Sildenafil Exposure and Hemodynamic Effect After Fontan Surgery


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Abstract

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 0.45 mg/kg over 20 min).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 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 × 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.

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