This article provides a review of the use of sildenafil in the treatment of PAH in children. A recent study conducted by Roldan and colleagues in children found that there was a statistically significant increase in adverse drug reaction (ADR) frequency in patients receiving higher-than-recommended doses. Lee JE, Hillier SC, Knoderer CA. Table 5 gives a summary of the recent case series and studies on the use of sildenafil in the pediatric population in the last 5 years (2009-2013). It lowered systemic and PVRI in all nine children, with no dose-response effect. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Nil: Shaltout et . Indicators of a successful response include improved oxygenation indices, a 3 kPa increase in arterial oxygen partial pressure (PaO2), ability to wean fractional inspired oxygen (FiO2), an increase in the arterial/alveolar pO2 ratio and a decrease in the oxygenation index (OI). No reports of alteration in vision or hearing and no priapism. Single-dose IV sildenafil (0.25 mg/kg, 0.35 mg/kg, or 0.45 mg/kg over 20 min. CDH: 4, PPHN-1, IPAH-3, ALL post-chemotherapy PVOD-1, BPD/multiple pulmonary emboli-1, post repair of CHD-15, By nasogastric tube or orally 0.25 mg per kg per dose and increased this to 1 mg/kg/dose administered four times daily as tolerated and by observation of clinical effect. [16,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43], Summary of the recent case series and studies on the use of sildenafil in the pediatric population (2009-13)[16,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43], AE Adverse events; ALL Acute lymphatic leukemia; AP window Aortopulmonary window; ASD Atrial septal defect; AVSD Atrioventricular septal defect; AVSD-L Unbalanced atrioventricular septal defect with left dominance; AVSD-R Unbalanced atrioventricular septal defect with right dominance; BPD Bronchopulmonary dysplasia; CDH Congenital diaphragmatic hernia; CHD Congenital heart disease; CPB Cardiopulmonary bypass; D Day; do Dose; ECMO extracorporeal membrane oxygenation; FiO2 Fraction of inspired oxygen; GA General anesthesia; HLHS Hypoplastic left heart syndrome; h Hour; IPAH Idiopathic pulmonary arterial hypertension; iNO Inhaled nitric oxide; min Minute; mo Month; mPAP Mean pulmonary artery pressure; mSBP Mean systemic blood pressure; NG Nasogastric; OG Orogastric; OI Oxygenation index; OST Oral sildenafil therapy; PDA Patent ductus arteriosus; PA/AO Pulmonary artery to aortic pressure ratios; PA Pulmonary artery; PPHN Persistent pulmonary hypertension of the newborn; PH Pulmonary hypertension; PVR Pulmonary vascular resistance; PVRI Pulmonary vascular resistance index; PVOD Pulmonary veno-occlusive disease; RV Right ventricular; TA Tricuspid atresia; TGV+PS+strad AVV Transposition of the great vessels, pulmonary stenosis, straddling atrioventricular valve; VSD Ventricular septal defect; WU Wood units; Wk Week; Yr Year, Sildenafil is useful in relieving transient postoperative PAH associated with CHD surgery. The failure group had a higher daily sildenafil dose (180 vs. 115.5 mg; p = 0.06), with 42.8 % of patients at the highest sildenafil dose failing the transition. Hepatic cytochrome P (CYP) 3A4 (major) and CYP-2C9 (minor) enzyme systems are responsible for the formation of active metabolites. First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension. Ghofrani HA, Wiedemann R, Rose F, et al. In August 2012, the USFDA released a strong warning against the use of sildenafil for pediatric patients (ages 1-17 years) with PAH. Use: Treatment of erectile dysfunction. Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. In adults, it is rapidly absorbed after oral administration and the maximum serum concentrations are reached within 0.5-2 h of administration. Nyp M, Sandritter T, Poppinga N, Simon C, Truog WE. Ten infants received milrinone in combination with sildenafil. 2005 Jun 1;171(11):1292-7 Drug Des Devel Ther. Stocker and colleagues showed that when used in conjunction with iNO, sildenafil did produce reductions in the PVRI,[62] but that this was also associated with worsened arterial oxygenation and reduction in systemic blood pressure. [12] The issue of administering sildenafil to children weighing less than 8 kg has not been addressed. Administration of tadalafil suspension was generally safe and well tolerated. It also requires fewer daily doses than sildenafil.[70]. [10] The drug undergoes extensive first-pass metabolism in the liver, and the oral bioavailability is 40%. PMC Nine children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: Median age and weight 5.2 years and 16.3 kg, respectively. Ikeda D, Tsujino I, Ohira H, et al. [53] The generally scarce evidence underlines that sildenafil should be used cautiously in infants with BPD-associated PH as a rescue therapy, even though the possibility of long term benefits of sildenafil on lung growth exists. Systolic PA pressure was reduced with sildenafil (4611 to 356 mmHg vs placebo). Sildenafil is USFDA-approved only in adults with PAH, not in children. Primary pulmonary hypertension in hiv patients: A systematic review. With the exception of post-operative pediatric cardiac surgery patients, sildenafil has not been associated with significant adverse effects in any of the subtypes of PH for which it has been studied. Neonates continued to receive the standard treatment for PPHN consisting of hyperventilation, inotropes, oxygen, and sedation. Mortality: Group 1: 1 early death from intractable PH; Group 2: 4 from hypoxia and central venous hypertension; Group 3: None. Simonneau G, Galie N, Rubin LJ, et al. Inhaled nitric oxide (iNO), iloprost, bosentan, and sildenafil are used in the treatment of children with PAH. Pulmonary arterial hypertension (PAH), characterized by the progressive obliteration of the pulmonary vasculature, is associated with high mortality and great morbidity, especially in children. Sildenafil injection (Revatio) for the treatment of pulmonary arterial hypertension (PAH) in patients who are unable to take sildenafil orally (March 2011) Funding decision: Recommended with restrictions Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. When sildenafil is used to treat PAH, it's often marketed under the name Revatio and uses a reduced dosage of sildenafil. The goal dose was 1 mg/kg three times daily for a duration of 6-51 mo prior to follow-up. The other 17 patients were in the control group with mean age of 5914 months and 10 (59%) males. Phosphodiesterase (PDE)-5 inhibitors (e.g., sildenafil). 21 - 23 In 2005, sildenafil was approved for use in PAH at a dose of 20 mg 3 times daily, based in large part to the SUPER trial. Need for more data regarding long-term coadministration, Combination may decrease sildenafil levels and efficacy, and may increase bosentan levels, risk of hypotension, and other adverse effects, Additive effect. Careers, Unable to load your collection due to an error. Countervailing influences of nitric oxide and angiotensin ii. Tantini B, Manes A, Fiumana E, et al. Durongpisitkul K, Pornrattanarungsi S, Panjasamanvong P, Chungsomprasong P. Keogh AM, Jabbour A, Weintraub R, Brown K, Hayward CS, Macdonald PS. It has twice the potency of oral sildenafil. Includes sildenafil side effects, interactions and indications. Schfer A, Bauersachs J. High-altitude pulmonary edema:Potential protection by red wine. [General anesthesia with mechanical ventilation and a FiO. m 2, was confirmed by right heart catheterization at baseline. government site. Although PAH has no curative treatment, a greater understanding of pathophysiology, technological advances resulting in early diagnosis, and the availability of several newer drugs have improved the outlook for patients with PAH. Administer sildenafil tablet doses 4 to 6 hours apart. They will produce the same SFC plasma concentration at their. [66] Bhutta and colleagues[67] have pointed out that the interpretation of the study results by the USFDA has added to the confusion. No deaths due to RV failure. Vachiery JL, Huez S, Gillies H, Layton G, Hayashi N, Gao X, et al. This leads to vasoconstriction, smooth muscle proliferation, intra-arterial thrombosis, reduction in pulmonary arterial lumen size, and plexogenic arteriopathy. Reiter CD, Wang X, Tanus-Santos JE, et al. Among these, sildenafil is the most widely used and has, in great part, contributed to improved survival in this group, from a historical less-than-1-year survival in untreated children in the 1980s to a 97% 5-year survival rate in children with severe PAH. There was a trend towards a decrease in PVR in the treatment groups (Aldashev et al 2005). Safety and tolerability of targeted therapies for pulmonary hypertension in children. Similarly, Schulze-Neick et al. May increase the risk of hypotension. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. The site is secure. Gali N, Manes A, Uguccioni L, et al. Pulmonary hypertension in sickle cell disease:Cardiac catheterization results and survival. Efficacy and safety of sildenafil added to treprostinil in pulmonary hypertension. The observed problems of systemic hypotension and impaired oxygenation experienced by patients receiving IV sildenafil raises concerns and could limit its use. Pediatric Pulmonary Hypertension Network (PPHNet). Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Sildenafil exposure and hemodynamic effect after fontan surgery. Sutton LL, Castro O, Cross DJ, et al. [1] However, it must be conceded that most of the agents mentioned are used off-label in children and the use is based mainly on experience in adults with PAH. The active metabolite N-desmethyl sildenafil makes up for 40% of its serum concentrations and is responsible for 20% of its pharmacological activity. After its release for the use in ED, sildenafil was found to be an effective pulmonary artery vasodilator. Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients with hemoglobinopathies. Ghofrani HA, Schermuly RT, Rose F, et al. Tadalafil is a once-daily PDE-5I approved for the treat-ment of patients with World Health Organization (WHO)group 1 PAH at a dose of 40 mg daily.8Tadalafil's longerhalf-life of 17.5 hours in healthy individuals and 35 hours inpatients with PAH,9compared with that of sildenafil at 4 to5hours,10allows for once-daily dosing. Sildenafil for the treatment of pulmonary hypertension in pediatric patients. The authors have no conflicts of interest to declare. -, Ann Intern Med. The studies leading to the USFDA rulings have been criticized. Increase the risk of severe hypotension, Risk of hypotension and reduced sildenafil clearance, Possibility of subtherapeutic levels of sildenafil in view of its increased clearance, Monitoring of levels advisable, as doses may have to be increased, Safer to add sildenafil over the short term. Itoh T, Nagaya N, Fujii T, et al. Assessment report for Revatio. Sildenafil was also associated with improvements in WHO functional class and haemodynamic parameters, and was generally well tolerated. Most men who use sildenafil to treat ED take the medication 30 minutes to one hour before sexual activity. National Library of Medicine National Library of Medicine A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Department of Pediatrics, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra, India. Various studies and case series have shown beneficial effects of sildenafil in pediatric PAH; however, caution has to be taken regarding its long-term use with higher doses, as recently highlighted by the USFDA. Epub 2007 Oct 24. Pollman MJ, Yamada T, Horiuchi M, et al. Group 1: Baseline mPAP/mSBP ratio decreased significantly after the second and fourth doses of OST. 2004, Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), Associated with significant venous or capillary involvement, Pulmonary capillary hemangiomatosis (PCH), Persistent pulmonary hypertension of the newborn, Pulmonary hypertension (PH) with left heart disease, Left-sided atrial or ventricular heart disease, PH associated with lung disease and/or hypoxemia, PH due to chronic thrombotic and/or embolic disease, Thromboembolic obstruction of proximal pulmonary arteries, Thromboembolic obstruction of distal pulmonary arteries, Non-thrombotic pulmonary embolism (tumor, parasites, foreign material), Sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangiomatosis, compression of pulmonary vessels by adenopathy, tumor fibrosing mediastinitis, or other process, Randomized, placebo controlled, double blind, crossover, Randomized double blind, placebo controlled, 6 min walk 170 m at end of placebo phase vs 266 m at end of sildenafil phase, p<0.005, Exercise treadmill time 475168 s at end of placebo phase vs 686224 s at end of sildenafil phase, p<0.0001, Placebo corrected increase in mean 6 min walk distance 20, 40, and 80 mg; 45, 46, and 50 m (p<0.001), Significant improvement in Borg dyspnea score and PASP, Significant improvement in cardiac index and QOL, no change in PASP, Significant improvement in mPAP, CI (40 and 80 mg dose), PVR,WHO functional class, no change in time to worsening or Borg dyspnea scale, Increased rate of headache and epistaxis in sildenafil group, 6 minute walk distance (placebo corrected, in meters). 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