Paediatrica Indonesiana

May 

VOLUME 53

NUMBER 3

Original Article

Ibuprofen vs. indomethacin for persistent ductus

arteriosus closure in preterm infants
Deny Salverra Yosy1, Ria Nova1, Julniar M. Tasli1,Theodorus2

Abstract
Background ,QGRPHWKDFLQDQGLEXSURIHQDUHDQWLSURVWDJODQGLQ
( DJHQWV DGPLQLVWHUHG IRU SHUVLVWHQW GXFWXV DUWHULRVXV 3'$
FORVXUH,EXSURIHQKDVZHDNHUF\FORR[\JHQDVHLQKLELWRUDIILQLW\
than that of indomethacin, causes decreased gastrointestinal
circulation, as well as brain and kidney side effects.
Objective To compare the efficacy of oral ibuprofen and
LQGRPHWKDFLQIRU3'$FORVXUHLQSUHWHUPLQIDQWV
Methods A randomized double-blind controlled trial on preterm
LQIDQWV ZLWK 3'$ ZDV SHUIRUPHG LQ 0RHKDPPDG +RHVLQ
+RVSLWDO3DOHPEDQJIURP2FWREHUWR'HFHPEHU3HUVLVWHQW
ductus arteriosus was diagnosed by echocardiography. Subjects
were divided into two groups, and received either ibuprofen or
LQGRPHWKDFLQ,EXSURIHQZDVJLYHQDWDGRVHRIPJNJ%:G
RQGD\DQGPJNJ%:GRQGD\VDQG,QGRPHWKDFLQZDV
JLYHQLQWKUHHGRVHVRYHUKRXULQWHUYDOVWKHILUVWGRVHZDV
PJNJDQGWKHVHFRQGDQGWKLUGGRVHVZHUHPJNJHDFK
Results 6L[W\LQIDQWVZHUHHQUROOHGLQWKLVVWXG\ER\V
DQGJLUOV)LIW\WZRVXEMHFWVFRPSOHWHGWKHVWXG\SURWRFRO
'XFWXVDUWHULRVXV'$FORVXUHDIWHUWUHDWPHQWZDVREVHUYHGLQ
RXWRIVXEMHFWVLQWKHLEXSURIHQJURXSDQGRXWRIVXEMHFWV
LQ WKH LQGRPHWKDFLQ JURXS 3  7KH PHDQ '$ GLDPHWHU
reductions after administration of ibuprofen or indomethacin were
6'PPDQG6'PPUHVSHFWLYHO\&,
RIGLIIHUHQFHVWR3 6HUXPFUHDWLQLQHZDVHOHYDWHG
in the indomethacin group following treatment compared to the
LEXSURIHQJURXS>3 &,RIGLIIHUHQFHVWR@
'XFWXVDUWHULRVXVUHRSHQLQJRFFXUUHGLQRXWRIVXEMHFWVLQWKH
indomethacin group, while none in the ibuprofen group.
Conclusions ,EXSURIHQLVEHWWHUWKDQLQGRPHWKDFLQLQWHUPVRI
KLJKHU3'$FORVXUHUDWHDQGPHDQ'$GLDPHWHUUHGXFWLRQDIWHU
WUHDWPHQW,QDGGLWLRQDOLQGRPHWKDFLQKDVVLJQLILFDQWO\JUHDWHU
increase in mean serum creatinine level after treatment than
ibuprofen. [Paediatr Indones. 2013;53:138-43.].
Keywords: persistent ductus arteriosus, preterm
infants, ibuprofen, indomethacin.

138Paediatr Indones, Vol. 53, No. 3, May 2013

XFWXV DUWHULRVXV '$ FORVXUH LQ SUHWHUP

infants is mandatory before complications
occur that prohibit the administration of
SKDUPDFRORJLFDJHQWV,QGRPHWKDFLQLVDQHIIHFWLYH
GUXJ IRU '$ FORVXUH LQ SUHWHUP LQIDQWV ,W KDV WZR
LVRIRUPV F\FORR[\JHQDVH &2; LQKLELWRU DQG
F\FORR[\JHQDVH &2; LQKLELWRU RI ZKLFK WKH
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anti-prostaglandin agent of similar efficacy, but fewer
VLGHHIIHFWVFRPSDUHGWRLQGRPHWKDFLQ,QGRPHWKDFLQ
is more costly and less widely available than
ibuprofen. Until now, there have been few reports
on the comparative efficacy of these two agents in
WKH0RHKDPPDG+RHVLQ+RVSLWDO3DOHPEDQJ7KH
current standard of treatment for persistent ductus
DUWHULRVXV 3'$ LQ 0RHKDPPDG +RHVLQ +RVSLWDO
is indomethacin.
The aims of this study were to compare the
efficacy of ibuprofen and indomethacin in preterm
LQIDQWVZLWK3'$DQGWRDVVHVVWKHWLPHQHHGHGIRU
DA closure for each intervention.

From the Department of Child Health DQG 3KDUPDFRORJ\, Sriwijaya

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Reprint requests to:'HQ\6DOYHUUD<RV\'HSDUWPHQWRI&KLOG+HDOWK
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3DOHPEDQJ ,QGRQHVLD 7HO   )D[
(PDLOochie_dr@yahoo.co.id.

Deny Salverra Yosy et al: ,EXSURIHQYVLQGRPHWKDFLQIRUSHUVLVWHQWGXFWXVDUWHULRVXVFORVXUHLQSUHWHUPLQIDQWV

Methods
A randomized double-blind controlled trial was
conducted in the Department of Neonatology, the
1HRQDWDO ,QWHQVLYH &DUH 8QLW DQG WKH 5RRPLQJ
in Nursery in the Department of Child Health at
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2FWREHUWR'HFHPEHU
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JHVWDWLRQZLWK3'$FRQILUPHGE\HFKRFDUGLRJUDSK\
ZHUH VWXGLHG :H H[FOXGHG LQIDQWV ZLWK UHQDO
G\VIXQFWLRQ GLXUHVLV  FFNJK DQG FUHDWLQLQH
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mm3, ductal-dependent congenital heart disease,
major congenital anomalies, necrotizing enterocolitis,
LQWUDYHQWULFXODU KDHPRUUKDJH JUDGHV ,,,,9 RU
QHRQDWDOVHSWLFHPLD3HUVLVWHQWGXFWXVDUWHULRVXVZDV
confirmed by echocardiography using a Philips HD7
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6XEMHFWVZHUHQXPEHUHGWRWKHQGLYLGHG
into two groups by consecutive sampling, either the
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JLYHQDWDGRVHRIPJNJ%:GRQGD\DQGPJ
NJ%:GRQGD\VDQG,QGRPHWKDFLQZDVJLYHQLQ
WKUHHGRVHVLQKRXULQWHUYDOV7KHILUVWGRVHZDV
PJNJ%:DQGWKHVHFRQGDQGWKLUGGRVHVZHUH
PJNJ%:
The parameters of treatment response were
DA closure and diameter reduction, taken in serial
measurements. Ductus arteriosus reopening was
defined as a DA that reopened after closure, as
determined by echocardiographic evaluation after
three doses of oral ibuprofen or indomethacin
administration.
Ductus arteriosus monitoring was performed
XVLQJHFKRFDUGLRJUDSKLFH[DPLQDWLRQVGD\V
DQGRUWUDQVIRQWDQHOODUXOWUDVRXQGGD\VDQG
0RQLWRULQJRIVLGHHIIHFWVZDVSHUIRUPHGE\URXWLQH
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diuresis was monitored daily.
Subjects were considered to have dropped out of
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RIPHGLFDWLRQRUEHIRUHHFKRFDUGLRJUDSKLFH[DPLQDWLRQ
IRUWKHIXOOGD\VWRPRQLWRUUHRSHQLQJVHSWLFHPLD
bleeding, gastrointestinal perforation, necrotizing
enterocolitis, or decreased renal function in the first
to third days of medication administration.

The Ethics Committee of Sriwijaya University

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WKLV VWXG\ ,QIRUPHG FRQVHQW ZDV REWDLQHG IURP DOO
parents.
6WDWLVWLFDO VLJQLILFDQFH ZDV VHW DW WKH &,
level. Differences between groups were analyzed by
students T-test. Differences in proportions between
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Chi-square tests. Survival rate was analyzed with
Kaplan-Meier test.

Results
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+RHVLQ+RVSLWDO3DOHPEDQJVXEMHFWVZLWK3'$
were enrolled in this study. Subjects were divided
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the indomethacin group. The basic characteristics of
subjects are shown in Table 1.
Four infants in the ibuprofen group and four in
the indomethacin group dropped out due to pulmonary
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LQIDQWRUJDVWURLQWHVWLQDOEOHHGLQJEHIRUHFRPSOHWLQJ
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,QSDLUHG7WHVWUHYHDOHGDVLJQLILFDQWGLIIHUHQFH
LQ '$ GLDPHWHU UHGXFWLRQ E\  6'  PP
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JURXS DQG  6'  PP ZLWK 3  
&,WRLQWKHLQGRPHWKDFLQJURXSTable
2a, Table 2b
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RUDO LEXSURIHQ ZHUH  RXW RI  VXEMHFWV DQG RUDO
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Unpaired T-test was also performed to compare
DA constriction after three doses of oral ibuprofen
and indomethacin. Similarly, there was a significant
GLIIHUHQFHEHWZHHQWKHWZRJURXSV3 &,
WR%\.DSODQ0HLHUVXUYLYDODQDO\VLVZH
found no significant difference in mean days to closure
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6'GD\VDQG6'GD\VUHVSHFWLYHO\3 
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shown in Table 3a and Table 3b.
One infant in the indomethacin group had
LQFUHDVHG SODVPD FUHDWLQLQH WR  PJG/ DQG
GHFUHDVHG GLXUHVLV WR  FFNJK 6HUXP FUHDWLQLQH

Paediatr Indones, Vol. 53, No. 3, May 2013139

Deny Salverra Yosy et al: ,EXSURIHQYVLQGRPHWKDFLQIRUSHUVLVWHQWGXFWXVDUWHULRVXVFORVXUHLQSUHWHUPLQIDQWV

was monitored before and after therapy for both

groups. We found no significant difference in the
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There was significantly higher creatinine serum
elevation after indomethacin administration com-

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Paediatr Indones, Vol. 53, No. 3, May 2013141

Deny Salverra Yosy et al: ,EXSURIHQYVLQGRPHWKDFLQIRUSHUVLVWHQWGXFWXVDUWHULRVXVFORVXUHLQSUHWHUPLQIDQWV

SDUHGWRWKDWRIWKUHHGRVHVRILEXSURIHQ>PHDQ
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As shown in Figure 1, the consort diagram of
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failed to respond to treatment in the ibuprofen group
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the indomethacin group, but none occurred in the
ibuprofen group.

Discussion
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3'$PHWRXULQFOXVLRQFULWHULD6LPLODUO\6HNDUet al.
VKRZHGWKDWWKHLQFLGHQFHUDWHRI3'$LQSUHWHUP
LQIDQWVZDV3
,QRXUVWXG\WKHUHZHUHER\V DQG
girls $JHVYDULHGIURPWRKRXUV7KHILUVW
echocardiography was performed when the subjects
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and Coceani et al., DA closure functionally occurs
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After three doses of ibuprofen or indomethacin
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VXEMHFWVLQWKHLEXSURIHQJURXSDQGRXWRI
in the indomethacin group, respectively. Heyman et
al. reported that the effectiveness of ibuprofen was
6 Also, Fanos et al. and Richard et al. reported the
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Furthermore, DA diameter reduction was significantly
JUHDWHULQWKHLEXSURIHQJURXS3 &,
WR)URP.DSODQ0HLHUVXUYLYDOWHVWDQDO\VLVWKH
PHDQWLPHXQWLO'$FORVXUHZDVGD\V6LPLODUO\
Overmeire et al. reported that the mean closure day
was at the third and fourth days.
7KURPERF\WRSHQLD ZDV IRXQG LQ ILYH RI 
LQIDQWVJLYHQRUDOLQGRPHWKDFLQ,EXSURIHQLVDZHDNHU
&2;LVRIRUPFRPSDUHGWRLQGRPHWKDFLQ$OOHJDHUW
et al. reported that there are fewer renal side effects
from ibuprofen than indomethacin.  We found
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LQGRPHWKDFLQZLWKDFUHDWLQLQHOHYHORI!PJG/
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finding was similar to that of Van Overmeire et al.,
who showed that serum creatinine elevation occurred
GD\VDIWHULQGRPHWKDFLQDGPLQLVWUDWLRQ Serum
creatinine was significantly more elevated after three

142Paediatr Indones, Vol. 53, No. 3, May 2013

doses of indomethacin compared to three doses of

ibuprofen.
'XFWXV DUWHULRVXV UHRSHQLQJ RFFXUUHG LQ 
RI   SUHYLRXVO\ FORVHG '$ SDWLHQWV LQ WKH
indomethacin group, while none reopened in the
ibuprofen group. Similarly, Heyman et al. reported no
DA reopening in the ibuprofen group.64XLQQet al.
reported that the incidence rate of DA reopening after
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Reopening may be caused by pulmonary disorders. The mechanism involved response of DA to
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FRQGLWLRQRISXOPRQDU\GLVRUGHUVHOLPLQDWLRQRI3*(
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subjects were pneumonia, hyaline membrane disease,
and transient tachypnea of the newborn.
A limitation of this study was the occurrence of
complications, such as septicemia, hyaline membrane
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difficult to monitor patients for long periods due
to the high incidence of morbidity and mortality.
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the intervention or complication, often occurs in
premature infants.
 ,QFRQFOXVLRQWKHUHLVDVLJQLILFDQWGLIIHUHQFH
in the closure of DA after ibuprofen administration
compared to that of indomethacin. Also, DA diameter
reduction is significantly greater after ibuprofen
administration compares to that of indomethacin.
There is also a significantly higher serum creatinine
elevation after indomethacin administration compares
to that of ibuprofen.

Acknowledgment
We would like to thank the pediatricans, H. Bermawi and A.
5DPDGDQWLDQGWKHSKDUPDFLVWV$PUL]DO(<XQLWD&:LOLD
and Henny, for their contributions to this study.

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VKXQW3KLODGHOSKLD0RVE\(OVHYLHUS
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LQGRPHWKDFLQRULEXSURIHQ-3HULQDWRO
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,QGLDQ3HGLDWU
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EXWQRWFORVXUHRIGXFWXVDUWHULRVXV$P-3K\VLRO+HDUW&LUF
3K\VLRO 
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VXVSHQVLRQLQSUHPDWXUHQHZERUQVDSLORWVWXG\3HGLDWULFV

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3KDUPDFRO
5LFKDUGV--RKQVRQ$)R[*&DPSEHOO0$VHFRQGFRXUVH
of ibuprofen is effective in the closure of a clinically significant
3'$LQ(/%:LQIDQWV3HGLDWULFV
9DQ2YHUPHLUH%6PHWV./HFRXWHUH'YDQGH%URHN+
:H\OHU-'H*URRWH.et al. A comparison of ibuprofen and
indomethacin for closure of patent ductus arteriosus. N Engl
-0HG
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UHQDOGUXJFOHDUDQFHLQQHRQDWHV-0DWHUQ)HWDO1HRQDWDO
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6.

Paediatr Indones, Vol. 53, No. 3, May 2013143