Abstract
This is a review article that discusses the role of sildenafil in pediatric pulmonary hypertension. The etiopathogenesis as well as prognosis for pediatric pulmonary hypertension (PH) differs from adults. The basic tenets of targeted management of PH however are similar. Sildenafil and other phosphodiesterase-5 inhibitors play a very important role in PH management, especially because of the ease of administration, low adverse effect profile, better tolerability and relative cost effectiveness. This is especially vital in situations where inhaled nitric oxide is not easily available and fills an important therapeutic gap. Large double blinded and controlled studies studying the effects of sildenafil in pediatric PH are not available. Equally vital would be long term efficacy studies, which should be initiated through large multicenter trials, to study the beneficial as well as long term side effects of this medication in the pediatric age group.
Introduction
Pulmonary Hypertension (PH) is a serious and often fatal disease, which may be either “idiopathic” (IPH) or “acquired” (APH) as the end result of systemic disorders of varied etiologies. The modern era has seen a lot of therapeutic strides made in improving the short term outlook for this disease, but a “complete cure” is still elusive. This is because the various nuances in the pathogenesis of this disease process are still not completely unraveled. The incidence of pulmonary hypertension is estimated at 2/1000 live births with reported mortality rates in various US centers between 4%-33%. 1 Recent evidence from the French registry suggests a prevalence of 12 per million. 2 PH may occur in children in association with congenital heart defects, chronic lung disease of infancy, or as IPH, and carries with it a variable prognosis, depending on the etiology.
The mortality curve of this disease has been altered by the newer drugs that have been developed in the past 2 decades. The current one year mortality on modern therapies has been quoted at approximately 15%. 3 Prior to the advent of IV epoprostenol, pulmonary hypertension was associated with a mean survival of 2.8 years, and an estimated 5 year survival of 34%.1–3 Our increasing understanding of the pathogenesis of pulmonary hypertension is reflected in a new generation of targeted, effective therapies, including aerosolized prostacyclins and analogs, inhaled nitric oxide (NO), endothelin receptor blockers, and phosphodiesterase 5 (PDE-5) inhibitors such as sildenafil. Sildenafil was initially developed as an antihypertensive drug, which targeted the renal tubules. It was subsequently found to have powerful vasodilatation and platelet inhibition properties. Sildenafil is a selective inhibitor of cyclic GMP (cGMP) specific PDE-5 enzyme. This enzyme is abundant in the pulmonary artery smooth muscle cells, leading to investigation of sildenafil's role in the treatment of pulmonary hypertension in animal models and subsequently, in human trials.4–6 Several placebo controlled trials have shown short term improvement in subjective parameters as well as objective measures like the six minute walk test, in adult and pediatric patients on sildenafil, however long term data are not yet available.6–8 None of the studies have shown reversal of pulmonary hypertensive changes in the lungs or complete normalization of pulmonary hemodynamics with any drugs thus far developed.
Pathogenesis of PH
There is still much to be understood regarding complex interactions among the various factors influencing the pathobiology of pulmonary hypertension. 9 There are significant differences in the histopathology of vascular lesions with IPAH in adults and children. There is a greater proportion of plexiform lesions and intimal fibrosis in adults as compared to a greater extent of medial hypertrophy in children.10,11 This is probably reflected in the greater vascular reactivity seen in younger patients to acute vasodilator testing, as well as more frequent acute life threatening pulmonary hypertensive crises in younger children, in response to various triggers. The disease is thought to be secondary to pulmonary artery endothelial dysfunction resulting from an imbalance of endogenous vasoactive mediators. The pulmonary endothelium synthesizes several vaso-active mediators including NO, prostacyclin (PGI2), endothelin-1, thromboxane, angiotensin-1 and norepinephrine, which are in delicate balance. Endothelial dysfunction (either because of genetic predisposition or triggered by mediators), results in this balance tilting in favor of vaso-proliferative mediators.12,13 This results in vasoconstriction, smooth muscle cell activation, inhibition of apoptosis, potassium and calcium channel dysfunction, collagen deposition and activation of inflammatory cytokines. In turn, this leads to fibroblast proliferation, angiogenesis, smooth muscle cell hyperplasia and hypertrophy. Understanding these molecular processes will ultimately result in further appropriate diagnostic testing as well as developing therapies targeted at correcting the endothelial imbalance.12–14
Pharmacodynamics of Sildenafil
Sildenafil is a potent PDE-5 inhibitor that leads to accumulation and increased activity of cGMP thereby enhancing the actions of NO such as vasodilation and growth inhibition. Nitric oxide is a powerful, short-acting pulmonary vasodilator which acts within the smooth muscle cell to activate guanylyl cyclase, generating cGMP, and through a series of second messengers, results in pulmonary vasodilatation.
Guanylyl cyclase is inhibited by phosphodiesterase-5 (PDE-5), causing vasoconstriction. Studies have shown a high concentration of PDE-5 in pulmonary artery smooth muscle.4,5,15 Thus, inhibiting PDE-5 offers a reasonable approach to targeting medial muscular hypertrophy and inducing vasodilation in the pulmonary vasculature. There has been speculation that sildenafil works by inducing vasodilation, preventing vascular remodeling as well as preventing hypertrophy. The mechanism for vascular remodeling has been hypothesized to be cGMP mediated suppression of extracellular signal–-regulated kinase phosphorylation and decreased AML1B transcription factor, resulting in decreased smooth muscle cell production of endogenous vascular elastase. 6 Humpl et al studied the effect of Sildenafil in 14 children over 1 year and found that there was reduced PVR even in those children with no acute response to iNO and with no change in cardiac output, suggesting that the change in PVR was independent of the cardiac output and that the improvement in patients without acute responsiveness suggests long term vascular remodeling. It has been also hypothesized that PDE-5A inhibition blocks TRPC6 gene induction in cardiac myocytes and thus prevents cardiac hypertrophy through inhibition of Gαq mediated signaling and calcineurin (Cn) signaling. 16 De Visser et al studied two neonatal rat models, one with sildenafil treatment, initiated at the time of exposure to hyperoxia after birth, and another with sildenafil initiated post hypoxia exposure for a few days and then return to normoxia–-to simulate bronchopulmonary dysplasia. 17 They demonstrated prolonged survival, increased pulmonary cGMP levels, reduced inflammatory response, fibrin deposition, septal thickness, and stimulated alveolarization. Sildenafil also restored pulmonary angiogenesis and reduced hypertrophy in the group with experimental BPD.
Pharmacokinetics
Sildenafil is rapidly absorbed through the gut, with a bioavailability of 40% and is metabolized by the hepatic cytochrome P450 system, primarily CYP3A4 and CYP2C9 hepatic microsomal enzymes. 18 The pharmacokinetic profile has not been evaluated in children, and all data is from adult literature. The maximum serum concentrations of sildenafil in children are reached 0.5-1.5 hours after an oral dose administration and are dose-dependent. 19 The half life of sildenafil has been shown to be approximately 4 hours and hence the drug is effective in a 6-8 hourly dosing schedule. 20 Sildenafil is given in a dose range of 1-5 milligrams per kilogram per day in 4 divided doses; however recent studies have reported doses of up to 8 mg/kg/day in neonates, without deleterious effects.21,22 It is advisable to start at a lower dose and titrate up if no hypotension or other side effects are noted. Side effects with sildenafil in children are not severe and often are masked by the underlying hemodynamics. 23 Mild hypotension has been reported (especially in combination with nitrates in adults), and in patients with liver dysfunction, sildenafil has to be administered with care. This is especially relevant if the liver dysfunction is secondary to other drugs used for pulmonary hypertension, like endothelin receptor blockers which are associated with hepatotoxicity. It is also advisable that children being placed on sildenafil should get periodic ophthalmologic examinations as there have been some reports of visual deficits in adults on sildenafil, though there is no conclusively proven link between the two.23,24 In premature babies, with preexisting retinopathy of prematurity, there have been no studies conclusively linking the use of sildenafil to worsening of ocular problems. 23
Current Understanding
To date most of the literature pertaining to the use of sildenafil in the treatment of pulmonary hypertension in children has been limited to animal studies and several uncontrolled studies, but there have been several large studies in the adult literature.22,25 In 2005, Galie et al, published results of the SUPER study group involving 278 adults studied over 12 weeks, showed that Sildenafil in the short term improved exercise capacity, functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension. 25 The extension of this study (in 222 subjects) showed that the improvement in the 6MWD was sustained at the end of 1 year. The same year, Humpl et al published the results of a 12 month open-label, pilot study examining the effects of sildenafil on exercise tolerance in children. The subjects in this study were NO non-responders suggesting more advanced disease. 6 The study assessed 6 minute walk distance (6MWD) and hemodynamic testing in the subjects. Patients were given oral sildenafil 0.25-1 mg/kg/day, with follow up at 3,6,12 months. The 6MWD increased from 278+/-114 to 443+/-107 minutes. The mean pulmonary artery pressure decreased from 60 to 50 mm, although this did not correlate to degree of clinical improvement and the 6MWD. Interestingly in this study, a plateau in 6MWD was reached between 6 and 12 months, and a longer term of testing was suggested.
In 2006, Herrera et al and Baquero et al, independently published two separate randomized controlled studies, done to examine the efficacy of sildenafil versus conventional therapy persistent PH of the newborn (PPHN) in centers without iNO availability, and found similar results.26,27 There was a statistically significant rise in oxygenation in the sildenafil group compared to the control group, becoming significant at 72 hours. There were significant differences in mean arterial pressures in the two groups. Sildenafil has been also shown to be extremely beneficial in the post-operative setting, while weaning a patient off iNO, or in situations where iNO is not readily available.28,29 Sildenafil used in this manner can be rapidly weaned off over a period of a few days to weeks after surgery. We have reported reversal of right to left cardiac shunts in a group of children with severe lung disease of infancy, to the extent that some of the patients required catheter or surgical intervention to close their shunts. However, most of the patients reported still require medication to keep their PH at an acceptable level, even after shunt closure. 30
Another important application of Sildenafil is as a primary medication for treatment of PH in situations where iNO is not available. Ajami et al used a single dose of sildenafil administered enterally to test feasibility for surgery in 15 patients with secondary PAH. They found reduction in PA pressures and resistance in all the patients, after 45 minutes of administering a single dose at 0.5 mg per kilogram. 31 Oral sildenafil has been also used extensively in post-operative situation, either as an adjunct to or while weaning iNO, with excellent results.29,31–33 Stocker et al as well as other groups studied the effects of a combination of iNO and intravenous sildenafil in post-operative patients and found that though both drugs reduced the pulmonary resistance significantly, sildenafil was associated with systemic hypotension and impaired oxygenation, possibly secondary to ventilation-perfusion mismatch and intrapulmonary shunting.32,33 However, this effect is not significant with oral sildenafil and many studies have shown that oral doses from 0.5 to 2 mg per Kg in 4-6 hourly intervals do not cause significant systemic hypotension, and the higher dose range do not confer a significant therapeutic advantage. 34
Conclusion
Our growing understanding of the pathogenesis of pulmonary hypertension has lead to the development of several new therapeutic approaches. Inhibition of PDE-5 with sildenafil has offered targeted and effective treatment for PH, improving outcomes for patients of all age groups. The safety and short term efficacy of sildenafil for the treatment of pulmonary hypertension are encouraging. However, long term safety reports of sildenafil usage in childhood are still unavailable. In addition, controlled data on dosage for pediatric patients as well as safety profile of sildenafil patients with severe lung disease as well as combination of sildenafil with other agents is lacking. Large, randomized controlled multi center clinical trials evaluating sildenafil as mono-therapy and in combination with other agents tracking patients over years are needed to confirm the safety of sildenafil in patients with pulmonary hypertension.
Disclosures
The authors report no conflicts of interest.