Sildenafil in pediatric pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease of varied etiologies. 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. Sildenafil is one of the therapeutic agents used extensively in the treatment of PAH in children, as an off-label drug. In 2012, the United States Food and Drug Administration (USFDA) issued a warning regarding the of use high-dose sildenafil in children with PAH. This has led to a peculiar situation where there is a paucity of approved therapies for the management of PAH in children and the use of the most extensively used drug being discouraged by the regulator. This article provides a review of the use of sildenafil in the treatment of PAH in children.

Introduction

Pulmonary arterial hypertension (PAH), characterized by the progressive obliteration of the pulmonary vasculature, is associated with high mortality and great morbidity, especially in children.[1] Better understanding of the pathophysiology of PAH, advances in technology allowing for early diagnosis, and the availability of several newer therapeutic agents have improved the outlook for patients with PAH. Inhaled nitric oxide (iNO), iloprost, bosentan, and sildenafil are used in the treatment of children with PAH. 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.[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 recently issued U.S. Food and Drug Administration (USFDA) warning has created fresh doubts in the minds of treating pediatricians regarding the use of sildenafil in children with PAH.[2] This communication attempts to review the place of sildenafil in the treatment of childhood PAH.

PAH in children: Pathophysiology and classification

PAH is defined as a mean pulmonary artery pressure (PAP) of 25 mmHg or higher at rest, with a normal pulmonary capillary wedge pressure (<15 mmHg) and increased pulmonary vascular resistance (PVR) index (PVRI>3 Woods units × m²).[3] This definition applies to all but the youngest patients. According to the latest classification provided by the World Congress on Pulmonary Hypertension [Table 1],[4] PAH forms a segment of the wider pulmonary hypertension (PH) spectrum. Additionally, PAH is subcategorized into the idiopathic (IPAH) and associated (APAH) forms secondary to other pathologies. Recent genetic evidence identifying PAH-associated alleles has further divided IPAH into hereditary (HPAH) forms as well.

Table 1

Classification of PAH*[4]

PAH

Idiopathic PAH

Heritable

BMPR2

ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia)

Unknown

Drug- and toxin-induced

Associated with:

Connective tissue diseases

HIV infection

Portal hypertension

CHDs

Schistosomiasis

Chronic hemolytic anemia

PPHN

Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

PH owing to left heart disease

Systolic dysfunction

Diastolic dysfunction

Valvular disease

PH owing to lung diseases and/or hypoxia

Chronic obstructive pulmonary disease

Interstitial lung disease

Other pulmonary diseases with mixed restrictive and obstructive pattern

Sleep-disordered breathing

Alveolar hypoventilation disorders

Chronic exposure to high altitude

Developmental abnormalities

Chronic thromboembolic pulmonary hypertension

Pulmonary hypertension with unclear multifactorial mechanisms

Hematologic disorders: Myeloproliferative disorders, splenectomy

Systemic disorders: Sarcoidosis, pulmonary Langerhans cell histiocytosis, Lymphangioleiomyomatosis, neurofibromatosis, vasculitis

Metabolic disorders: Glycogen storage disease, Gaucher disease, thyroid disorders

Others: Tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

*Classification provided by the World Congress on Pulmonary Hypertension held in Dana Point, CA, USA in 2008; PAH – Pulmonary arterial hypertension; BMPR2 – Bone morphogenetic protein receptor type II; ALK1 – Activin receptor-like kinase-1; HIV – Human immunodeficiency virus; CHD – Congenital heart disease; PPHN – Persistent pulmonary hypertension of the newborn

The etiology of PH in children is more diverse. In children, the predominant diagnoses are PAH associated with congenital heart disease (CHD) and IPAH.[1] Persistent PH of the newborn (PPHN) is the most common cause of PH in the neonatal period. PH associated with neonatal and chronic lung disease [e.g., bronchopulmonary dysplasia (BPD)] is another less common and probably underreported cause encountered in the pediatric population.[1] There are other differences as well. Children with PAH seem to have a greater inability to increase cardiac output in response to exercise, hence, these children commonly present with exercise-associated syncopal attacks. In addition, while adults typically present with a diminished cardiac index, children usually have a normal cardiac index at the time of presentation. Due to the difficulties in applying the Dana Point classification to children, a working group of the Pulmonary Vascular Research Institute developed a unique pediatric classification [Table 2]. In this classification, PH in children is defined as in adults for a biventricular circulation, but PH in the setting of single-ventricle physiology is defined as PVRI >3.0 Wood units × m2 or a transpulmonary gradient >6 mm Hg.[5]

Table 2

Pulmonary vascular research institute classification of pediatric PH vascular disease (Panama 2011)[5]

Prenatal or developmental pulmonary vascular disease
Perinatal pulmonary vascular maladaptation
Pediatric cardiovascular disease
BPD
Pediatric lung diseases
Multifactorial pulmonary vascular disease in congenital malformation syndromes
Isolated pediatric PAH
Pediatric thromboembolic disease
Pediatric hypobaric hypoxic exposure
Pulmonary vascular disease associated with other system disorders

PH – Pulmonary hypertension; BPD – Bronchopulmonary dysplasia

An imbalance between the vasoconstrictor substances (thromboxane and endothelins) and vasodilatory substances [nitric oxide (NO) and prostacyclin] with increased concentrations of the former and reduced ones of the latter seem to be the predominant basis for the occurrence of PAH. This leads to vasoconstriction, smooth muscle proliferation, intra-arterial thrombosis, reduction in pulmonary arterial lumen size, and plexogenic arteriopathy.[6] Thus, medical therapies that interfere with these pathogenic processes are likely to yield beneficial results. The therapeutic options, therefore, consist of the following:[6]

Vasodilators of varying mechanisms:

Prostacyclin analogs that increase intracellular cyclic adenosine monophosphate (cyclic AMP or cAMP).

Calcium channel antagonists.

Endothelin antagonists (ambrisentan, bosentan, sitaxentan).

Phosphodiesterase (PDE)-5 inhibitors (e.g., sildenafil).

Oral anticoagulants that prevent thrombosis.

Antifibrinolytic agents (e.g., prostacyclin).

Despite the differences in etiologies, compensatory mechanisms, and presentation, the basic pathophysiology of PAH appears to be similar in children and adults, and thus most therapies used for treatment in adults seem to be also efficacious in children.

To date, sildenafil has been the most widely used treatment option for pediatric patients with PAH.[6] As recent developments have cast a shadow of doubt regarding the safety of sildenafil for use in infants and young children, it is most appropriate to review the available information and also the role of sildenafil to gain a proper perspective.

As shown in Table 3, sildenafil was initially sought to be developed for the treatment of angina pectoris; the idea was given up due to its short half-life. Its “side effect” of male patients developing erections during the clinical trials was researched further and the molecule was licensed for the treatment of erectile dysfunction. However, even after the license was obtained for this indication, research continued regarding its use in treating PH.[278]

Table 3

Milestones in the development and role of sildenafil as a drug for the management of PAH in children[278]

Year		Milestone
1986		Pfizer Laboratories formed a research team for developing a selective PDE-5 inhibitor for treating patients with angina.
1989		Sildenafil, the selective PDE-5 inhibitor, was selected as candidate drug for clinical development for cardiovascular indications.
1990		The role of NO as a neurotransmitter released from the cavernous nerve during sexual stimulation was elucidated.
		The potential role of PDE-5 in the lung vasculature was elucidated in a number of basic research studies in the 1990s. Several PDE-5 inhibitors were studied in the experimental models of PH.
1993		Sildenafil was found to have a relatively short half-life and hence was not further developed for cardiovascular indications. Its efficacy in enhancing erectile responses during sexual acts was proved.
1998		Sildenafil received USFDA approval for use in erectile dysfunction. The first studies for determination of efficacy of sildenafil in PH were planned and initiated.
2000		First report on the successful treatment of a patient with primary PH with long-term use of sildenafil was published.
2002		Publication of several reports regarding successful treatment of patients with PH with oral sildenafil. Phase III trial for assessing the efficacy of sildenafil in pulmonary arterial hypertension (SUPER-1) was initiated.
2005		Sildenafil was approved for the treatment of PAH in adults by the USFDA and the EMEA.
2012		USFDA published warning against the use of sildenafil in pediatric PH.
2014		USFDA clarified warning about pediatric use in PAH.

PAH – Pulmonary arterial hypertension; NO – Nitric oxide; PH – Pulmonary hypertension; PDE-5 inhibitor – Phosphodiesterase-5 inhibitor; USFDA – United states food and drug administration; EMEA – European medicines agency

Sildenafil: Pharmacology

Sildenafil(1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine) is a water-soluble aromatic compound.[67] Being an inhibitor of PDE-5, it increases the levels of cycline guanosine monophosphate (cGMP), thereby promoting vasodilatation in the pulmonary vascular bed.[69]

The pharmacokinetic profile of oral sildenafil has not been extensively evaluated in children. In adults, it is rapidly absorbed after oral administration and the maximum serum concentrations are reached within 0.5-2 h of administration.[10] The drug undergoes extensive first-pass metabolism in the liver, and the oral bioavailability is 40%. Hepatic cytochrome P (CYP) 3A4 (major) and CYP-2C9 (minor) enzyme systems are responsible for the formation of active metabolites. The active metabolite N-desmethyl sildenafil makes up for 40% of its serum concentrations and is responsible for 20% of its pharmacological activity.[11] Sildenafil is eliminated as metabolites primarily in the feces (approximately 80% of the administered dose), with approximately 13% excreted in the urine.[11]

Administration

Sildenafil is available as tablets (20 mg), oral suspension (20 mg/mL, after reconstitution with 90 mL of water) and injection for intravenous (IV) use (10 mg/12.5 mL). The oral preparation of sildenafil is widely used in the management of PAH. The USFDA and the European Medicines Agency (EMEA) have approved a dose of 20 mg three times daily for adults with PAH. Doses higher than 20 mg are not approved as there is a flat, nonsignificant relationship between higher doses (20-80 mg three times daily) and clinical benefit.[7] While licensing it for the management of PAH in adults in 2005, the USFDA label stated that when prescribing it to children with PAH, the risks and benefits need to be weighed. However, this statement was amended by the USFDA in 2012 to state that sildenafil is not recommended (especially for long-term use) for children aged 1-17 years.[2] The EMEA allows for pediatric dosing: For children weighing 8-20 kg, 10 mg three times daily; for those weighing over 20 kg, 20 mg three times daily.[12] The issue of administering sildenafil to children weighing less than 8 kg has not been addressed. The dose of 0.5-2 mg/kg three times daily is generally used. The British National Formulary for Children advises a starting dose of 0.5 mg/kg/dose up to a maximum of 2 mg/kg/dose/every 6 h.[13] Because of its relatively short half-life, sildenafil may have to be given every 4 h, although it is usually administered every 6 h.[14] In 2012, an IV 0.8 mg/mL formulation of sildenafil gained European approval for the management of PAH in adults. This IV bolus is given three times daily for the continuation of sildenafil therapy in patients unable to tolerate oral administration. It has twice the potency of oral sildenafil.[15] It is not licensed for use in children. There are only limited reports of patients with PAH being treated with IV[16] and/or nebulized routes.[17]

Adverse effects

Adverse effects such as epistaxis, respiratory symptoms (cough and nasal congestion), diarrhea and vomiting, gastroesophageal reflux and abdominal pain, headaches, tremors, erections, facial flushing, dizziness, irritability and rarely psychiatric disorders, fever, skin disorders, pain in limbs, and edema have been reported in children on sildenafil.[1819] The Sildenafil in Treatment-Naïve Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension long-term extension (STARTS-2) trial[19] showed worse survival in children receiving high doses of sildenafil as monotherapy. 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. However, it was not associated with a lower survival rate.[18] Sildenafil has the potential to adversely affect vision. Photophobia is a known side effect. Sildenafil has been blamed for retinal dysfunction, but the link is as yet unproven.[20]

Drug interactions

Sildenafil augments the vasodilatory and antihypertensive effects of nitrates (e.g., glyceryl trinitrate) and can produce profound hypotension leading to decreased coronary perfusion and myocardial infarction, which is problematic, and thus it is contraindicated in patients taking nitrates.[21] Sildenafil is metabolized primarily by cytochrome P450 (CYP450) 3A4, which is vulnerable to inhibition and induction by various agents, as outlined in Table 4.[22232425]

Table 4

Important drug-drug interactions[22232425]

Name of the drug	Interaction/Effect	Mechanism	Recommendation
Macrolide antibiotics	Tend to increase the Cmax and AUC of sildenafil	CYP450 inducer. Decreased clearance of sildenafil	No dose adjustment required
Cimetidine
Sequinavir
Ritonavir	Tend to increase the Cmax and AUC of Sildenafil	P450 inducer. Decreased clearance of sildenafil	Coadministration not recommended
Nitrates	Synergistic effect. Increase the risk of severe hypotension	Similar mechanism of action	Coadministration contraindicated
Beta blockers	Risk of hypotension and reduced sildenafil clearance	Additive effect	Caution advised
Calcium channel blockers	Risk of hypotension	Additive effect	Caution advised
Carbamazepine	Possibility of subtherapeutic levels of sildenafil in view of its increased clearance	CYP450 inducer	Monitoring of levels advisable, as doses may have to be increased
Bosentan	Safer to add sildenafil over the short term. 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	Caution advised
Prostanoids	Additive effect. May increase the risk of hypotension	Additive effect	Caution advised

Cmax – Maximum serum concentration; AUC – Area under the curve; CYP450 – Cytochrome P450

Contraindications

Coadministration with nitrates is contraindicated.[7] Other contraindications include the presence of severe hypotension including volume depletion, left ventricular outflow obstruction, pulmonary veno-occlusive disease, multiple system atrophy, sickle cell anaemia associated-PAH; and additional caution is necessary if patients are receiving alpha-blockers.[725] The withdrawal of sildenafil is recommended in the context of sudden visual loss, and sildenafil is contraindicated in ischemic optic neuropathy and hereditary degenerative retinal disorders.[25]

Sildenafil: Clinical uses

According to the guidelines of the European Society of Cardiology and within the National Pulmonary Hypertension Service framework, sildenafil is a first-line drug for the management of nonvasoreactive pediatric IPAH and PAH associated with CHD in patients over 1 year of age.[26] This is based on data showing increases in maximum oxygen consumption of 10.2% after 16 weeks of sildenafil monotherapy (vs 0.5% on placebo) and reinforced by the STARTS trial revealing associated 90% 3-year survivals.[1927]

Following its success in licensed applications, sildenafil has been subject to substantial off-license applications, some of which have been reported in the published literature.

A review published by Huddlestone and coauthors in 2009 suggested that sildenafil is useful for weaning children who have undergone cardiac surgery from iNO. It is well-tolerated by children with IPAH and PAH associated with CHD.[11] However, the review also recommended large-scale randomized controlled trials (RCTs) to be conducted to confirm the overall safety and efficacy of sildenafil in the pediatric population. 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).[1628293031323334353637383940414243]

Table 5

Summary of the recent case series and studies on the use of sildenafil in the pediatric population (2009-13)[1628293031323334353637383940414243]

Author, year, study period	Patient population and characteristics	Therapy	Efficacy observations	Safety observations
Tunks et al., 2014. Prospective dose-escalation trial[28] [Mar. 2011-Oct. 2012]	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.	Single-dose IV sildenafil (0.25 mg/kg, 0.35 mg/kg, or 0.45 mg/kg over 20 min. [General anesthesia with mechanical ventilation and a FiO2 of 0.21].	Sildenafil improved stroke volume and cardiac output, with no significant change in heart rate. It lowered systemic and PVRI in all nine children, with no dose-response effect. PA pressures decreased and pulmonary blood flow increased.	Nil.
Singh et al., 2014. Retrospective, observational study[29] [Oct. 2007-Feb. 2012]	97 orthotopic heart transplant recipients divided into two groups: Sildenafil group (n=73): Age 0.1-16.8 years, with 54% females. Non-sildenafil group (n=24): Age 0.1-20.9 years, with 45% females. Mean pretransplant PVRI, which was higher at 6.8±3.9 WU in the sildenafil group compared to 2.5±1.7 WU in the non-sildenafil group (P=0.002).	Sildenafil started at 10.2±5, 1d after transplantation. Initial dose 0.5 mg/kg/do orally every 8 h. Dose increased by 0.5 mg/kg/dose every 48-72 h [Max: 1.5 mg/kg/do (30 mg/do, if >20 kg). Sildenafil was weaned off on outpatient basis upon serial right heart catheterization results. If the patient’s PVRI was <3 WU, sildenafil dose was halved (or discontinued once at 0.5 mg/kg/do).	Sildenafil group: Significant reductions in systolic pulmonary artery pressure, mPAP, transpulmonary gradient, and PVRI (4.7±2.9 WU before sildenafil initiation to 2.7±1WU on sildenafil, P=0.0007), posttransplant, While intubation time, length of inotrope use, and time to hospital discharge were longer in the sildenafil group, survival was similar in the two groups.	Sildenafil discontinued in 3 (13%) within 72 h of initiation due to pulmonary edema and/or hypoxia. No deaths due to RV failure.
Giordano et al. 2013. Retrospective study[30] [Jan. 2008-Mar. 2012]	30 children undergoing Fontan operation by extracardiac conduit were included. Of the patients, 13 were in the sildenafil group with mean age of 55±12 months and 8 (61%) males. The other 17 patients were in the control group with mean age of 59±14 months and 10 (59%) males.	Sildenafil group: Was treated with sildenafil 0.35 mg/kg through a nasogastric tube and then orally every 4 h, at the start of cardiopulmonary bypass and for the first postoperative week; then reduced and discontinued. Control group: No vasodilator administered. No other vasodilator was administered in both groups.	The total and relative drainage loss was lower in sildenafil group. The hemodynamic parameters showed a better condition in the sildenafil group, with a lower mPAP and better mPAP/mSBP ratio. There was no difference in peripheral oxygen saturation. The sildenafil group had lower inotropic score, intubation time, timing for chest drainage removal, and ICU stay.	Nil
Peiravian et al., 2013. Prospective study[31] [2008-2010]	48 postoperative children stratified into three groups: Milrinone, sildenafil, and combination groups (received both milrinone and sildenafil). Sildenafil group consisted of 16 patients, with mean age of 12.3±11.6 mo and mean weight of 7.1±3.1 kg. Intraoperative PA/AO pressure ratio was 0.78±0.14.	Patients in sildenafil group received sildenafil, 0.3 mg/kg every 3 h by nasogastric or oral route started before the initiation of cardiopulmonary bypass and continued throughout the hospital stay.	Postoperatively, patients in milrinone group incurred lower systolic PA and PA/AO pressures compared to sildenafil group, but it was the same in sildenafil and combination groups. Significant rise in PAP was noticed after discontinuation of milrinone, which was not observed in the combination group. No mortality was noticed in any of the groups.	Pulmonary hypertensive crisis noted in 6 patients in sildenafil group and 3 patients in combination group.
Hill et al., 2013[32] [Mar. 2011-Jan. 2012]	12 children post-stage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: Median age 1.9 years, weight 11 kg.	Single-dose IV sildenafil (0.125 mg/kg, 0.25 mg/kg, 0.35 mg/kg, or 0.45 mg/kg over 20 min). [GA with mechanical ventilation and an FiO2 of 0.21].	Sildenafil lowered PVRI in all with no dose-response effect. It improved pulmonary blood flow and saturations in those with baseline PVRI ≥2 WU×m² (n=7). Sildenafil lowered mSBP.	Nil
Shaltout et al. 2012. Randomized clinical trial.[33] [May 2008- May 2011]	200 neonates diagnosed PPHN were randomly divided into two groups: Group S [treated with sildenafil (mean age: 4.2±2.5 d, Gestational age: 37.5±1.1 wk with 54% males)] and group M [treated with MgSO4 (mean age: 3.6±1.3d, Gestational age: 37.1±1.14 weeks and 58% males)]. Associated PDA noted in 82% of group S and 76% of group M.	Group S treated with oral sildenafil 1 mg/kg/6 h by nasogastric tube. Neonates continued to receive the standard treatment for PPHN consisting of hyperventilation, inotropes, oxygen, and sedation.	Both groups: Significant improvement in their pulmonary artery pressure 48 h after therapy. However, estimated PAP was significantly lower 5 d after therapy in neonates in sildenafil group compared to those receiving MgSO4. Sildenafil group: Significantly shorter duration to improvement of oxygenation and a shorter duration on mechanical ventilation.	Group S: 20% developed hypotension, 4% suffered bleeding. None developed rash or diarrhea. Comparative mortality rates: 10% in group S and 12% in group M.
Palma et al., 2011. retrospective study[34] [Sept. 2005-Nov. 2009]	38 children with moderate-to-severe PAH (PA/AO >0.7) who underwent cardiac surgery divided into 2 groups: Sildenafil group (15) and control group (23). The mean age in the sildenafil group was 12.1±7.6 mo, compared with 11±4.6 mo in the control group.	Sildenafil group: Sildenafil 0.35 mg/kg orally every 4 h; beginning 1 wk before surgery and continued for 1 wk thereafter. Control group: Received this dose before the start of CPB and for 1 wk postoperatively. Therapy also included dopamine, cisatracurium for muscle relaxation, and remifentanil and midazolam for sedation.	Postoperatively, the 15 patients given preoperative sildenafil had significantly lower mPA pressures (25.6±3.1 vs 30.4±5.7 mmHg) and PA/AO (0.35±0.05 vs 0.42±0.07) than did the other 23 patients. The preoperative therapy also shortened cardiopulmonary bypass time, mechanical ventilation time, and lengths of ICU and hospital stays. No postoperative deaths occurred in either group.	No hypertensive crisis or significant systemic hypotension detected in either group. No sildenafil-related sequelae occurred in pre- or postoperative use.
Goldberg et al., 2011. RCT[35]	27 subjects were randomized to start a 6-wk course of either placebo or sildenafil (phase 1). Next, after a 6-wk washout period of no drug or placebo, subjects switched treatments for an additional 6 wk (phase 2). Mean age 14.9±5.1 years; two-thirds were males. Single-ventricle CHD after the Fontan operation. (54% subjects had single RV morphology; 46% had either single- left or mixed ventricular morphology. Each subject underwent an exercise stress test at the start and finish of each phase.	Oral sildenafil 20 mg three times daily for 6 wk.	After taking sildenafil, there was a significant decrease in respiratory rate and minute ventilation at peak exercise. At the anaerobic threshold, subjects had significantly decreased ventilatory equivalents of CO2. There was no change in O2 consumption during peak exercise, although there was a suggestion of improved oxygen consumption at the anaerobic threshold. Improvement at the anaerobic threshold was limited to the subgroup with single left or mixed ventricular morphology and to the subgroup with baseline serum brain natriuretic peptide levels 100 pg/mL. Sildenafil significantly improved ventilatory efficiency during peak and submaximal exercise.	Headache: 33%; flushing: 19%; dizziness: 7%; nausea/vomiting: 7%; abdominal pain: 4%; kidney stone: 4%; photosensitivity: 4%; rash: 4%. No reports of alteration in vision or hearing and no priapism.
Fraisse et al., 2011[36] [Oct. 2003- Jan. 2005]	17 patients (median age 5 mo; Range: 3 mo-14 yr; 9 males), experiencing postoperative PH. Randomized and treated, 5 with placebo and 4 each with low-, medium-, and high-dose sildenafil. Immediate postoperative PH in children undergoing congenital heart surgery. Cardiac lesions recorded at screening were: VSD; ASD, primum type; AV canal, complete; Regurgitant aortic/mitral valve requiring valvuloplasty or replacement; left heart obstruction with two fully developed ventricles; truncus arteriosus.	Three IV sildenafil dosage regimens were selected to achieve target sildenafil plasma concentrations of approximately 40 ng/mL, 120 ng/mL, and 360 ng/mL in the low-, medium- and high-dose groups, respectively. Regimen consisted of a bolus-loading dose infused over 5 min followed immediately by a maintenance infusion over 24-72 h.	In the first 24 h, 40% of placebo and 17% of sildenafil patients required additional therapy. Median time to extubation (3 vs 8d) and ICU (6 vs 15d) were shorter for sildenafil patients. Systolic PA pressure was reduced with sildenafil (46±11 to 35±6 mmHg vs placebo).	Nil.
Khorana et al., 2011. Prospective study[37] [Jan. 2006- Dec. 2008]	11 infants with PPHN. Infants with PPHN with the initial median OI was 31.95 (24.25-48.25)	Oral sildenafil was given with a starting dose of 0.25-0.5 mg/kg/do [Mechanical ventilation, sedation, and inotropic drugs].	OI decreased 4.6% from baseline after 1 h of starting oral sildenafil and progressively decreased by 13%, 27%, 37%, 41%, and 90% at 2 h, 4 h, 6 h, 12 h, and 24 h, respectively.	Systemic hypotension in 2, Death: 1, Discontinued: 1. iloprost/iNO added in 2 for hypotension/ deterioration.
Humpl et al., 2011. open-label, single-drug study.[38][Nov. 2000-Jan. 2005]	25 patients with either symptomatic or rebound pulmonary hypertension following iNO withdrawal. Median age of 180d (10-1790d), 11 males and 14 females. 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. Median duration of therapy for patients whose pulmonary artery pressures decreased to near normal levels and in whom sildenafil was discontinued (n=11) was 34 days.	The median RV/systemic systolic BP ratio before sildenafil therapy was 1.0 (0.5-1.4) and decreased to 0.5 (range: 0.3-1.3). In 5, the baseline PVRI was 10 (7.1-13.6) WU m2 and decreased to 5.8 (2.7-15.6) WU m2 at 6 mo. Ten patients were treated with sildenafil for a median of 34d (9-499) until resolution of PAH continued to do well. Six patients continued sildenafil therapy for a median of 1002d (384-1574) with improvement but without resolution of PH. No change in serum creatinine, urea, liver function tests, or platelet count. In 15, sildenafil abolished rebound PAH following withdrawal of iNO. Median RV pressure to systemic systolic pressure ratio decreased from 1.0 (0.8-1.4) during NO withdrawal to 0.4 (0.3-0.8) after pretreatment with sildenafil.	Nine patients in the cohort died after a median of 119d (12-1345). None of the deaths were attributable to sildenafil therapy.
Uslu et al. 2011. Prospective randomized controlled study.[39][Feb. 2007-Apr. 2008]	Newborns with hypoxemic respiratory failure associated with PPHN. Thirty-four infants in MgSO4 group [gestational age: 38.3±1.7 wk, males: 20 (58.8%)] and 31 infants in sildenafil group [gestational age: 38.5±1.6 wk, males: 16 (51.6%)].	Dose of 0.5 mg/kg given via an OG tube every 6 h. The dose could be doubled (until reaching a maximum of 2 mg/kg) if the OI did not improve. Sildenafil dose was tapered 50% after reaching the OI level <15 and PAP<20 mmHg and terminated in 1 day.	Time to reach adequate clinical response (defined as OI level of <15, a PA pressure of <20 mmHg) was significantly shorter in the sildenafil group. Duration of mechanical ventilation was longer and the number of patients requiring inotropic support higher in the MgSO4 group.	Three patients with unknown etiologies died (2 in MgSO4 group and 1 in sildenafil group).
Uhm et al., 2010. Retrospective study.[40] [Jan 2001- Dec 2007]	45 postoperative patients with CHD. Median age at operation of 32.6mo (Range 6 d-17 yr). Patients categorized into three groups according to clinical indications: Group 1 (n=15): Stabilization of pulmonary vascular reactivity after biventricular repair, Group 2 (n=12): Lowering of PVR after bidirectional cavopulmonary shunt and Group 3 (n=18): Improvement of post-Fontan hemodynamics.	Sildenafil citrate was administered orally 4 times per day at a mean amount of 0.9±0.3 mg/kg/dose. [34 of 45 (75.6%)] had been receiving iNO therapy before the initiation of oral sildenafil therapy.	Group 1: Baseline mPAP/mSBP ratio decreased significantly after the second and fourth doses of OST. Group 2: Baseline SpO2 increased after the fourth dose of OST, without significant changes in mPAP Group 3: Baseline mPAP decreased significantly after the first and second doses of OST, without changes in SpO2. In 92% subjects, iNO discontinued within a median of 2d after the initiation of OST, without rebound phenomena.	Mortality: Group 1: 1 early death from intractable PH; Group 2: 4 from hypoxia and central venous hypertension; Group 3: None.
Nemoto et al. 2010. Retrospective review.[41][Oct. 2003-Mar. 2008]	100 patients with postoperative PH. Age distribution of <1 mo (n=26), >1-<6 mo (n=36), >6-<12 mo (n=19), 1-3 yr (n=8), 4-9 yr (n=9) and >10 yr (n=2) at the time of surgery. The surgeries were performed for VSD closure (n=17), arterial switch (n=30), truncus arteriosus repair (n=10), complete AVSD repair (n=12), total anomalous venous drainage repair (n=9), and other (n=22).	Sildenafil administered at the starting dose of 0.5mg/kg via an NG tube or orally and was increased stepwise by 0.5 mg/kg every 4-6 h up to a maximum of 2 mg/kg. After successful weaning from a ventilator, sildenafil was gradually reduced and discontinued over next 5-7 d. Concomitant iNO treatment was performed in 66 patients.	Pulmonary arterial pressure decreased in 28, was unchanged in 5 and elevated in 1 patient out of the total of 34 cases, for which data from continuous pressure monitoring were available. Bosentan was added in three cases with persistent symptoms due to PH despite sildenafil treatment. After sildenafil administration, modest oxygen desaturation occurred in 7, but no “rebound” PH occurred.	The only adverse event was facial flushing, which occurred temporarily in 5 cases.
Reinhardt et al. 2010. Retrospective review.[42][Jan. 2006-Jul. 2008]	13 patients with severe Fontan complications. The mean age at the completion of the Fontan circulation was 4.5 (2.6-10) yr. Mean interval between Fontan completion and onset of complications 2.5 (0.1-13) yr. Four presented with bronchial casts, protein-losing enteropathy: 3, severe cyanosis: 2, prolonged chylous effusions: 2, previous failure of Fontan and take-down, arrhythmias, and end-stage cardiac failure: 1 each.	Sildenafil was given at a dose of 1-2 mg/kg 3-4 times/d. Treatment duration was for 24 mo and was weaned off gradually according to clinical response.	Protein-losing enteropathy and a-1-antitrypsin levels improved in all 3 patients on sildenafil. One of these patients had a concomitant catheter creation of a fenestration, as did two patients presenting with bronchial casts and both patients with persistent chylous effusions. All 4 patients with bronchial casts and 2 patients with cyanosis improved significantly on sildenafil treatment. Chylous effusions decreased after sildenafil use and stent enlargement of a fenestration.	No significant side effects.
Steinhorn et al. Open-label, dose-escalation trial;[16] 2009	36 neonates with PPHN at a mean of 34±17 h of age, GA: 39±2 wk, female/male: 19/17; 29 were already receiving iNO. Meconium aspiration syndrome: 20, respiratory distress syndrome: 8, sepsis: 4, pneumonia: 2, Idiopathic PPHN: 2.	For group 1, sildenafil infusion started with an IV loading dose (0.008±0.005 mg/kg) of sildenafil for 5 min. The loading dose duration was changed for groups 2-6 (30 min), group 7 (no loading dose), and group 8 (dose: 0.427±0.046 mg/kg over 3 h followed by a maintenance dose of 1.64±0.17 mg/kg/d) after a review of the pharmacokinetic and tolerability data for the previous groups. Sildenafil was administered for a minimum of 48 h and for a max of 7 D. Twenty-nine were already receiving iNO. Ten infants received milrinone in combination with sildenafil.	The study included 8 sequential ‘‘step-up’’ dosing groups. Significant improvement in OI (28.7 to 19.3) was observed after 4 h of sildenafil infusion in the higher dose cohorts. Seven neonates were enrolled before developing the need for iNO. In these neonates, OI improved significantly by 4 h after initiation of sildenafil infusion (24.6 to 14.7); 6 neonates completed treatment without the need for iNO or ECMO. One death unrelated to sildenafil treatment.	Six treatment-related AE reported in 5; Severity: Mild or moderate. Five events related to hypotension or blood pressure lability. One infant developed PDA associated with left-to-right shunting 50 h after beginning sildenafil; resolved without further intervention; 2 infants developed treatment-related severe hypotension requiring discontinuation of sildenafil.
Morchi et al, 2009.[43]Retrospective review	6 patients with Fontan physiology, persistent symptoms of cyanosis or effusion, and poor hemodynamics were given sildenafil. Mean age at Fontan: 18-26 mo. Mean PA pressure greater than 15 (17.4±1.5 mmHg), with mean estimated PVR 3.5±1.0 WU×m2prior to starting sildenafil.	The goal dose was 1 mg/kg three times daily for a duration of 6-51 mo prior to follow-up.	Sildenafil significantly increased the systemic arterial oxyhemoglobin saturation. Significant decrease in PAP and in estimated PVR post-sildenafil treatment in 4 of 5 patients who underwent follow-up catheterization.	Priapism: 1, three wk into treatment. No relief on weaning the doses. Subsequently discontinued.

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

Transient postoperative PAH

Sildenafil is useful in relieving transient postoperative PAH associated with CHD surgery. This is a frequently employed but contentious application. It is not yet clear whether sildenafil should be used routinely to assist weaning from iNO or as an adjunct to therapy.[44] Furthermore, its prophylactic use is also being explored.[45] Here, one-off doses of 0.4 mg/kg have led to reductions in intensive care duration and time on mechanical ventilation. In a case report, sildenafil has been associated with the resolution of protein-losing enteropathy after the Fontan procedure.[46] Sildenafil is often used in combination with extracorporeal membrane oxygenation (ECMO) to facilitate the process of getting a patient come off cardiopulmonary bypass.[47]

Acute management of PAH

NO remains the gold-standard acute agent for the management of acute PAH. However, it carries the risk of development of methemoglobinemia. This risk has been reduced by delivering NO via inhalation (or, iNO) or by administering sildenafil concomitantly. Newborns receiving the combination should, however, be closely watched for the development of systemic hypotension.[48] NO therapy withdrawal is also associated with the risk of rebound PAH. This risk is minimized when sildenafil is used in combination with NO.[45] In a recent case report, oral sildenafil led to dramatic improvement in ventilation and saturation within 45 min when used as a rescue therapy in a 26-week-old infant in presumed pulmonary hypertensive crisis.[49]

Persistent PH of the newborn (PPHN)

In patients with PPHN, the PVR fails to regress after birth. A growing body of evidence supporting the use of sildenafil is fast emerging.[50] The Cochrane review found that sildenafil use was associated with increased arterial oxygenation and reduction in mortality.[50] It is necessary to confirm the drug's utility for this indication, as evidence is available from only a limited number of clinical trials.[51] Although there is no official guidance, doses ranging 250-500 μg/kg/dose three times daily (maximum: 30 mg/D) are in use. 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). The response time varies 20-180 min after oral administration. The duration of treatment is not yet well-defined. One approach is to stop the medication if a clear response is obtained or if there is no response even after the administration of six to eight doses. Reduction in dose or cessation of treatment would be necessary if hypotension developed despite inotropic support.[14]

BPD-associated PH

The treatment of PH secondary to BPD in infants has evolved in recent years, improving survival rate and quality of life. Sildenafil is one of the potential agents that can be used in management. A recent review summarizing the evidence base for sildenafil alone and in combination with other recognized therapeutic agents for ameliorating pediatric PH in the presence of BPD[52] concluded that sildenafil is both safe and effective, as it improves survival from 61% to 81% at 12 months. Furthermore, there is data suggesting that the addition of endothelin antagonists and prostacyclin analogs to sildenafil therapy could be useful in the management of treatment-refractory PH. In contrast, another study enrolled 21 preterm infants with BPD-associated PH and demonstrated that a majority of patients showed no improvement in gas exchange at 48 h of treatment with sildenafil, and that four infants died during treatment, despite showing a significant reduction in estimated right ventricular peak systolic pressure.[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. It is also advisable that its use be restricted to specialist units and physicians, ideally with experience in dealing with both BPD and PH.

Congenital diaphragmatic hernia

Congenital diaphragmatic hernia is associated with PH directly and via links with BPD. Sildenafil has shown its efficacy in improving cardiac output via alleviation of PAPs. Its use in difficult cases has been established.[54] However, more evidence needs to be generated through appropriately powered RCTs before firm recommendations can be made.

Eisenmenger's syndrome

Limited evidence from case series and case reports suggests that sildenafil alone or in combination with L-arginine could be useful in patients with Eisenmenger's syndrome.[5556] However, in these patients, sildenafil has the potential to cause a reduction in pulmonary blood flow and an increase in cyanosis as a result of even mild systemic vasodilation and consequent increased right-to-left shunting.[22] Hence, larger trials are required to establish the safety of sildenafil in patients with Eisenmenger's syndrome.

Sildenafil combination therapy

Combination therapy can be used in patients who fail to respond to monotherapy. A randomized placebo-controlled trial showed that the addition of sildenafil to long-term IV epoprostenol therapy improved exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life.[57] A combination of bosentan, sildenafil, and inhaled iloprost has been shown to improve survival and reduce the need for lung transplantation in adult patients with severe PAH.[58] However, evidence in the case of children is still lacking, being limited to a few case series.[5960]

Intravenous sildenafil

Sildenafil is available as an IV injection in several countries including India (10 mg/12.5 mL). It reduces PAP, shortens time to extubation, and limits intensive care unit (ICU) stays in children with postoperative PH.[36] Its use in children who have undergone Fontan surgery has shown improvements in cardiopulmonary hemodynamics, cardiac index, and PVRI.[3228] Studies have shown that IV sildenafil infusion improves the OI in newborns with PPHN.[16] In an infant with respiratory failure, the substitution of oral sildenafil with IV infusion has resulted in clinical improvement where the former was ineffective.[61] However, some have raised certain concerns. 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. Similarly, Schulze-Neick et al. showed that although IV sildenafil reduced PVR in children undergoing catheterization or cardiac surgery, it resulted in significant intrapulmonary shunting.[63]

The observed problems of systemic hypotension and impaired oxygenation experienced by patients receiving IV sildenafil raises concerns and could limit its use. Further studies are needed to determine the optimal dose needed to decrease PVR while still avoiding significant adverse events.

Recent Controversies With the Use of Sildenafil in Pediatric Population

Other than iNO licensed for the treatment of newborns with PPHN and severe respiratory failure, there are no PAH therapies specifically approved for children.[66] Sildenafil (Revatio; Pfizer, New York, NY, USA), is approved by the USFDA for the treatment of PAH in adults. It has been used extensively in an off-label manner for the treatment of neonates, infants, and children with PAH associated with diverse heart and lung diseases.[1636556465] Although the published literature has generally suggested favorable effects and outcomes in infants and young children with PAH, these reports constitute uncontrolled observations.[65]

In August 2012, the USFDA released a strong warning against the use of sildenafil for pediatric patients (ages 1-17 years) with PAH.[2] It stated that children taking a high dose of Revatio had a higher risk of death than children taking a low dose and that the low doses of Revatio are not effective in improving exercise ability. This was based on 3-year follow-up data in children showing dose-dependent increases in mortality (mortality ratio 3.5; P = 0.015) when using high doses (80 mg three times daily in children with body weight >45 kg) relative to low doses (10 mg three times daily in body weight >45 kg).[19] This warning, which is now part of the package insert, states that sildenafil is not to be used in children.

The studies leading to the USFDA rulings have been criticized.[12666768] Abman and colleagues pointed out that there were substantial problems with the design of the study on the basis of whose data the recommendation was made.[66] In addition, there was no standardization of therapy after the initial 4-month trial period, there was substantial center-to-center variability in management, and information about the use of other therapies beyond sildenafil lacked clarity.

Ironically, based on the same data, the EMEA recommended the use of sildenafil in children aged 1-17 years with a maximum daily dosage of 10 mg three times daily in children weighing less than 20 kg or 20 mg three times daily in those weighing over 20 kg.[12] They cautioned against using higher doses. The Pediatric Pulmonary Hypertension Network has recommended using sildenafil in accordance with the EMEA dosing recommendation.[66] Bhutta and colleagues[67] have pointed out that the interpretation of the study results by the USFDA has added to the confusion. The STARTS investigators[19] reported that in patients who received long-term sildenafil therapy, deaths were related to underlying etiology and baseline disease. They further pointed out that multivariate analysis of STARTS-2 results shows that factors associated with mortality were HPAH etiology, high PVRI, and high right atrial pressure and adjustment, for these three factors reduced the hazard ratios for mortality for the high versus the low dose. They conducted a review of the Pediatric Health Information System (PHIS) database to assess the landscape of sildenafil use among children and highlighted the impact of the USFDA warning on the pediatric population.[67] Their investigation showed that sildenafil use has increased over the study period (January 2004-December 2011) and that there was a temporally associated decrease in mortality. The reduction in mortality cannot be attributed to sildenafil alone. It may be due to a variety of reasons, such as use in lower-risk populations, different dosing regimens of sildenafil, and concomitant use of other therapeutic agents. More carefully designed studies that are adequately powered to detect differences in mortality are needed for better understanding of the role of sildenafil either as monotherapy or in conjunction with other therapies.

In view of the criticism and the recently published results of the STARTS-2 trial, the USFDA in a recent communication in 2014 clarified the warning issued in August 2012, stating that its warning was mainly against using high doses and chronic use of the drug, and that sildenafil may be considered in situations where the benefits of treatment with the drug are likely to outweigh its potential risks for each patient.[868]

Novel PDE-5 inhibitors

To date, sildenafil is the most extensively studied PDE-5 inhibitor. Currently, two more PDE-5 inhibitors, tadalafil and vardenafil, are under evaluation. The newer compounds are considered to be better than sildenafil in terms of greater selectivity for PDE-5, absence of the effect of food on absorption, faster onset of action, and longer duration of action.[69] Tadalafil has the least effect on PDE-6 and is thus not associated with visual disturbances of blurring and blue-green color tinges that may occur with sildenafil.[69] Tadalafil has a greater effect on PDE-11; thus, backache and myalgia can occur frequently after its use.[69] Tadalafil is the most heavily researched alternative and has proven efficacy at 1 mg/kg doses in pediatric PAH.[25] In addition, its longer half-life enables once-daily dosing, improving outpatient compliance. Tadalafil has been found to improve functional capacity and oxygen saturation better than sildenafil. It also requires fewer daily doses than sildenafil.[70]

PDE-5 inhibitors are emerging as novel therapeutic tools with the potential to protect or enhance endothelial function in humans and to selectively improve regional blood flow. In addition to PH, these are being tried for conditions such as Raynaud's phenomenon, respiratory disorders with ventilation/perfusion mismatch, congestive cardiac failure, hypertension, and stroke.[69] It is hoped that this group of drugs will soon emerge as a novel weapon in the armamentarium against various cardiovascular and pulmonary diseases.

Conclusion

The past decade has shown a major development in the management of PH by the introduction of sildenafil and other PDE-5 inhibitors. Sildenafil is USFDA-approved only in adults with PAH, not in children. Data from adults were extrapolated for its use in children. 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. Sildenafil is a cost-effective option for the treatment of pediatric PAH, especially for developing countries. Health care professionals must consider whether the benefits of treatment with the drug are likely to outweigh its potential risks for each patient. Further research with appropriately chosen study groups is needed for USFDA approval of this drug.