EL-MINIA MED., BULL., VOL. 18, NO. 2, JUNE, 2007
Abdel Wahab & Mahfuz
COMPARISON BETWEEN IBUPROFEN AND INDOMETHACIN
FOR CLOSURE OF PATENT DUCTUS ARTERIOSUS
IN PRETERM INFANTS
By
Walid Abdel Wahab1,3, Ahmed Mahfuz2,3
Departments of Pediatrics1, and Community Medicine2,
College of Medicine, King Khalid University, Abha, Saudi Arabia, and Aseer
Regional Committee of Neonatal Care3
ABSTRACT:
Background: Patent ductus arteriosus (PDA) is commonly found in very low birth
weight infants. Indomethacin and more recently, ibuprofen have been used to treat
hemodynamically PDA in preterm infants. Both are cyclo-oxygenase inhibitors but
seem to have a different influence on regional circulation. In a prospective
randomized study, we compared ibuprofen and indomethacin with regard to efficacy
and safety for the early non-invasive treatment of PDA in preterm infants.
Methods: A total of 41 preterm infants with respiratory distress syndrome who had
gestational age of < 30 weeks, postnatal age of 2-7 days, and echocardiographic
evidence of hemodynamically significant PDA were enrolled in the study. Exclusion
criteria were major congenital anomalies, IVH, recent bleeding (less than 48 hours
previously), a platelet count of 100,000 / mm3 or less, urine output less than 1 ml / kg
/ hour during the previous 12 hours, serum creatinine level > 1.5 mg / dL, blood urea
nitrogen (BUN) concentration > 50 mg / dL or concurrent administration of
nephrotoxic medications. Patients were randomized into two groups: the first group of
neonates (n = 20) received oral ibuprofen 10 mg/kg, followed by 5 mg / kg after 24
and 48 hours; the second group (n = 21) received intravenous indomethacin 0.2 mg/kg
every 12 hours for three doses.
Results: The efficacy of the pharmacological treatment was similar in the two groups.
PDA closed in 15 (75%) patients from the ibuprofen group and in 16 (76%) patients
in the indomethacin group. Serum creatinine and blood urea nitrogen levels were
significantly lower (p < 0.001) in the ibuprofen group than in the indomethacin group.
We found a significantly lower urine output in the indomethacin group than the
ibuprofen group at 24 and 48 hours after treatment.
Conclusion: Oral ibuprofen is as efficacious as indomethacin for the treatment of
PDA in preterm infants and is significantly less likely to cause renal dysfunction.
KEYWORDS:
Patent ductus arteriosus
Preterm infant.
Ibuprofen
Indomethacin
development of symptomatic PDA
which has been associated with an
increased risk of intraventricular
hemorrhage (IVH), Necrotizing enterocolitis (NEC), bronchopul-monary
dysolasia (BPD), and death4. Consequently, prophylactic or curative
INTRODUCTION:
The incidence of patent ductus
arteriosus (PDA) in infants weighing
501-1500 gram is approximately 31 %
1-3
. The occurrence of respiratory
distress syndrome (RDS) strongly
predisposes an infant to the
64
EL-MINIA MED., BULL., VOL. 18, NO. 2, JUNE, 2007
Abdel Wahab & Mahfuz
/ mm3 or less, urine output less than 1
ml / kg / hour during the previous 12
hours, serum creatinine level > 1.5 mg
/ dL, blood urea nitrogen (BUN)
concentration > 50 mg / dL or
concurrent administration of nephrotoxic medications.
treatment has been advocated before
the critical left-to-right shunting
occurs5.
Until recently, indomethacin
has been the drug of choice. However,
renal and cerebral hemodynamic side
effects have been frequently reported68
. These adverse effects have prompted
the search for new, safer pharmacological strategies for PDA closure9.
After
obtaining
informed
parental consent, patients enrolled in
the study at each unit were randomly
placed into two groups. The first group
of neonates (group A, n = 20) (11 male
and 9 female), received oral ibuprofen
10 mg / kg followed by 5 mg / kg after
24 and 48 hours. Ibuprofen was given
undiluted through a feeding tube and
flowed by flushing with distilled water.
Ibuprofen has been shown to
close the ductus arteriosus in animals
without affecting cerebral blood flow
or intestinal and renal hemodynamics10,11. More recently, ibu-profen has
emerged as a potential alternative to
indomethacin in the treatment of
PDA12.
Doses
and
interval
for
ibuprofen were in accordance with
recommendations for its use in
neonates based on preliminary pharmacodynamic data13.
The efficacy if ibuprofen has
not yet been adequately addressed in
extremely premature infants9.
The aim of this study was to
compare the efficacy and safety of
ibuprofen with that of indomethacin
for closure of PDA in preterm infants.
The second group of the
patients (group B, n = 21) (12 male and
9 female) received intravenous indomethacin. The initial dose was 0.2
mg/kg. Two further doses were
administered after 12 and 24 hours.
SUBJECTS AND METHODS:
This study was conducted at
neonatal intensive care units of Abha
General and Aseer Central Hospitals,
Abha, Southwestern Saudia Arabia
between between January 2003 and
December 2004. Preterm infants
admitted to both units were eligible for
the trial if the following criteria were
met: 1) Gestational age < 30 weeks, 2)
Postnatal age 2-7 days, 3) RDS treated
with mechanical ventilation, and 4)
Echocardiographic evidence of hemodynamically significant PDA.
Statistical analysis:
Frequencies, percentage, arithmetic mean and standard deviation
were used to present the data. Chisquare and Student “t” were used as
tests of significance at 5 % level.
Statistical analysis was performed by
using the (SPSS) software.
RESULTS:
A total of 41 preterm infants
with significant PDA were enrolled in
the study. The first group of neonates ,
were treated with oral ibuprofen (n =
20), [11 (55 %) male and 9 ( 45 %)
female], their mean gestational age
(GA) was 27.3 + 1.2, range (25-30)
weeks while their mean birth weight
Exclusion criteria were major
congenital anomalies, IVH, recent
bleeding (less than 48 hours previously), a platelet count of 100,000
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EL-MINIA MED., BULL., VOL. 18, NO. 2, JUNE, 2007
(BW) was 813 + 21.3,
1150) gram.
range (650-
Abdel Wahab & Mahfuz
Safety of treatment
Serum creatinine levels and
blood urea nitrogen concentrations are
shown in tables 2 and 3 respectively.
The ibuprofen group had significantly
lower (p < 0.001) serum creatinine
levels and lower (p < 0.001) BUN at
24 and 48 hours after treatment than
the indomethacin group. Urine output
are shown in table 4. We found a
significantly lower urine output in the
indomethacin group than in the
ibuprofen group at 24 and 48 hours
after treatment.
The second group of preterm
infants were treated with intravenous
indomethacin (n = 21), [12 (57 %)
male and 9 (43 %) female], their mean
gestational age was 27.2 + 1.0, range
(26-29) weeks while their mean birth
weight was 845 + 0.8, range (710-990)
gram.
Antenatal corticosteroids were
given to the mothers of 8 (40 %)
preterm infants in the first group and to
the mothers of 9 (43 %) neonates in the
second group. We found no significant
differences between the two treated
groups as regards GA, BW, and
antenatal corticosteroids.
Regarding the outcome of our
patients, gastric bleeding occurred in
one preterm infant in the indomethacin
group however, no patients in the
iburprofen group developed this
adverse effect. Two patients in the
indomethacin group had necrotizing
enterocolitis but no infants in the
ibuprofen group had this complication.
One patient in each group developed
IVH. Regarding the respiratory
outcome, four patients in the ibuprofen
group and five patients in the
indomethacin
group
developed
bronchopulmonary
dysplasia.
Statistically, there were no significant
differences in gastric bleeding, NEC,
IVH, and BPD between the ibuprofen
and indomethacin groups.
Efficacy of treatment
Patent ductus arteriosus closed
in 15 (75 %) patients in the ibuprofen
group, and in 16 (76%) patients in the
indomethacin group as shown in table
1. PDA reopening occurred in one
patient in each group. One patient in
the ibuprofen group and two patients in
the indomethacin group required
referral to higher center for surgical
ligation. Regarding the efficacy of
treatment, we found no significant
differences between the ibuprofen and
indomethacin groups, both are
effective in PDA closure.
Table 1: Efficacy of treatment
PDA closure: n. (%)
PDA reopening: n. (%)
Transferred for surgical ligation: n. (%)
*p values, not significant
66
Ibuprofen
(n = 20)
Indomethacin
(n = 21)
15 (75)
1 (5)
1 (5)
16 (76)*
1 (4.7)*
2 (9.5)*
EL-MINIA MED., BULL., VOL. 18, NO. 2, JUNE, 2007
Abdel Wahab & Mahfuz
Table 2: Serum creatinine levels in mg /dL, (mean + SD)
Pretreatment
24 hr after
treatment
48 hr after
treatment
Ibuprofen (n = 20)
0.82 + 0.09*
0.86 + 0.08**
0.94 + 0.08**
Indomethacin (n= 21)
0.76 + 0.11
1.42 + 0.31
1.58+ 0.28
*p = 0.7, ** p < 0.001
Table 3: Blood urea nitrogen concentrations in mg / dL, (mean + SD)
Pretreatment
24 hr after
treatment
48 hr after
treatment
Ibuprofen (n = 20)
13.8 + 3.1*
20.3 + 3.8**
23.1 + 3.7**
Indomethacin (n = 21)
12.5 + 3.6
33.6 + 8.6
45.1+ 11.9
*p = 0.2, ** p < 0.001
Table 4: Urine output of the study infants in ml / kg / hr, (mean + SD)
Pretreatment
24 hr after
treatment
48 hr after
treatment
Ibuprofen (n = 20)
4.3 + 0.6*
4.0 + 0.6**
4.1 + 0.4***
Indomethacin (n = 21)
4.2 + 0.5
1.4 + 0.7
3.5+ 0.5
*p = 0.8, ** p < 0.001, ***p = 0.001
extremely preterm neonates require
closure
of
hemodynamically
17,18
significant PDA
.
Vasodilator prostaglandins (PGs),
PGE2 and PGI2 play a significant role
in maintaining ductus patency during
fetal and neonatal life19.
DISCUSSION:
Patent ductus arteriosus is a
common complication of preterm birth
and its incidence is inversely related to
the gestational age14. A significant
PDA in premature infants contributes
to prolonged ventilator dependent,
longer hospitalization, increased costs,
and development of many complications including chronic lung disease,
IVH, NEC and retinopathy of
prematurity15,16. More than 50-70 % of
Indomethacin a prostaglandin
synthesis inhibitor, has been used
widely in the prophylaxis and treatment
of
significant
PDA20,21.
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EL-MINIA MED., BULL., VOL. 18, NO. 2, JUNE, 2007
Abdel Wahab & Mahfuz
Treatment
with
indomethacin,
however, may be associated with
adverse reactions such as reduced
renal22, mesentric23, and cerebral
perfusion24-25. Decreased perfusion to
these vascular beds may lead to renal
dysfunction, NEC, gastrointestinal
hemorrhage and IVH or periventricular
leukomalacia26.
The
difference
between
ibuprofen and indomethacin might be
because indomethacin acts in part
through mechanisms other than an
inhibition of prostaglandin syntheses11.
Other possibility is that both drugs
inhibit the cyclo-oxyagenase enzyme
system in the neonatal kidneys to
different extent36.
Ibuprofen, a cyclo-oxygenase
inhibitor has been proved to be
effective in closing PDA without
reducing cerebral blood flow or
affecting intestinal or renal hemodynamics27-29. Furthermore, ibuprofen
enhances cerebral blood flow autoregulation and has been shown to protect
neurological
functions
following
oxidative stress in animal models30,31.
We found 2 (9.5%) patients in
the indomethacin group developed
necrotizing enterocolitis however no
patients in the ibuprofen group had this
morbidity. These results are in
consistent with that of the study done
by Pezzati et al.,29.
Our data support that ibuprofen
does
not
significantly
reduce
mesenteric blood flow as compared
with indomethacin.
Ibuprofen has been shown to be
effective in ductal closure by several
investigators who administered it
intravenously9, 12, 32.
CONCLUSION:
Based on our data, we conclude
that oral ibuprofen is as efficacious as
indomethacin for the treatment of PDA
in preterm infants and is significantly
less likely to cause renal dysfunction.
Ibuprofen may become the drug of
choice for ductal closure in premature
neonates.
Heyman et al., reported that
oral ibuprofen might be an effective
and safe alternative to intravenous
ibuprofen for PDA closure in
premature infants26. The pharmacokinetics of oral ibuprofen among
preterm infants had been studied and
reported. The finding indicated that
ibuprofen is absorbed rapidly after oral
administration and peak concentrations
in plasma are observed after 1 to 2
hours33, 34.
Acknowledgments We would like to
thank cardiology department and all
nurses of the neonatal intensive care
units of Abha General and Aseer
Central Hospitals for their support in
carrying out this study.
In our study, we found that oral
ibuprofen therapy was as effective as
indomethacin for the treatment of PDA
in premature infants. Neonates treated
with ibuprofen had significantly higher
urine volume, lower serum creatinine
and lower blood urea nitrogen values
than neonates treated with indomethacin. The same findings have
previously been reported by Lago et
al.,35.
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‫‪Abdel Wahab & Mahfuz‬‬
‫‪EL-MINIA MED., BULL., VOL. 18, NO. 2, JUNE, 2007‬‬
‫”مقارنة بين عقار األيبوبروفين واألندوميثاسين لعالج األنبوبة الشريانية‬
‫المفتوحة بين األورطى والشريان الرئوي فى األطفال الخدج“‬
‫وليد عبد الوهاب عيد‪ , 1‬أحمد محفوظ‬
‫طب األطفال‪ ,1‬الصحة العامة‪ -2‬كلية الطب‪-‬جامعة الملك خالد‪ -‬أبها‪-‬المملكة العربية السعودية‬
‫‪2‬‬
‫خلفية وهدف البحث‪:‬‬
‫يصاب حوالي ‪ % 31‬أو أكثر من األطفال الخدج (غير مكتملي العمر الحملي) باإلصابة‬
‫بانفتاح األنبوبة الشريانية بين األورطي والشريان الرئوي ويتسبب ذلك فى العديد من‬
‫المضاعفات الخطيرة والتى قد تؤدي إلى الوفاة‪ .‬يستخدم األندوميثاسين فى عالج هذا المرض‬
‫منذ سنوات طويلة وعلى الرغم من فاعلية هذا الدواء لكنه له العديد من اآلثار الجانبية خاصة‬
‫على الكلى‪.‬هدفت هذه الدراسة إلى إجراء مقارنة بين األيبوبروفين واألندوميثاسين من ناحية‬
‫الفاعلية واألمان لعالج هذا المرض فى األطفال الخدج‪.‬‬
‫طريقة البحث‪:‬‬
‫شملت هذه الدراسة‪ 41‬طفال من األطفال الخدج المصابين بانفتاح األنبوبة الشريانية بعد‬
‫تشخيصها بواسطة األشعة التلفزيونية على القلب والبالغ أعمارهم أقل من ‪ 30‬أسبوع رحمي‪.‬‬
‫انقسم هؤالء األطفال إلى مجموعتين‪ :‬المجموعة األولى بلغ عددها ‪ 20‬طفال وأخذوا عالج‬
‫األيبوبروفين عن طريق أنبوب التغذية‪ ,‬والمجموعة األخرى اشتملت على ‪ 21‬طفال وأخذوا‬
‫عالج األندوميثاسين عن طريق الوريد‪ .‬وتراوح عمر هؤالء األطفال بين ‪ 7-2‬أيام بعد والدتهم‪.‬‬
‫استبعد من الدراسة األطفال المصابين بارتفاع فى مستوى البولينا والكرياتينين فى الدم وكذلك‬
‫األطفال المصابين بنزيف أو انخفاض فى عدد الصفائح الدموية‪.‬‬
‫نتائج البحث‪:‬‬
‫أثبتت الدراسة أن فاعلية األيبوبروفين واألندوميثاسين فى عالج هذا المرض متساوية تقريبا‬
‫حيث بلغت حوالي ‪ .%75‬كما أثبتت أيضا ارتفاع مستوى البولينا والكرياتينين فى دم األطفال‬
‫الذين أخذوا عالج األندوميثاسين مقارنة بالمجموعة األخرى التى أخذت األيبوبروفين وذلك بعد‬
‫‪ 24‬و ‪ 48‬ساعة من أخذ الدواء‪ .‬كما لوحظ أيضا أن كمية البول كانت أقل فى األطفال الذين‬
‫أخذوا عقار األندوميثاسين‪ .‬وكانت كل هذه الفروق ذات داللة إحصائية‪.‬‬
‫اإلستنتاجات‪:‬‬
‫عقار األيبوبروفين له نفس الفاعلية في عالج األنبوبة الشريانية المفتوحة فى األطفال الخدج‬
‫مثل األندوميثاسين غير أنه يتفوق عليه بقلة اآلثار الجانبية خاصة على الكلى‪.‬‬
‫‪71‬‬