was repeated in 30 minutes with no response. Baby died
at 36 hours of age from persistent hypoxemia andcirculatory failure. Case 2: A full term 3250 grams female newborn was Oral Sildenafil for PPHN in
born by emergency LSCS for fetal bradycardia. Therewas a history of maternal antepartum hemorrhage one-
Neonates: Selection of patients
week prior, that was managed conservatively. Motherhad poor nutritional status with severe anemia (Hb 4.4
Remains a Dilemma?
g%) and was delivered with thick old meconium. Babyrequired direct tracheal suction and IPPV with Apgar
scores of 4, 7, 8 at 1, 5 and 10 minutes respectively. At20 minutes of age, baby developed respiratory distress
Persistent pulmonary hypertension (PPHN) in neonates
and prolonged capillary filling time. Baby was thus,
has varied etiologies.1-4 It remains a condition with high
referred to us. At 4 hours of age, baby was initiated on
mortality. The mortality reported from Western literature
mechanical ventilation for desaturations and increasing
is 10-15%, which may be significantly more in Indian
respiratory distress (Blood gas at this stage showed
subcontinent due to non-availability of inhaled nitric
hypoxemia PO2 42 mmHg without hypercapnia or
oxide and extracorporeal membrane oxygenation.1
acidosis). Sepsis screen, hematocrit (45%) and USG
Multiple pharmacological approaches have been
cranium was normal. Chest X-ray done was consistent
suggested for its management.4 Sildenafil, a phospho-
with meconium aspiration syndrome. Baby remained
diesterase inhibitor shows promise in our settings due to
hypoxemic with maximum ventilation (30/5 rate 65 and
ease of availability, administration and low cost.
FiO2 100%). A dose of surfactant was given with no
However, it’s off label use is still not allowed due to
response. Echocardiography ruled out cyanotic
inconsistent responses.5 We share our experience of
congenital heart disease but showed suprasystemicpulmonary pressures. Baby was managed with
failure to demonstrate any beneficial response with oral
hyperventilation, alkalization and vasopressor support
with persistent hypoxemia. A rescue dose of oral
Case 1: A 1450 grams near term small for gestational
sildenafil was given at a dose of 1.5 mg/kg at 10 hours
age, male baby was delivered at a small peripheral
of age without any improvement in oxygenation index.
health facility by emergency cesarean section, for
Baby died at 16 hours of age due to refractory shock.
severe oligohydramnios and prolonged rupture of
We used oral sildenafil as a rescue measure after
membranes, was brought in respiratory distress having
discussions with the family and verbal consent. We
a positive sepsis screen at admission. Chest X-ray
discussed in detail about the unavailability of inhaled
revealed low volume lungs with generalized opacity
nitric oxide and ECMO at other higher centres, and
suggesting pulmonary hypoplasia and a small right
instability of the babies for transport. In both the babies
pneumothorax. Baby was given surfactant at eight
oral sildenafil was used once the criteria for
hours of age and ventilated on Synchronized
extracorporeal membrane oxygenation were met
Intermittent Mechanical Ventilation (SIMV) mode with
(Oxygenation index > 40). We prepared sildenafil
pressure support (Maquet, Servo I, Sweden). He
(25 mg) by dissolving in 10 ml distilled water and gave
required very high pressures PIP 28/5 rates 60 and 100
the solution through oro-gastric tube. Both the cases
FiO2. Sequential X-rays showed an enlarging right
represent common scenarios faced by neonatologists in
pneumothorax that was managed with chest drainage.
India and other developing countries.6,12 Three major
After a transient response, blood gases showed
patho-physiological derangements in PPHN have been
persistent severe hypoxemia (PO2 25-34 mmHg).
described: underdevelopment of the lung, mal-
Echocardiography confirmed PPHN with suprasystemic
development of the lung and mal-adaptation of the lung
pulmonary pressures (gradient 25 mmHg). Baby was
with the latter group showing the best response to
started on maximum vasopressor support, hyper-
vasodilator therapy.4 A search of electronic databases
ventilated and given sodium bicarbonate in vain. Oral
(MEDLINE, EMBASE, PsycINFO AND CINAHL) was
Sildenafil 0.5 mg/kg was tried at 18 hours of age and
done using key words sildenafil and neonates andsildenafil and PPHN. Reports in which sildenafil wasused for PPHN in only in neonatal age group (excluding
Department of Pediatrics, Central Hospital and Research
children) were retrieved. Case reports in which sildenafil
was used for PPHN secondary to congenital heart
Correspondence: Dr. Pankaj Garg, B-342, Sarita Vihar,
disease and bronchopulmonary dysplasia were
excluded. Thus, only five publications were left, which
included one recent placebo randomized controlled trial
Received April 12, 2007; accepted October 24, 2007.
enrolling 13 newborns with use of oral sildenafil in seven
Journal of The College of Physicians and Surgeons Pakistan 2008, Vol. 18 (2): 132-133
Oral sildenafil for PPHN in neonates: selection dilemma?
newborns.5-9 Overall combining all reports, oral
and admission, diagnosis), maternal variables, ventilator
sildenafil have been used in 12 new borns with PPHN
indices and parameters into account.
reporting dramatic responses in 11 babies who survived. One report highlighted successful use of intravenous
sildenafil.10 The dose of oral sildenafil used has been
Cook LN, Stewart DL. Inhaled nitric oxide in the treatment of
0.5 mg/kg to 1.5 mg/kg/dose. In animal studies, a dose
persistent pulmonary hypertension / hypoxic respiratory failure
of 3 mg/kg have been suggested.11 Simiyu et al. and
in neonates: an update. J Ky Med Assoc 2005; 103: 138-47.
Juliana et al. have shown good response in PPHN
Konduri GG. New approaches for persistent pulmonary
hypertension of newborn. Clin Perinatol 2004; 31: 591-611.
shown survival in impaired alveolarisation that was
Dakshinamurti S. Pathophysiologic mechanisms of persistent pulmonary
proven by lung biopsy.8 However, in the first case, we
hypertension of the newborn. Pediatr Pulmonol 2005; 39: 492-503.
could not confirm pulmonary hypoplasia and poor
Oishi P, Fineman JR. Pharmacologic therapy for persistent
response may be due to slightly delayed and low dose
pulmonary hypertension of the newborn: as “poly” as the
of sildenafil use. Some studies have suggested repeat
disease itself. Pediatr Crit Care Med 2004; 5:94-6.
dose of sildenafil at six hours, but was not used because
Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil
the perfusion had became markedly deteriorated and
with persistent pulmonary hypertension of the newborn: a pilot
second oral dose of drug would be futile. Baquero has
randomized blinded study. Pediatrics 2006; 117: 1077-83.
shown good response in meconium aspiration syndrome in
Simiyu DE, Okello C, Nyakundi EG, Tawakal AH. Sildenafil in
their trial.5 However, we could not demonstrate response in
management of persistent hypertension of the newborn: report
the second case also, probably we used it slightly late
of two cases. East Afr Med J 2006; 83: 337-40.
Juliana AE, Abbad FC. Severe persistent pulmonaryhypertension of the newborn in a setting where limited
Table I: Ventilator indices pre and *post sildenafil
resources exclude the use of inhaled nitric oxide: successful treatment with sildenafil. Eur J Pediatr 2005; 164: 626-9.
Chaudhari M, Vogel M, Wright C, Smith J, Haworth SG.
Sildenafil in neonatal pulmonary hypertension due to impaired
alveolarisation and plexiform pulmonary ateriopathy. Arch Dis Child Fetal Neonatal Ed 2005; 90: F527-8.
Garcia Martinez E, Ibarra de la Rosa I, Perez Navero JL, Tejero
Matro I, Exposito Montes JF, Suarez de Lezo ycruz Conde J. *Post indices are 30 minutes after oral administration of sildenafil
Sildenafil in the treatment of pulmonary hypertension. Ann Pediatr (Barc) 2003; 59:110-3.
Other confounding variables like status of the baby at
10. Harris K. Extralobar sequestration with congenital
birth, out-born status, poor transport system and low
diaphragmatic hernia: a complicated case study. Neonatal Netw 2004; 23: 7-24.
birth weight in the first case may have contributed topoor outcomes. There is an urgent need for multi-
11. Binns-Loveman KM, Kaplowitz MR, Fike CD. Sildenafil and an
early stage of chronic hypoxia-induced pulmonary hypertension
centric randomized controlled trials from the Indian
in newborn piglets. Pediatr Pulmonol 2005; 40: 72-80.
subcontinent. A clinical prediction rule needs to be
12. Patole S, Travadi J. Sildenafil for "blue babies". Ethics,
developed, which includes neonatal variables (age, sex,
conscience, and science have to be balanced against limited
weight, and gestational age, condition of baby at birth
resources. BMJ 2002; 325:1174.
Journal of The College of Physicians and Surgeons Pakistan 2008, Vol. 18 (2): 132-133
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