Paediatrica Indonesiana

VOLUME 53 May  NUMBER 3

Original Article

Ibuprofen vs. indomethacin for persistent ductus

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

D
Abstract XFWXV DUWHULRVXV '$ FORVXUH LQ SUHWHUP
Background ,QGRPHWKDFLQDQGLEXSURIHQDUHDQWLSURVWDJODQGLQ infants is mandatory before complications
( 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.
occur that prohibit the administration of
SKDUPDFRORJLFDJHQWV,QGRPHWKDFLQLVDQHIIHFWLYH
GUXJ IRU '$ FORVXUH LQ SUHWHUP LQIDQWV ,W KDV WZR
Objective To compare the efficacy of oral ibuprofen and LVRIRUPV F\FORR[\JHQDVH &2; LQKLELWRU DQG
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
F\FORR[\JHQDVH &2; LQKLELWRU RI ZKLFK WKH
&2;LQKLELWRULVVWURQJHU,EXSURIHQLVDQRWKHU
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
Results 6L[W\LQIDQWVZHUHHQUROOHGLQWKLVVWXG\ER\V
DQGJLUOV)LIW\WZRVXEMHFWVFRPSOHWHGWKHVWXG\SURWRFRO DUWHULRVXV 3'$ LQ 0RHKDPPDG +RHVLQ +RVSLWDO
'XFWXVDUWHULRVXV'$FORVXUHDIWHUWUHDWPHQWZDVREVHUYHGLQ is indomethacin.
RXWRIVXEMHFWVLQWKHLEXSURIHQJURXSDQGRXWRIVXEMHFWV The aims of this study were to compare the
LQ WKH LQGRPHWKDFLQ JURXS 3  7KH PHDQ '$ GLDPHWHU efficacy of ibuprofen and indomethacin in preterm
reductions after administration of ibuprofen or indomethacin were
6'PPDQG6'PPUHVSHFWLYHO\&,
LQIDQWVZLWK3'$DQGWRDVVHVVWKHWLPHQHHGHGIRU
RIGLIIHUHQFHVWR3 6HUXPFUHDWLQLQHZDVHOHYDWHG DA closure for each intervention.
in the indomethacin group following treatment compared to the
LEXSURIHQJURXS>3 &,RIGLIIHUHQFHVWR@
'XFWXVDUWHULRVXVUHRSHQLQJRFFXUUHGLQRXWRIVXEMHFWVLQWKH
indomethacin group, while none in the ibuprofen group.
Conclusions ,EXSURIHQLVEHWWHUWKDQLQGRPHWKDFLQLQWHUPVRI
KLJKHU3'$FORVXUHUDWHDQGPHDQ'$GLDPHWHUUHGXFWLRQDIWHU
WUHDWPHQW,QDGGLWLRQDOLQGRPHWKDFLQKDVVLJQLILFDQWO\JUHDWHU From the Department of Child Health DQG 3KDUPDFRORJ\, Sriwijaya
increase in mean serum creatinine level after treatment than 8QLYHUVLW\0HGLFDO6FKRRO3DOHPEDQJ,QGRQHVLD
ibuprofen. [Paediatr Indones. 2013;53:138-43.].
Reprint requests to:'HQ\6DOYHUUD<RV\'HSDUWPHQWRI&KLOG+HDOWK
6ULZLMD\D8QLYHUVLW\0HGLFDO6FKRRO-DODQ-HQGHUDO6XGLUPDQ.P
Keywords: persistent ductus arteriosus, preterm 3DOHPEDQJ ,QGRQHVLD 7HO   )D[
infants, ibuprofen, indomethacin. (PDLOochie_dr@yahoo.co.id.

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

 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
0RKDPPDG +RHVLQ +RVSLWDO 3DOHPEDQJ IURP
2FWREHUWR'HFHPEHU
 $OO SUHWHUP LQIDQWV RI OHVV WKDQ ZHHN
JHVWDWLRQZLWK3'$FRQILUPHGE\HFKRFDUGLRJUDSK\
ZHUH VWXGLHG :H H[FOXGHG LQIDQWV ZLWK UHQDO
G\VIXQFWLRQ GLXUHVLV  FFNJK DQG FUHDWLQLQH
The Ethics Committee of Sriwijaya University
0HGLFDO 6FKRRO 3DOHPEDQJ ,QGRQHVLD DSSURYHG
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
WKHWZRJURXSVZHUHDQDO\]HGZLWK)LVKHUVH[DFWDQG
Chi-square tests. Survival rate was analyzed with
Kaplan-Meier test.
VHUXPOHYHOPJG/SODWHOHWFRXQW Results
mm3, ductal-dependent congenital heart disease,
major congenital anomalies, necrotizing enterocolitis, 2IWKHSUHWHUPLQIDQWVDGPLWWHGWR0RKDPPDG
LQWUDYHQWULFXODU KDHPRUUKDJH JUDGHV ,,,,9 RU
QHRQDWDOVHSWLFHPLD3HUVLVWHQWGXFWXVDUWHULRVXVZDV
confirmed by echocardiography using a Philips HD7
XEZLWKVWUDQVGXFHU
6XEMHFWVZHUHQXPEHUHGWRWKHQGLYLGHG
into two groups by consecutive sampling, either the
LEXSURIHQ RU LQGRPHWKDFLQ JURXS ,EXSURIHQ ZDV
+RHVLQ+RVSLWDO3DOHPEDQJVXEMHFWVZLWK3'$
were enrolled in this study. Subjects were divided
LQWRWZRJURXSVRIHDFKWKHLEXSURIHQJURXSDQG
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
JLYHQDWDGRVHRIPJNJ%:GRQGD\DQGPJ KHPRUUKDJHLQIDQWVGLVFKDUJHWRDQRWKHUKRVSLWDO
NJ%:GRQGD\VDQG,QGRPHWKDFLQZDVJLYHQLQ LQIDQWRUJDVWURLQWHVWLQDOEOHHGLQJEHIRUHFRPSOHWLQJ
WKUHHGRVHVLQKRXULQWHUYDOV7KHILUVWGRVHZDV WKUHHGRVHVPHGLFDWLRQLQIDQWV
PJNJ%:DQGWKHVHFRQGDQGWKLUGGRVHVZHUH ,QSDLUHG7WHVWUHYHDOHGDVLJQLILFDQWGLIIHUHQFH
PJNJ%: LQ '$ GLDPHWHU UHGXFWLRQ E\  6'  PP
The parameters of treatment response were ZLWK3 &,WRLQWKHLEXSURIHQ
DA closure and diameter reduction, taken in serial JURXS DQG  6'  PP ZLWK 3  
measurements. Ductus arteriosus reopening was &,WRLQWKHLQGRPHWKDFLQJURXSTable
defined as a DA that reopened after closure, as 2a, Table 2b
determined by echocardiographic evaluation after 3DWLHQWVZLWK3'$FORVXUHDIWHUWKUHHGRVHVRI
three doses of oral ibuprofen or indomethacin RUDO LEXSURIHQ ZHUH  RXW RI  VXEMHFWV DQG RUDO
administration. LQGRPHWKDFLQ ZHUH  RXW RI  VXEMHFWV LW ZDV D
Ductus arteriosus monitoring was performed VLJQLILFDQWGLIIHUHQFH3 
XVLQJHFKRFDUGLRJUDSKLFH[DPLQDWLRQVGD\V Unpaired T-test was also performed to compare
DQGRUWUDQVIRQWDQHOODUXOWUDVRXQGGD\VDQG DA constriction after three doses of oral ibuprofen
0RQLWRULQJRIVLGHHIIHFWVZDVSHUIRUPHGE\URXWLQH and indomethacin. Similarly, there was a significant
EORRGWHVWV&UHDFWLYHSURWHLQ&53OHYHODQGUHQDO GLIIHUHQFHEHWZHHQWKHWZRJURXSV3 &,
IXQFWLRQ WHVWV RQ GD\V  DQG  'XULQJ WUHDWPHQW WR%\.DSODQ0HLHUVXUYLYDODQDO\VLVZH
diuresis was monitored daily. found no significant difference in mean days to closure
Subjects were considered to have dropped out of LQWKHLEXSURIHQDQGLQGRPHWKDFLQJURXSVZLWK
WKHVWXG\LIWKHIROORZLQJRFFXUUHGGHDWKEHIRUHGD\V 6'GD\VDQG6'GD\VUHVSHFWLYHO\3 
RIPHGLFDWLRQRUEHIRUHHFKRFDUGLRJUDSKLFH[DPLQDWLRQ
IRUWKHIXOOGD\VWRPRQLWRUUHRSHQLQJVHSWLFHPLD
bleeding, gastrointestinal perforation, necrotizing
enterocolitis, or decreased renal function in the first
to third days of medication administration.
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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 OHYHO  PJG/ EHIRUH DQG DIWHU LQGRPHWKDFLQ
groups. We found no significant difference in the DGPLQLVWUDWLRQ ZDV VLJQLILFDQWO\ GLIIHUHQW >3 
PHDQVHUXPFUHDWLQLQHOHYHOPJG/EHIRUHDQG 6'&,WR@
DIWHULEXSURIHQDGPLQLVWUDWLRQ>3 6' There was significantly higher creatinine serum
&,WR@+RZHYHUPHDQVHUXPFUHDWLQLQH elevation after indomethacin administration com-

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Table 2a/GCPFWEVWUCTVGTKQUWUFKCOGVGTDGHQTGCPFCHVGTVTGCVOGPVYKVJKDWRTQHGPQTKPFQOGVJCEKP
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140Paediatr Indones, Vol. 53, No. 3, May 2013

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

 Deny Salverra Yosy et al: ,EXSURIHQYVLQGRPHWKDFLQIRUSHUVLVWHQWGXFWXVDUWHULRVXVFORVXUHLQSUHWHUPLQIDQWV

SDUHGWRWKDWRIWKUHHGRVHVRILEXSURIHQ>PHDQ doses of indomethacin compared to three doses of

PJG/3 6'&,WR@ ibuprofen.
As shown in Figure 1, the consort diagram of 'XFWXV DUWHULRVXV UHRSHQLQJ RFFXUUHG LQ 
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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.
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
RUDOLQGRPHWKDFLQDGPLQLVWUDWLRQZDV
Reopening may be caused by pulmonary disor-
ders. The mechanism involved response of DA to
Discussion SURVWDJODQGLQ(3*(DQGORZR[\JHQSUHVVXUH,Q
FRQGLWLRQRISXOPRQDU\GLVRUGHUVHOLPLQDWLRQRI3*(
)URP  SUHWHUP LQIDQWV  LQIDQWV  ZLWK LQWKHOXQJZLOOGHFUHDVHWKHUHIRUHWKHOHYHORI3*(
3'$PHWRXULQFOXVLRQFULWHULD6LPLODUO\6HNDUet al. ZLOOULVH,QSXOPRQDU\GLVRUGHUVWKHR[\JHQSUHVVXUH
VKRZHGWKDWWKHLQFLGHQFHUDWHRI3'$LQSUHWHUP DOVRGHFUHDVHVWRK\SR[LDDQGDFLGRVLVWKDWZLOOOHDGWR
LQIDQWVZDV3 WKHUHOD[DWLRQRI'$3XOPRQDU\GLVRUGHUVIRXQGLQRXU
,QRXUVWXG\WKHUHZHUHER\V DQG subjects were pneumonia, hyaline membrane disease,
girls $JHVYDULHGIURPWRKRXUV7KHILUVW
echocardiography was performed when the subjects
DJHZDVDWOHDVWKRXUV$FFRUGLQJWRUHSRUWVE\3DUN
and Coceani et al., DA closure functionally occurs
ZLWKLQKRXUVDIWHUELUWK
After three doses of ibuprofen or indomethacin
DGPLQLVWUDWLRQ '$ FORVXUH RFFXUUHG LQ  RXW RI
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
HIILFDF\RILEXSURIHQWREHDQGUHVSHFWLYHO\
Furthermore, DA diameter reduction was significantly
JUHDWHULQWKHLEXSURIHQJURXS3 &,
and transient tachypnea of the newborn.
A limitation of this study was the occurrence of
complications, such as septicemia, hyaline membrane
GLVHDVH DQG RWKHU SXOPRQDU\ GLVHDVHV ,W ZDV DOVR
difficult to monitor patients for long periods due
to the high incidence of morbidity and mortality.
,QDGGLWLRQDOWKHVLGHHIIHFWVWKDWPD\DULVHGXHWR
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.
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
GHFUHDVHGUHQDOIXQFWLRQLQLQIDQWZKRZDVJLYHQ
LQGRPHWKDFLQZLWKDFUHDWLQLQHOHYHORI!PJG/
DIWHUWUHDWPHQWDQGXULQHYROXPHRIFFNJK7KLV
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
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.
References
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142Paediatr Indones, Vol. 53, No. 3, May 2013

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C, et al. Endothelin a receptor is necessary for O constriction
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M. Closure of patent ductus arteriosus with oral ibuprofen
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and renal tolerability of ibuprofen vs. indomethacin in
preterm infants with patent ductus arteriosus. Fundam Clin
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of ibuprofen is effective in the closure of a clinically significant
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:H\OHU-'H*URRWH.et al. A comparison of ibuprofen and
indomethacin for closure of patent ductus arteriosus. N Engl
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Paediatr Indones, Vol. 53, No. 3, May 2013143