Sildenafil exposure and hemodynamic effect after stage ii single-ventricle surgery

Kevin D. Hill, Robert Tunks, Piers C.A. Barker, Daniel K. Benjamin, Michael Cohen-Wolkowiez, Gregory A. Fleming, Matthew Laughon, Jennifer S. Li

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Abstract

OBJECTIVES: To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. DESIGN: Prospective, dose escalation trial. SETTING: Single-center, pediatric catheterization laboratory. PATIENTS: Twelve children poststage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range, 0.8, 4.0), weight 11 kg (8, 13), nine females, and 10 with a single right ventricle. INTERVENTIONS: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 min). MEASUREMENTS: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. MAIN RESULTS: Maximum sildenafil concentrations ranged from 92 to 775 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type 5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index in all 12 subjects (median pulmonary vascular resistance index 2.2 [range, 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU × m2; p < 0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p = 0.04) and saturations (+2% [0, 16], p = 0.04) in those with baseline pulmonary vascular resistance index ≥ 2 WU × m2 (n = 7). Change in saturations correlated inversely with change in pulmonary vascular resistance index (r2 = 0.74, p < 0.01). Sildenafil also lowered mean blood pressure (-12% [-20, +10]; p = 0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. CONCLUSIONS: Sildenafil demonstrated nonlinear exposure with high interindividual variability but was well tolerated and effectively lowered pulmonary vascular resistance index in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.

Original languageEnglish (US)
Pages (from-to)593-600
Number of pages8
JournalPediatric Critical Care Medicine
Volume14
Issue number6
DOIs
StatePublished - Jul 1 2013

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Hemodynamics
Vascular Resistance
Cardiac Catheterization
Catheterization
Echocardiography
Sildenafil Citrate
Type 5 Cyclic Nucleotide Phosphodiesterases
Heart Ventricles
Pediatrics
Blood Pressure
Weights and Measures
Lung

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Critical Care and Intensive Care Medicine

Cite this

Hill, K. D., Tunks, R., Barker, P. C. A., Benjamin, D. K., Cohen-Wolkowiez, M., Fleming, G. A., ... Li, J. S. (2013). Sildenafil exposure and hemodynamic effect after stage ii single-ventricle surgery. Pediatric Critical Care Medicine, 14(6), 593-600. https://doi.org/10.1097/PCC.0b013e31828aa5ee
Hill, Kevin D. ; Tunks, Robert ; Barker, Piers C.A. ; Benjamin, Daniel K. ; Cohen-Wolkowiez, Michael ; Fleming, Gregory A. ; Laughon, Matthew ; Li, Jennifer S. / Sildenafil exposure and hemodynamic effect after stage ii single-ventricle surgery. In: Pediatric Critical Care Medicine. 2013 ; Vol. 14, No. 6. pp. 593-600.
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abstract = "OBJECTIVES: To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. DESIGN: Prospective, dose escalation trial. SETTING: Single-center, pediatric catheterization laboratory. PATIENTS: Twelve children poststage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range, 0.8, 4.0), weight 11 kg (8, 13), nine females, and 10 with a single right ventricle. INTERVENTIONS: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 min). MEASUREMENTS: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. MAIN RESULTS: Maximum sildenafil concentrations ranged from 92 to 775 ng/mL and were above the in vitro threshold needed for 77{\%} phosphodiesterase type 5 (PDE-5) inhibition in 80{\%} of subjects and 90{\%} inhibition in 80{\%} of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index in all 12 subjects (median pulmonary vascular resistance index 2.2 [range, 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU × m2; p < 0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8{\%} [0, 20], p = 0.04) and saturations (+2{\%} [0, 16], p = 0.04) in those with baseline pulmonary vascular resistance index ≥ 2 WU × m2 (n = 7). Change in saturations correlated inversely with change in pulmonary vascular resistance index (r2 = 0.74, p < 0.01). Sildenafil also lowered mean blood pressure (-12{\%} [-20, +10]; p = 0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. CONCLUSIONS: Sildenafil demonstrated nonlinear exposure with high interindividual variability but was well tolerated and effectively lowered pulmonary vascular resistance index in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.",
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Hill, KD, Tunks, R, Barker, PCA, Benjamin, DK, Cohen-Wolkowiez, M, Fleming, GA, Laughon, M & Li, JS 2013, 'Sildenafil exposure and hemodynamic effect after stage ii single-ventricle surgery', Pediatric Critical Care Medicine, vol. 14, no. 6, pp. 593-600. https://doi.org/10.1097/PCC.0b013e31828aa5ee

Sildenafil exposure and hemodynamic effect after stage ii single-ventricle surgery. / Hill, Kevin D.; Tunks, Robert; Barker, Piers C.A.; Benjamin, Daniel K.; Cohen-Wolkowiez, Michael; Fleming, Gregory A.; Laughon, Matthew; Li, Jennifer S.

In: Pediatric Critical Care Medicine, Vol. 14, No. 6, 01.07.2013, p. 593-600.

Research output: Contribution to journalArticle

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T1 - Sildenafil exposure and hemodynamic effect after stage ii single-ventricle surgery

AU - Hill, Kevin D.

AU - Tunks, Robert

AU - Barker, Piers C.A.

AU - Benjamin, Daniel K.

AU - Cohen-Wolkowiez, Michael

AU - Fleming, Gregory A.

AU - Laughon, Matthew

AU - Li, Jennifer S.

PY - 2013/7/1

Y1 - 2013/7/1

N2 - OBJECTIVES: To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. DESIGN: Prospective, dose escalation trial. SETTING: Single-center, pediatric catheterization laboratory. PATIENTS: Twelve children poststage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range, 0.8, 4.0), weight 11 kg (8, 13), nine females, and 10 with a single right ventricle. INTERVENTIONS: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 min). MEASUREMENTS: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. MAIN RESULTS: Maximum sildenafil concentrations ranged from 92 to 775 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type 5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index in all 12 subjects (median pulmonary vascular resistance index 2.2 [range, 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU × m2; p < 0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p = 0.04) and saturations (+2% [0, 16], p = 0.04) in those with baseline pulmonary vascular resistance index ≥ 2 WU × m2 (n = 7). Change in saturations correlated inversely with change in pulmonary vascular resistance index (r2 = 0.74, p < 0.01). Sildenafil also lowered mean blood pressure (-12% [-20, +10]; p = 0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. CONCLUSIONS: Sildenafil demonstrated nonlinear exposure with high interindividual variability but was well tolerated and effectively lowered pulmonary vascular resistance index in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.

AB - OBJECTIVES: To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery. DESIGN: Prospective, dose escalation trial. SETTING: Single-center, pediatric catheterization laboratory. PATIENTS: Twelve children poststage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range, 0.8, 4.0), weight 11 kg (8, 13), nine females, and 10 with a single right ventricle. INTERVENTIONS: Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 min). MEASUREMENTS: Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance. MAIN RESULTS: Maximum sildenafil concentrations ranged from 92 to 775 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type 5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index in all 12 subjects (median pulmonary vascular resistance index 2.2 [range, 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU × m2; p < 0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p = 0.04) and saturations (+2% [0, 16], p = 0.04) in those with baseline pulmonary vascular resistance index ≥ 2 WU × m2 (n = 7). Change in saturations correlated inversely with change in pulmonary vascular resistance index (r2 = 0.74, p < 0.01). Sildenafil also lowered mean blood pressure (-12% [-20, +10]; p = 0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events. CONCLUSIONS: Sildenafil demonstrated nonlinear exposure with high interindividual variability but was well tolerated and effectively lowered pulmonary vascular resistance index in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.

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