Teaching PowerPoint presentation on evidence based use of Sildenafil in the treatment of PDA in neonates.

1. Sildenafil in Pulmonary
Hypertension
Dr.Sid Kaithakkoden MD
MBBS,DCH,DNB,MD,MRCPCH,FCPS
alavisaid@aol.com

2. Pharmacology
• Sildenafil is a selective Phosphodiesterase-5
inhibitor that has been reported to be a potent
pulmonary vasodilator
• Sildenafil selectively inhibits phosphodiesterase
5 (PDE5 is abundant in pulmonary and penile
tissue) which leads to stabilization of cyclic
guanosine monophosphate (cGMP)

3. • cGMP is a second messenger of nitric
oxide (NO)
• Stabilization of cGMP results in increasing
nitric oxide (NO) at the tissue level leading
to pulmonary vessel vasodilatation
• Nitric oxide has been considered the
closest thing to an ideal vasodilator

4. • Sildenafil is a more potent acute pulmonary
vasodilator than inhaled nitric oxide, however,
Sildenafil is not pulmonary vascular specific
• Sildenafil administered orally has been shown
to have beneficial effects in patients with PAH
even during treatment with inhaled NO
• Sildenafil also prevents rebound pulmonary
vasoconstriction on withdrawal of inhaled NO

6. Figure 1 Lung histology. (A) Arrow showing pulmonary vasculopathy with intimal proliferation
and marked medial thickening. (B) Arrow showing impaired alveolarisation.

7. Rashid, A et al. Arch Dis Child 2005;90:92-98
Figure 1 Algorithm of the treatment of paediatric pulmonary arterial hypertension.
•Decrease in the mean pulmonary artery pressure and resistance by 20%, or greater, with a fall to near normal
levels (<40 mg Hg)
•Experience no change or an increase in their cardiac index
•Exhibit no change or a decrease in the ratio of pulmonary vascular resistance to systemic vascular resistance
•Normal right atrial pressure and cardiac output

8. PEDIATRICS Vol. 117 No. 4 April 2006, pp.
1077-1083 (doi:10.1542/peds.2005-0523)
Oral Sildenafil in Infants With
Persistent Pulmonary Hypertension of
the Newborn: A Pilot Randomized
Blinded Study
Hernando Baquero, MD, Amed Soliz, MD, Freddy
Neira, MD, Maria E. Venegas, MD and Augusto Sola,
MD
Division of Neonatology, Universidad del Norte, Barranquilla, Colombia
Division of Neonatology, Miami Children's Hospital, Miami, Florida
Division of Neonatology, Emory University, Atlanta, Georgia

9. • OBJECTIVE.
– to evaluate the feasibility of using oral Sildenafil and its
effect on oxygenation in PPHN.
• DESIGN.
– randomized, masked study in infants >35.5 weeks'
gestation and <3 days old with severe PPHN and
oxygenation index (OI) >25 admitted to the NICU
(Hospital Niño Jesús, Barranquilla, Colombia)
– The first dose (1 mg/kg) or placebo was given by
orogastric tube <30 minutes after randomization and
every 6 hours
– Preductal saturation and blood pressure were monitored
continuously
– OI was calculated every 6 hours
– The main outcome variable was the effect of oral
Sildenafil on oxygenation
– Sildenafil or placebo was discontinued when OI was <20
or if there was no significant change in OI after 36 hours.

10. • RESULTS
– Six infants with an OI of >25 received placebo, and 7
received oral Sildenafil at a median age of 25 hours. All
infants were severely ill, on fraction of inspired oxygen
1.0, and with similar ventilatory parameters.
– In the treatment group, OI improved in all infants within 6
to 30 hours, all showed a steady improvement in pulse
oxygen saturation over time, and none had noticeable
effect on blood pressure; 6 of 7 survived
– In the placebo group, 1 of 6 infants survived.
• CONCLUSIONS.
– Oral Sildenafil improved OI in infants with severe PPHN,
which suggests that oral Sildenafil may be effective in
the treatment of PPHN and underscores the need for a
large, controlled trial.

11. Cochrane review
• Kanthapillai P, Lasserson TJ, Walters EH.
Sildenafil for pulmonary hypertension. Art.
No.: CD003562. DOI:
10.1002/14651858.CD003562.pub2. Date
of last subtantive update: August 01. 2004

12. • Objectives
– To determine the clinical efficacy of Sildenafil,
administered via any route to people with pulmonary
hypertension in primary or secondary forms.
• Search strategy
– MEDLINE, EMBASE and CENTRAL were searched with
pre-defined search terms. Searches were unto October
2005.
• Selection criteria
– Randomised controlled trials were considered for
inclusion in the review.

13. • Main results
– Four studies recruiting 77 participants met the inclusion
criteria of the review
– Two studies assessed the acute effects of Sildenafil
– Two small crossover study assessed the effects of long
term administration
– The 'acute effect' studies indicated that Sildenafil has a
pulmonary vasodilatory effect
– The two crossover studies showed improvement in
symptoms
– One study showed improvement in fatigue domains from
a validated health status questionnaire
– Both crossover studies reported that the drug was well
tolerated.