Emerging Role of Sildenafil in Neonatology MANISH MALIK AND RAHUL NAGPAL 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. firstname.lastname@example.org
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 . 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 , 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 .
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 . 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 .
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 .
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 . 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 . 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  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 .
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 . 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. 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 . 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
 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 .
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 .
in association with chronic lung disease in childrenless than 2 years of age . 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 . 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
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sildenafil in infants with persistent pulmonary hypertension
We could not find any Indian data or case report
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on use of sildenafil in PPHN. There is a feeling that
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Although we discourage the use of Sildenafil except
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on an experimental basis, we urge that experience of
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A controlled multicenter study with adequate
sildenafil citrate in management of pediatric pulmonary
sample size is needed to evaluate the safety, efficacy,
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neonates with PPHN. Research is also needed to
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pharmacokinetics, and dose optimisation for the
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individual patient. An intravenous preparation of
cardiac diseases in children.Working Group on
Sildenafil should also be made available as this would
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be monitored and reported. It must be remembered
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Contributors: The article was researched and written by MM. RN
went through the manuscript and gave suggestions and advice
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prematurity (ROP) in a premature baby treated with
sildenafil acetate (Viagra) for pulmonary hypertension. Br J
Competing interests: None stated.
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Lecturers and Participants Prof. Dr. Robert Bednarz Department of Geography - Texas A&M University, USA Prof. Dr. James F. Petersen Department of Geography - Texas State University, USA Dr. Anna Lyth Prof. Dr. Min Wang Department of Geography – Beijing Normal University, China Dr. Ueli Nagel Zurich University of Teacher Education, Switzerland Mr. Wolfgang Pekny
TEORIA GENERAL DE LOS HECHOS Y ACTOS JURÍDICOS E . B e t t i , F . M e s s i n e o , A . T o r r e z V a s q u e z EL ACTO JURIDICO COMO ESPECIE DE HECHO JURIDICO.1 CLASIFICACIÓN DE LOS ACTOS JURÍDICOS .3 EFECTOS DE LOS ACTOS JURÍDICOS EN RELACIÓN AL DERECHO .5 EL ACTO JURIDICO COMO ESPECIE DE HECHO JURIDICO Entre hecho jurídico y acto jurídico existe una relación de g