Sildenafil exposure and hemodynamic effect after fontan surgery

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 0.45mg/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.

Original languageEnglish (US)
Pages (from-to)28-34
Number of pages7
JournalPediatric Critical Care Medicine
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2014

Fingerprint

Hemodynamics
Cardiac Catheterization
Catheterization
Vascular Resistance
Echocardiography
Type 5 Cyclic Nucleotide Phosphodiesterases
Lung
Sildenafil Citrate
Cardiac Output
Stroke Volume
Heart Ventricles
Arterial Pressure
Heart Rate
Pediatrics
Safety
Weights and Measures

All Science Journal Classification (ASJC) codes

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

Cite this

Tunks, R., Barker, P. C. A., Benjamin, D. K., Cohen-Wolkowiez, M., Fleming, G. A., Laughon, M., ... Hill, K. D. (2014). Sildenafil exposure and hemodynamic effect after fontan surgery. Pediatric Critical Care Medicine, 15(1), 28-34. https://doi.org/10.1097/PCC.0000000000000007
Tunks, Robert ; Barker, Piers C.A. ; Benjamin, Daniel K. ; Cohen-Wolkowiez, Michael ; Fleming, Gregory A. ; Laughon, Matthew ; Li, Jennifer S. ; Hill, Kevin D. / Sildenafil exposure and hemodynamic effect after fontan surgery. In: Pediatric Critical Care Medicine. 2014 ; Vol. 15, No. 1. pp. 28-34.
@article{d52af0e440614a279734bd64955e0ab7,
title = "Sildenafil exposure and hemodynamic effect after fontan surgery",
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 0.45mg/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.",
author = "Robert Tunks and Barker, {Piers C.A.} and Benjamin, {Daniel K.} and Michael Cohen-Wolkowiez and Fleming, {Gregory A.} and Matthew Laughon and Li, {Jennifer S.} and Hill, {Kevin D.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1097/PCC.0000000000000007",
language = "English (US)",
volume = "15",
pages = "28--34",
journal = "Pediatric Critical Care Medicine",
issn = "1529-7535",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

Tunks, R, Barker, PCA, Benjamin, DK, Cohen-Wolkowiez, M, Fleming, GA, Laughon, M, Li, JS & Hill, KD 2014, 'Sildenafil exposure and hemodynamic effect after fontan surgery', Pediatric Critical Care Medicine, vol. 15, no. 1, pp. 28-34. https://doi.org/10.1097/PCC.0000000000000007

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

In: Pediatric Critical Care Medicine, Vol. 15, No. 1, 01.01.2014, p. 28-34.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Sildenafil exposure and hemodynamic effect after fontan surgery

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.

AU - Hill, Kevin D.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84892798091&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892798091&partnerID=8YFLogxK

U2 - 10.1097/PCC.0000000000000007

DO - 10.1097/PCC.0000000000000007

M3 - Article

VL - 15

SP - 28

EP - 34

JO - Pediatric Critical Care Medicine

JF - Pediatric Critical Care Medicine

SN - 1529-7535

IS - 1

ER -

Tunks R, Barker PCA, Benjamin DK, Cohen-Wolkowiez M, Fleming GA, Laughon M et al. Sildenafil exposure and hemodynamic effect after fontan surgery. Pediatric Critical Care Medicine. 2014 Jan 1;15(1):28-34. https://doi.org/10.1097/PCC.0000000000000007