; 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. Copyright © 2013 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Tunks, RD; Barker, PCA; Benjamin, DK; Cohen-Wolkowiez, M; Fleming, GA; Laughon, M; Li, JS; Hill, KD
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