The Use of Sildenal in Persistent Pulmonary

Hypertension of the Newborn

Arturo Vargas-Origel, M.D., Sc.M.,
1
Guadalupe Go mez-Rodr guez, M.D., Sc.M.,
1
Carlos Aldana-Valenzuela, M.D.,
1
Ma Martha Vela-Huerta, M.D., Sc.M.,
1
Salvador Benjam n Alarco n-Santos, M.D., Sc.M.,
1
and Norma Amador-Licona, M.D., Sc.M.
2
ABSTRACT
We evaluated the effectiveness of sildenal in the treatment of neonatal pulmo-
nary hypertension. We performed a double-blind randomized clinical trial in 51 full-term
infants with persistent pulmonary hypertension conrmed by Doppler echocardiography.
Patients were divided in two groups: 20 infants in group A received placebo when the
oxygenation index was >20, and 31 infants in group B received 3 mg/kg of oral sildenal
every 6 hours. Arterial blood gases were taken at 1, 4, 7, 13, 19, and 25 hours after
treatment was started. Main outcome measures were oxygenation changes, time on
mechanical ventilation, and mortality. Both groups were comparable in general variables
as well as in illness severity. We observed better oxygenation parameters after 7 hours of
sildenal treatment, but no signicant changes were found in the placebo group. Mortality
was higher in the placebo group (40%) than in those infants who received sildenal (6%;
p 0.004), although no difference was found in time on mechanical ventilation between
groups. Our results conrm that sildenal may be a useful adjuvant therapy for term infants
with pulmonary hypertension in centers lacking inhaled nitric oxide and extracorporeal
membrane oxygenation.
KEYWORDS: Neonatal pulmonary hypertension, sildenal, oxygenation index
Persistent pulmonary hypertension of the neo-
nate (PPHN) is characterized by hyperreactivity of the
muscle layer in pulmonary arterioles and right-to-left
shunt across the ductus arteriosus and the foramen ovale
in absence of structural heart defects. It could also
include right ventricle dysfunction in many cases.
1,2
The reported incidence is 0.43 to 6.8/1000 live newborn
infants with a mortality of 10 to 20%.
3
The main objective of therapy in PPHN is to
reduce pulmonary vascular resistance. To this purpose,
inhaled nitric oxide (iNO) has been used in developed
countries.
4
However, 30% of these patients do not
respond to this therapy. Furthermore, it is expensive and
not always available; additionally, its long-term effects
are basically unknown.
3,5
Extracorporeal membrane oxygenation (ECMO)
is also useful in PPHN, but serious adverse effects have
been reported. Thus, other therapies such as high-
frequency ventilation and surfactant have been tried
with different success rates.
6
Recently, sildenal has been evaluated as
an alternative pulmonary vasodilator. It inhibits
1
Neonatal Intensive Care Unit, Unidad Medica de Alta Especialidad
No. 48;
2
Unidad de Investigacion en Epidemiolog a Cl nica, Instituto
Mexicano del Seguro Social, Leon, Guanajuato, Mexico.
Address for correspondence and reprint requests: Dr. Arturo
Vargas-Origel, Blvd. Jardines del Campestre # 349, Col. J. del
Campestre, ZC 37128, Leon, Guanajuato, Mexico (e-mail: artvaror
@hotmail.com).
Am J Perinatol 2010;27:225230. Copyright # 2010 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662.
Received: December 19, 2008. Accepted after revision: June 17,
2009. Published online: October 16, 2009.
DOI: http://dx.doi.org/10.1055/s-0029-1239496.
ISSN 0735-1631.
225
phosphodiesterase type 5 and elevates the concentra-
tion of cyclic guanosine monophosphate in the muscle
cells of pulmonary vessels, which in turn decreases
pulmonary vascular resistance.
7,8
In animal studies, sildenal has been able to
overcome experimentally induced PPHN in lambs.
9,10
In adult humans, these observations have also been
conrmed,
11
so the Food and Drug Administration in
the United States recently approved its use for adults
with pulmonary hypertension.
12
In some studies, silde-
nal use has been postulated to be better than iNO
13
;
there are also anecdotal reports on the benets of
sildenal on infants with PPHN from centers where
iNO is unavailable.
1417
Furthermore, it could also
decrease the risk of the rebound effect, when iNO is
discontinued.
18
Recently, two clinical trials compared sildenal
versus placebo in newborns with PPHN; one evaluated
24 patients, and the other, only 13 patients. Both of
them showed that sildenal signicantly improved the
oxygenation index and decreased mortality.
19,20
In our hospital, PPHN is managed in conven-
tional ways because of iNOs difcult accessibility. The
aim of this study was to evaluate the effectiveness of
sildenal in newborns with PPHN and whether it would
be able to improve oxygenation and decrease the time on
mechanical ventilation.
METHODS
We performed a prospective clinical trial in 51 term and
postterm newborns with PPHN. Patients were included
in case of <48 hours of extrauterine life and when
oxygenation index (OI) >20. All of them were born in
our hospital. Infants with diaphragmatic hernia and
major congenital defects were not included in the study.
The rst 40 patients were randomly assigned to
sildenal or placebo treatment. However, after this time
iNO was available in our hospital and the Bioethics
Committee considered it unethical to use placebo, so
only assignment to sildenal and iNO was permitted.
Patients in group B received 3 mg/kg of sildenal every 6
hours by orogastric tube. The 50-mg tablet was diluted
in 20 mL injectable water and a dilution was performed
to prepare all doses required in 24 hours; solutions were
maintained at 48C. Infants in group A received normal
saline as a placebo. Treatment was discontinued when
OI was <10. Supportive therapy was similar in both
groups and included conventional mechanical ventila-
tion, inotropic agents, and bicarbonate as needed. High-
frequency ventilation and ECMO are not available in
our hospital.
Arterial blood gases were measured at 1, 4, 7, 13,
19, and 25 hours from the umbilical artery catheter in
most patients. Only in ve patients, two from group A
and three from group B, blood gases were measured from
a peripheral artery catheter. The next respiratory insuf-
ciency indexes were calculated: OI, alveolar-arterial
oxygen difference (A-aDO
2
), and arterial/alveolar oxy-
gen tension ratio (a/A RO
2
) following the conventional
formulas.
21
Time on mechanical ventilation, mean air-
way pressure, complications, and mortality rate were also
evaluated.
PPHN was conrmed by Doppler echocardiog-
raphy demonstrating tricuspid regurgitation. We meas-
ured the transvalvular maximum velocity and the peak
gradient. Systolic pressure of the right ventricle was
calculated according to the following formula:
4tricuspid regurgitation
2
right atrium systolic pressure
Pulmonary velocity was evaluated; it was assumed
that the right ventricle systolic pressure is equal to the
systolic pressure of the pulmonary artery. A value
>40 mm Hg was considered as pulmonary hyperten-
sion.
22,23
Doppler echocardiography was only performed
at baseline.
The sample size was estimated before the study.
Group sample sizes of 30 patients would achieve an 80%
power to detect a predened meaningful difference of
20% in PaO
2
response between groups (increase of 50%
in the sildenal group and 30% in the control group),
with an a level of 0.05.
24
Demographic data of the two
groups were compared with Student t or Mann-Whitney
U test according to the variable distribution; analysis of
variance for repeated measures was used for the results of
the blood gas analysis adjusting for the group assign-
ment. For the OI, we performed Kruskall-Wallis be-
cause of the non-normal distribution. Morbidity and
mortality were evaluated by chi-square and Fisher exact
probability test.
25
The study was approved by the local ethical
committee of the Hospital of Gynecology and Obstetrics
in Leon, Mexico. Written informed consent was ob-
tained from the parents of each of the infants involved in
the study.
RESULTS
No difference was found on the general characteristics
between groups (Table 1). The predominant underlying
diagnoses were meconium aspiration syndrome, pneu-
monia, and transient tachypnea, without signicant
differences between groups (p 0.17). All patients
from both groups received amines, at similar doses.
There was no difference on most basal arterial
blood gas values and physiological indexes for respiratory
failure between groups. Even OI was similar when values
were stratied. Only PaCO
2
was higher in the control
group (Table 2).
In Fig. 1, the evolution of PaO
2
over time is
shown: in the sildenal group, there was a signicant
226 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 27, NUMBER 3 2010
increase after 7 hours of treatment (37.0 9.8 versus
70.3 22.8 mm Hg; p 0.04), which persisted in the
next hours. In addition, in the sildenal group the OI
decreased from the seventh hour of treatment (38.8
versus 20.0; p <0.0001) and persisted a long time, but
no difference was found in the control group (42.3 versus
31.0; p 0.81; Fig. 2). A signicant decrease was ob-
served in mean airway pressure from the thirteenth hour
(14.4 versus 12.1; p 0.001) of treatment without any
signicant change along time in the control group
(Fig. 3). A-aDO
2
decreased signicantly after 19 hours,
and a/A RO
2
rose signicantly after 1 hour of sildenal
treatment.
In the entire group of patients, there was an
increase in pH values and a decrease in PaCO
2
, but it
was not dependent on the group assignment. Time on
mechanical ventilation was similar in both groups:
120 hours (8 to 360 hours) in the sildenal group versus
72 hours (37 to 528 hours) in the control group
(p 0.69). These results persisted when only survivors
were considered. Mortality was higher in the control
group than in the sildenal group, 8/20 (40.0%) versus
2/31 (6.5%), respectively (p <0.004), which remained
signicant after considering only those patients with
basal OI >40 (p 0.003), but not in those with basal
OI <40 (p 0.71). Seven of the eight patients who died
in the control group and one of the two who died in the
sildenal group had an OI >40.
Within the sildenal group, one patient received
two doses, 18 received from ve to seven doses, and
Table 1 General Characteristics of the Two Study Groups*
Variable Control (n20) Sildenal (n31) p
Gender (F/M) 7/13 15/16 NS
Gestational age (wk) 38.81.9 37.81.6 NS
Birth weight (g) 3043563 2993532 NS
Postnatal age (h) 24.517.3 24.120.8 NS
Apgar scores
1 min 5 (48) 7 (67) NS
5 min 7 (68) 8 (78) NS
Mode of delivery, n (%)
Cesarean section 12 (60.0) 25 (80.6) NS
Vaginal 8 (40.0) 6 (19.3) NS
Underlying diagnosis, n (%)
Meconium aspiration syndrome 6 (30.0) 8 (25.8) NS
Pneumonia 8 (40.0) 17 (54.8) NS
Respiratory distress syndrome 0 (0) 2 (6.4) NS
Transient tachypnea 3 (15.0) 3 (9.6) NS
Perinatal asphyxia 2 (10.0) 0 (0) NS
Sepsis 1 (5.0) 1 (3.2) NS
*Mean and standard deviation. Apgar score in median and range.
Table 2 Initial Blood Gas Values and Respiratory Insufficiency Indexes*
Variable Control (n20) Sildenal (n31) p
pH 7.250.14 7.320.12 NS
PaCO
2
(mm Hg) 50.418.2 40.513.9 0.03
PaO
2
(mm Hg) 37.710.2 37.09.8 NS
HCO
3
(mEq/L) 20 0.4 4.8 19.14.0 NS
MAP (cm H
2
O) 15.53.1 14.42.4 NS
OI 38.8 (22.580.0) 42.3 (24.084.0)
2029 5 (25) 5 (16.1) NS
3039 4 (20.0) 13 (41.9) NS
40 11 (55.0) 13 (41.9) NS
FiO
2
1 1 NS
A-aDO
2
(mm Hg) 469.122.2 481.718.4 NS
a/A RO
2
0.060.01 0.080.09 NS
SPAP* (mm Hg) 64.313.6 65.414.7 NS
*Mean and standard deviation, except OI in median and range, and (%).
MAP, mean airway pressure; OI, oxygenation index; A-aDO
2
, alveolar-arterial oxygen difference; a/A RO
2
, arterial/alveolar oxygen tension ratio;
SPAP, systolic pulmonary arterial pressure.
SILDENAFIL IN PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN/VARGAS-ORIGEL ET AL 227
Figure 1 Changes in PaO
2
in treated (sildenal) and untreated (control) infants.
Figure 2 Changes in oxygenation index in treated (sildenal) and untreated (control) infants.
Figure 3 Changes in mean airway pressure (MAP) in treated (sildenal) and untreated (control) infants.
228 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 27, NUMBER 3 2010
12 received from eight to sixteen doses. None of the
patients in the sildenal group showed hypotension.
Five patients initially assigned to the placebo
group received iNO; because of that, they were not
included in the nal analysis. Because of the postran-
domization exclusions, we performed an intention-to-
treat analysis including ve patients who received iNO
instead of placebo. However, mortality remained higher
in this group than in sildenal group (32.0% versus 6.5%;
p 0.02).
DISCUSSION
The most relevant fact of this study, currently the trial
with the largest number of patients included, was the
signicantly higher survival rate in the treated patients
(93.5%) compared with the control group (60%). In
addition, there were signicant improvements in PaO
2
and several physiological indexes of respiratory failure in
the treated infants, although the time on mechanical
ventilation was similar, which made us think sildenal is
a useful drug for the treatment of PPHN in centers
lacking iNO and ECMO.
Previous smaller studies have also shown the
benets of sildenal in PPHN with reported survival
rates between 85 and 100%, signicantly higher than in
nontreated patients.
19,20
There is lack of consensus about when to start
sildenal use. Our criterion was OI >20, although in the
studies previously mentioned, OI >25 was chosen. This
may be interpreted as though the patients were not in a
condition critical enough to be compared. However,
75% of those belonging to the control group and 84%
from the sildenal group had an OI >30. Besides,
signicant changes between groups were found only in
patients in whom IO was 40 but not in cases of
IO<40.
Another difference with previous studies was the
dose of sildenal used. Recommended doses vary from
0.5 to 3 mg/kg per dose
6
; we decided to use the highest
dose without evidence of intolerance or serious adverse
effects. Data from the side effects of sildenal come from
adult patients. The most common are headache (16%),
blushing (10%), and blurred vision (11%). It seems that
these effects are dose-dependent. There is experimental
evidence that there are no genetic defects
26
and no
neurodevelopmental impairment associated with its
use.
6
In this study, as well as in the previous studies
mentioned,
19,20
no systemic hypotension was observed.
However, because sildenal inhibits PDE-6 in the
retina, the drug is contraindicated in premature infants
who may have higher risk for retinopathy.
27
Such as in the present study, the other trials
showed improvements in the OI and mean airway
pressure, although this occurred at different treatment
times. In our study, PaO
2
increased signicantly and
persistently after 7 hours; in the study by Herrera Torres
and colleagues, this occurred after 24 hours,
19
although
Baquero and colleagues documented this change at
6 hours,
20
along with signicantly decreased A-aDO
2
after 19 hours, which was much earlier than the other
reports, and the a/A RO
2
, not previously considered,
rose signicantly after 1 hour of treatment.
Our study supports the use of sildenal on term
newborns with PPHN in those centers without iNO and
ECMO. Further randomized studies are needed with
long-term follow-up for a better evaluation of this
promising therapy.
REFERENCES
1. Boden G, Bennett C. The management of persistent
pulmonary hypertension of the newborn. Curr Paediatr 2004;
14:290297
2. DAlonzo GE, Barst RJ, Ayres SM, et al. Survival in patients
with primary pulmonary hypertension. Results from a
national prospective registry. Ann Intern Med 1991;115:
343349
3. Travadi JN, Patole SK. Phosphodiesterase inhibitors for
persistent pulmonary hypertension of the newborn: a review.
Pediatr Pulmonol 2003;36:529535
4. Channick RN, Newhart JW, Johnson FW, et al. Pulsed
delivery of inhaled nitric oxide to patients with primary
pulmonary hypertension: an ambulatory delivery system and
initial clinical tests. Chest 1996;109:15451549
5. Kelly LK, Porta NF, Goodman DM, Carroll CL, Steinhorn
RH. Inhaled prostacyclin for term infants with persistent
pulmonary hypertension refractory to inhaled nitric oxide.
J Pediatr 2002;141:830832
6. Sola A, Baquero H. Sildenalo oral en medicina neonatal
Investigado para adultos, usado tambien por neonatos. An
Pediatr (Barc) 2007;66:167176
7. Beavo JA. Cyclic nucleotide phosphodiesterases: functional
implications of multiple isoforms. Physiol Rev 1995;75:
725748
8. Buck ML. Sildenal for the treatment of pulmonary
hypertension in children. Pediatr Pharm 2004;10:14
9. Weimann J, Ullrich R, Hromi J, et al. Sildenal is a
pulmonary vasodilator in awake lambs with acute pulmonary
hypertension. Anesthesiology 2000;92:17021712
10. Shekerdemian LS, Ravn HB, Penny DJ. Intravenous
sildenal lowers pulmonary vascular resistance in a model
of neonatal pulmonary hypertension. Am J Respir Crit Care
Med 2002;165:10981102
11. Sastry BKS, Narasimhan C, Reddy NK, et al. A study of
clinical efcacy of sildenal in patients with primary
pulmonary hypertension. Indian Heart J 2002;54:410414
12. Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R.
A randomized, placebo-controlled, double-blind, crossover
study to evaluate the efcacy of oral sildenal therapy in
severe pulmonary artery hypertension. Am Heart J 2006;151:
851; e1e5
13. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto
K, Archer S. Oral sildenal is an effective and specic
pulmonary vasodilator in patients with pulmonary arterial
hypertension: comparison with inhaled nitric oxide. Circu-
lation 2002;105:23982403
SILDENAFIL IN PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN/VARGAS-ORIGEL ET AL 229
14. Prasad S, Wilkinson J, Gatzoulis MA. Sildenal in primary
pulmonary hypertension. N Engl J Med 2000;343:13421343
15. Erickson S, Reyes J, Bohn D, et al. Sildenal (Viagra) in
childhood and neonatal pulmonary hypertension. J Am Coll
Cardiol 2002;39:402A
16. Fernandez Gonzalez N, Rodr guez Fernandez A, Jerez Rojas
J, et al. Sildenalo oral como tratamiento de un neonato con
hipertension pulmonar persistente. An Pediatr (Barc) 2004;
61:567568
17. Bonino A, Moraes M, Mortinotti M, et al. Sildenal:
?
una
alternativa para el tratamiento de la hipertension pulmonar
persistente? Arch Pediatr Urug 2005;76:130134
18. Namachivayam P, Theilen U, Butt WW, Cooper SM, Penny
DJ, Shekerdemian LS. Sildenal prevents rebound pulmo-
nary hypertension after withdrawal of nitric oxide in children.
Am J Respir Crit Care Med 2006;174:10421047
19. Herrera Torres R, Concha Gonzalez EP, Holberto Castillo J,
et al. Sildenal oral como alternativa en el tratamiento de
recien nacidos con hipertension pulmonar persistente. Rev
Mex Pediatr 2006;73:159163
20. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral
sildenal in infants with persistent pulmonary hypertension
of the newborn: a pilot randomized blinded study. Pediatrics
2006;117:10771083
21. Wood BR. Principios siologicos. In: Goldsmith JP,
Karotkin EH, eds. Ventilacion asistida neonatal. Bogota:
Editorial Distribuna; 2005:2561
22. Su BH, Watanabe T, Shimizu M, et al. Doppler assessment
of pulmonary artery pressure in neonates at risk of chronic
lung disease. Arch Dis Child Fetal Neonatal Ed 1997;
77:F23F27
23. Berger M, Haimowitz A, Van Tosh A, et al. Quantitative
assessment of pulmonary hypertension in patients with
tricuspid regurgitation using continuous wave Doppler
ultrasound. J Am Coll Cardiol 1985;6:359365
24. Halley SB, Cummings SR. Diseno de la investigacion cl nica.
Barcelona: Ediciones Doyma; 1993:232233
25. Dawson-Saunders B, Trapo RG. Bioestad stica medica. 2nd
ed. Mexico, DF. El Manual Moderno; 1997:124126149
160175177
26. Lemus-Varela ML, Sola A, Gomez-Meda BC, et al. Oral
sildenal citrate lacks genotoxicity and cytotoxicity in a
primate model: Callithrix jacchus. J Perinatol 2006;26:423
427
27. Marsh CS, Marden B, Newsom R. Severe retinopathy of
prematurity (ROP) in a premature baby treated with
sildenal acetate (Viagra) for pulmonary hypertension. Br J
Ophthalmol 2004;88:306307
230 AMERICAN JOURNAL OF PERINATOLOGY/VOLUME 27, NUMBER 3 2010