Emerging Role of Sildenafil in Neonatology
From the Department of Pediatrics, Division of Neonatology, Max Super Speciality Hospital, Saket, New Delhi, India.
Correspondence to: Dr Manish Malik, Senior Consultant Neonatologist, Max Super Speciality Hospital, Saket, New Delhi 110 017,India. [email protected]
Over the last few years, sildenafil is increasingly being used in the neonatal ICU for a variety of indications. The use is evenmore so in the developing world due to the limited availability of nitric oxide and extracorporeal membrane oxygenation(ECMO). There are still no clear cut guidelines for its use. At present the drug appears relatively safe and effective whenother treatment options have been optimized. However, the use of sildenafil must be monitored and reported. Due to itseasy availability and ease of administration we must guard against its inappropriate use.
Key words: Neonate, Management, Persistent Pulmonary Hypertension of Newborn (PPHN), Sildenafil.
The role of sildenafil in the treatment of The cost of its use is prohibitive. Also inhaled nitric oxide has the ability to displace oxygen and bind to hemoglobin forming methemoglobin, thereby further lay press way back in 2002 [1]. There was reducing the oxygen carrying capacity of blood. The much criticism about its use then. However, there availability of ECMO, even in developed countries, is were a few who felt that the use was justified [2], as limited to few specialist centers and almost always there were no other options for the attending involves transport of a very sick baby to the nearest neonatologist in face of non-availability of inhaled available centre. ECMO as an option is almost non- oxygenation (ECMO). There have been publishedreports of its usefulness in adult cardiac patients as well as in animal models, prior to its use in newborns include optimization of ventilation, fluid, electrolyte [3,4]. Since then there have been many more case and acid base balance along with the maintenance of reports and some small randomized studies regarding blood pressure. Oral sildenafil can be a useful adjunct the use of sildenafil in babies with severe PPHN. The to the treatment if nitric oxide is not available. It can drug is now frequently being used in many centers in also be used in conjunction with nitric oxide to India and other developing countries where the facilitate quicker weaning off nitric oxide [7].
availability of high frequency ventilation, nitric oxide The pulmonary vascular resistance (PVR) at birth is very high. With the onset of breathing, PVR falls The reported incidence of PPHN is 0.43-6.8 per and pulmonary blood flow increases. The failure of thousand newborns [5]. It is likely to be much more in this process in the transitional circulation results in developing countries, where little data is available.
PPHN. The various mechanisms regulating the PVR The mortality for the condition has remained static at are complex. Nitric oxide (NO)-guanylate cyclase- 10% to 20% over the last decade. Nitric oxide alone 3’5’ cyclic guanosine monophosphate (cGMP) does not appear to be a solution to the problem. Upto system plays an important role in regulating PVR in 30% infants fail to improve despite nitric oxide [6].
the perinatal as well as mature pulmonary vasculature. Nitric oxide activates soluble guanylate pressure closely, although this has been rarely a cyclase in vascular smooth muscle cells, resulting in problem. There have been reports of hypotension an increase in cGMP levels. Increased cGMP in the when it is used in conjunction with nitric oxide [13].
vascular smooth muscle results in vasodilation There has been a report of severe retinopathy of through the activation of cGMP dependent protein prematurity (ROP) in a preterm baby who received kinases. Intracellular cGMP levels are determined by Sildenafil [14]. However, this baby had multiple risk a balance between the synthesis of cGMP and its factors for developing ROP other than Sildenafil use.
degradation. Phosphodiesterases (PDEs) are the There is also a report of severe bleeding in a newborn enzymes responsible for the degradation of all cyclic following circumcision [15]. Thrombocytopenia is a nucleotides. The lung contains many PDEs but the relative contraindication for the use of sildenafil.
major component is a cGMP specific PDE calledPDE5. There is high PDE5 activity in the fetal A small randomised study of sildenafil versus pulmonary arteries. Sildenafil acts specifically by placebo [5] showed improvement in OI within 6- 30 inhibiting PDE 5 thus producing pulmonary hours with steady improvement in pulse oxygen vasodilation by increasing cGMP levels [8].
saturation over time. Six of seven babies survived inthe study group versus one of six in the placebo The dose of sildenafil was initially chosen group. All studied infants were extremely sick with empirically, starting at 0.5mg/kg and increasing up to high ventilator parameters, OI >25 and FiO2 of 2mg/kg per dose to achieve required response. It is 100%. A Cochrane review of the role of sildenafil in given every 6 hours. A recent study of the PPHN has also been published [16]. As there were pharmacokinetics of sildenafil shows that an oral few studies, it still recommends the use of the drug on recommended adult dose of 20 mg three times a day[9]. In this study, there was a high inter-patient Apart from PPHN, sildenafil has also been used in variability probably related to variable gut absorption the management of congenital diaphragmatic hernia of the drug. Also co- administration of fluconazole to improve oxygenation and bring down venti-lator resulted in 47% delayed clearance of sildenafil. The requirements [17]. Although this has been on a case to case basis, the results have been encouraging.
Management of Congenital Heart Diseases in India Sildenafil has also been used to treat pulmonary [10] is 0.5-5 mg/kg/day in 3-4 divided doses with hypertension (PH) associated with congenital heart dose reduction in renal and hepatic impairment. A disease, both in newborns and in older children [18].
commonly used dose is 1 mg/kg/dose given 6 hourly.
A recent meta-analysis showed its effectiveness in The duration of treatment is usually for 2-3 days.
treating pulmonary hypertension following However the drug can be stopped earlier if the oxygenation index (OI) improves to being below 20.
There are also a few reports of long term use of the Sildenafil has been used in the management of PH drug, without significant side effects [11].
in association with chronic lung disease in childrenless than 2 years of age [11]. It was used in 25 Oral sildenafil is fairly well tolerated, although children, with 22 (88%) achieving hemodynamic absorption can be erratic at times. Since no improvement after a median duration of 40 days.
intravenous preparation is available, it can only be Their data suggested that chronic Sildenafil therapy is given orally. A 50 mg tablet of sildenafil is crushed well-tolerated, safe and effective for infants with PH and dissolved in water in a concentration of 1 mg/mL and then given via nasogastric tube. Side-effectsreported in adult literature are secondary to Emerging data continues to show the safety and vasodilatation and include flushing headaches, effectiveness of oral sildenafil therapy. However the dizziness, hypotension, blurred vision and painful published studies are on small number of patients and erection [12]. There have been few reports of side caution must be exercised in the interpretation of effects in infants. One must watch the systemic blood their outcomes. Since the drug is easily available and convenient to administer, it has the potential for 5. Baquero H, Soliz A, Neira F, Venega M, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension We could not find any Indian data or case report of the newborn: a pilot randomized blinded study.
Pediatrics. 2006;117:1077-83.
on use of sildenafil in PPHN. There is a feeling that 6. Macrae DJ. Drug therapy in PPHN. Semin Neonatol.
the drug is being used by many neonatal intensivists.
Although we discourage the use of Sildenafil except 7. Namachivayam P, Theilen U, Butt W, Cooper S, Penny D, on an experimental basis, we urge that experience of Shekerdemian L. Sildenafil prevents rebound pulmonaryhypertension after withdrawal of nitric oxide in children.
use of the drug be shared in a peer reviewed journal.
Am J Respir Crit Care Med. 2006;174: 1042-7.
8. Leibovitch I, Matok I, Paret G. Therapeutic applications of A controlled multicenter study with adequate sildenafil citrate in management of pediatric pulmonary sample size is needed to evaluate the safety, efficacy, and long term outcome of treatment with sildenafil of 9. Ahsman MJ, Witjes BC, Wildschut ED, Sluiter I, Vulto AG, neonates with PPHN. Research is also needed to Tibboel D, et al. Sildenafil exposure in neonates with determine differences in drug efficacy between adults pulmonary hypertension after administration via anasogastric tube. Arch Dis Child Fetal Neonatal Ed.
pharmacokinetics, and dose optimisation for the 10. Saxena A, Juneja R, Ramakrishnan S. Drug therapy of individual patient. An intravenous preparation of cardiac diseases in children.Working Group on Sildenafil should also be made available as this would Management of Congenital Heart Diseases in India. IndianPediatr. 2009;46:310-38.
11. Mourani PM, Sontag MK, Ivy DD Abman SH. Effects of concentrations. All experiences with sildenafil, long-term sildenafil treatment for pulmonary hypertension whether it is used in conjunction with other in infants with chronic lung disease. J Pediatr.
established modalities or by itself, must continue to be monitored and reported. It must be remembered 12. Galie N, Ghofrani HA,Torbici A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary that current published research with sildenafil is arterial hypertension. N Engl J Med. 2005; 353: 2148-57.
limited to term or near term babies and it must be used 13. Shekerdemian LS, Ravn HB, Penny DJ. Interaction in them with extreme caution on a case to case basis.
between inhaled nitric oxide and intravenous sildenafil in aporcine model of meconium aspiration syndrome. Pediatr Contributors: The article was researched and written by MM. RN went through the manuscript and gave suggestions and advice 14. Marsh CS, Marden B, Newsom R. Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. Br J Competing interests: None stated.
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