The
role of sildenafil in the treatment of persistent pulmonary hypertension
in the newborn (PPHN) was first reported in the lay press way back in 2002
[1]. There was much criticism about its use then. However, there were a
few who felt that the use was justified [2], as there were no other
options for the attending neonatologist in face of non-availability of
inhaled nitric oxide and extracorporeal membrane oxygenation (ECMO). There
have been published reports of its usefulness in adult cardiac patients as
well as in animal models, prior to its use in newborns [3,4]. Since then
there have been many more case reports and some small randomized studies
regarding the use of sildenafil in babies with severe PPHN. The drug is
now frequently being used in many centers in India and other developing
countries where the availability of high frequency ventilation, nitric
oxide and ECMO is extremely limited.
The reported incidence of PPHN is 0.43-6.8 per thousand
newborns [5]. It is likely to be much more in developing countries, where
little data is available. The mortality for the condition has remained
static at 10% to 20% over the last decade. Nitric oxide alone does not
appear to be a solution to the problem. Upto 30% infants fail to improve
despite nitric oxide [6]. 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 reducing the oxygen carrying
capacity of blood. The availability of ECMO, even in developed countries,
is limited to few specialist centers and almost always involves transport
of a very sick baby to the nearest available centre. ECMO as an option is
almost non-existent in developing countries.
The management strategies for PPHN must include
optimization of ventilation, fluid, electrolyte and acid base balance
along with the maintenance of blood pressure. Oral sildenafil can be a
useful adjunct to the treatment if nitric oxide is not available. It can
also be used in conjunction with nitric oxide to facilitate quicker
weaning off nitric oxide [7].
The pulmonary vascular resistance (PVR) at birth is
very high. With the onset of breathing, PVR falls and pulmonary blood flow
increases. The failure of this process in the transitional circulation
results in PPHN. The various mechanisms regulating the PVR are complex.
Nitric oxide (NO)-guanylate cyclase-3’5’ cyclic guanosine monophosphate (cGMP)
system plays an important role in regulating PVR in the perinatal as well
as mature pulmonary vasculature. Nitric oxide activates soluble guanylate
cyclase in vascular smooth muscle cells, resulting in an increase in cGMP
levels. Increased cGMP in the vascular smooth muscle results in
vasodilation through the activation of cGMP dependent protein kinases.
Intracellular cGMP levels are determined by a balance between the
synthesis of cGMP and its degradation. Phosphodiesterases (PDEs) are the
enzymes responsible for the degradation of all cyclic nucleotides. The
lung contains many PDEs but the major component is a cGMP specific PDE
called PDE5. There is high PDE5 activity in the fetal pulmonary arteries.
Sildenafil acts specifically by inhibiting PDE 5 thus producing pulmonary
vasodilation by increasing cGMP levels [8].
The dose of sildenafil was initially chosen
empirically, starting at 0.5mg/kg and increasing up to 2mg/kg per dose to
achieve required response. It is given every 6 hours. A recent study of
the pharmacokinetics of sildenafil shows that an oral dose of 4.2
mg/kg/day is comparable to recommended adult dose of 20 mg three times a
day [9]. In this study, there was a high inter-patient variability
probably related to variable gut absorption of the drug. Also co-
administration of fluconazole resulted in 47% delayed clearance of
sildenafil. The dose recommended by Working Group on Management of
Congenital Heart Diseases in India [10] is 0.5-5 mg/kg/day in 3-4 divided
doses with dose reduction in renal and hepatic impairment. A commonly used
dose is 1 mg/kg/dose given 6 hourly. The duration of treatment is usually
for 2-3 days. 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 drug, without significant side effects [11].
Oral sildenafil is fairly well tolerated, although
absorption can be erratic at times. Since no intravenous preparation is
available, it can only be given orally. A 50 mg tablet of sildenafil is
crushed and dissolved in water in a concentration of 1 mg/mL and then
given via nasogastric tube. Side-effects reported in adult literature are
secondary to vasodilatation and include flushing headaches, dizziness,
hypotension, blurred vision and painful erection [12]. There have been few
reports of side effects in infants. One must watch the systemic blood
pressure closely, although this has been rarely a problem. There have been
reports of hypotension when it is used in conjunction with nitric oxide
[13]. There has been a report of severe retinopathy of prematurity (ROP)
in a preterm baby who received Sildenafil [14]. However, this baby had
multiple risk factors for developing ROP other than Sildenafil use. There
is also a report of severe bleeding in a newborn following circumcision
[15]. Thrombocytopenia is a relative contraindication for the use of
sildenafil.
A small randomised study of sildenafil versus placebo
[5] showed improvement in OI within 6- 30 hours with steady improvement in
pulse oxygen saturation over time. Six of seven babies survived in the
study group versus one of six in the placebo group. All studied infants
were extremely sick with high ventilator parameters, OI >25 and FiO2 of
100%. A Cochrane review of the role of sildenafil in PPHN has also been
published [16]. As there were few studies, it still recommends the use of
the drug on an experimental basis only.
Apart from PPHN, sildenafil has also been used in the
management of congenital diaphragmatic hernia to improve oxygenation and
bring down ventilator requirements [17]. Although this has been on a case
to case basis, the results have been encouraging.
Sildenafil has also been used to treat pulmonary
hypertension (PH) associated with congenital heart disease, both in
newborns and in older children [18]. A recent meta-analysis showed its
effectiveness in treating pulmonary hypertension following paediatric
cardiac surgery [19].
Sildenafil has been used in the management of PH in
association with chronic lung disease in children less than 2 years of age
[11]. It was used in 25 children, with 22 (88%) achieving hemodynamic
improvement after a median duration of 40 days. Their data suggested that
chronic Sildenafil therapy is well-tolerated, safe and effective for
infants with PH and chronic lung deseases.
Emerging data continues to show the safety and
effectiveness of oral sildenafil therapy. However the published studies
are on small number of patients and caution must be exercised in the
interpretation of their outcomes. Since the drug is easily available and
convenient to administer, it has the potential for inappropriate use.
We could not find any Indian data or case report on use
of sildenafil in PPHN. There is a feeling that the drug is being used by
many neonatal intensivists. Although we discourage the use of Sildenafil
except on an experimental basis, we urge that experience of use of the
drug be shared in a peer reviewed journal.
A controlled multicenter study with adequate sample
size is needed to evaluate the safety, efficacy, and long term outcome of
treatment with sildenafil of neonates with PPHN. Research is also needed
to determine differences in drug efficacy between adults and children, age
dependent patterns of pharmacokinetics, and dose optimisation for the
individual patient. An intravenous preparation of Sildenafil should also
be made available as this would probably provide more predictable plasma
concentrations. All experiences with sildenafil, whether it is used in
conjunction with other established modalities or by itself, must continue
to be monitored and reported. It must be remembered that current published
research with sildenafil is limited to term or near term babies and it
must be used in them with extreme caution on a case to case basis.
Contributors: The article was researched and
written by MM. RN went through the manuscript and gave suggestions and
advice resulting in the final draft.
Funding: None.
Competing interests: None stated.
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