Paediatrica Indonesiana

VOLUME 52 July ‡ NUMBER 4

Original Article

Efficacy of salbutamol-ipratropium bromide

nebulization compared to salbutamol alone in children
with mild to moderate asthma attacks
Matahari Harumdini, Bambang Supriyatno, Rini Sekartini

Abstract +RZHYHURWKHUFOLQLFDOSDUDPHWHUVZHUHQRWVLJQLILFDQWO\GLIIHUHQW
between the two groups. [Paediatr Indones. 2012;52:200-8].
Background The efficacy of salbutamol-ipratropium bromide
QHEXOL]DWLRQLQFKLOGUHQZLWKPRGHUDWHDVWKPDDWWDFNVUHPDLQV
XQFOHDU DQG VWXGLHV RQ SDWLHQWV ZLWK PLOG DWWDFNV KDYH EHHQ Keywords: children, mild to moderate asthma attack,
UHODWLYHO\ IHZ HVSHFLDOO\ LQ ,QGRQHVLD +RZHYHU LW LV FRPPRQ ipratropium bromide, salbutamol
practice for this drug combination to be given to patients with
PLOGPRGHUDWHDVWKPDDWWDFNV
Objective To compare the efficacy of salbutamol-ipratropium
bromide nebulization to salbutamol alone in children with mild
WRPRGHUDWHDVWKPDDWWDFNV

Methods This single-blind, randomized clinical trial was held
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+RVSLWDOWKH7HEHW&RPPXQLW\+HDOWK&HQWHUDQGWKH0+
7KDPULQ6DOHPED+RVSLWDORQFKLOGUHQDJHG\HDUVZLWK
PLOG WR PRGHUDWH DVWKPD DWWDFN :H UDQGRPL]HG VXEMHFWV
WRUHFHLYHHLWKHUPJVDOEXWDPROSOXVPJLSUDWURSLXP
bromide (experimental group) or 2.5 mg salbutamol alone
A
sthma is global health problem in children,
and is increasing in prevalence, even
though the pathogenesis, pathophysiology,
and management of asthma is well
XQGHUVWRRG7KH1DWLRQDO+HDOWK,QWHUYLHZ6XUYH\
LQWKH8QLWHG6WDWHVUHSRUWHGDQDVWKPDSUHYDOHQFH
FRQWURO JURXS 1HEXOL]DWLRQ ZDV JLYHQ WZLFH ZLWK D  RILQ In Indonesia, Rahajoe et al. reported
PLQXWH LQWHUYDO EHWZHHQ WUHDWPHQWV :H DVVHVVHG FOLQLFDO
VFRUHV YLWDO VLJQV R[\JHQ VDWXUDWLRQV DQG SHDN IORZ UDWHV
DVWKPDSUHYDOHQFHWREH2
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post-nebulization.
Results $ WRWDO RI  SDWLHQWV ZHUH UDQGRPL]HG WR HLWKHU WKH
H[SHULPHQWDORUWKHFRQWUROJURXS6XEMHFWVKDGVLPLODUEDVHOLQH
PHDVXUHPHQWV$WPLQXWHVSRVWQHEXOL]DWLRQWKHSHUFHQWDJH
LQFUHDVH RI 3)5 ZDV  KLJKHU LQ WKH H[SHULPHQWDO JURXS
Controversies in asthma management may
increase morbidity and mortality of patients. The
addition of ipratropium bromide for patients with
DVWKPD DWWDFNV KDV EHHQ FRQWURYHUVLDO %HWD 2 -
3 &,WR7KHSURSRUWLRQRI3)5UHYHUVLELOLW\
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There were no significant differences in clinical scores, oxygen
saturations, respiratory rates, or hospitalization rates between the
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Conclusion 6DOEXWDPROLSUDWURSLXP EURPLGH QHEXOL]DWLRQ
LPSURYHG 3)5 PHDVXUHPHQWV EHWWHU WKDQ VDOEXWDPRO DORQH
200‡Paediatr Indones, Vol. 52, No. 4, July 2012
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Reprint requests to0DWDKDUL+DUXPGLQL'HSDUWPHQWRI&KLOG+HDOWK
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agonists are potent bronchodilators, but multiple
or large doses may cause adrenergic side effects.
+RZHYHULSUDWURSLXPEURPLGHLVDQDQWLFKROLQHUJLF
bronchodilator with a slower onset, longer duration
of action, and less adrenergic side effects compared
to those of beta 2-agonists.  3UHYLRXV VWXGLHV
have shown that a combination of salbutamol and
LSUDWURSLXP LQ SDWLHQWV ZLWK VHYHUH DVWKPD DWWDFNV
EURPLGH WUHDWPHQW ZLWKLQ WKH  KRXUV SULRU WR
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consent.
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either salbutamol-ipratropium bromide (experimental
group) or salbutamol alone (control group), according
WR D GUXJ VHTXHQFH WDEOH JHQHUDWHG E\ EORFN
UDQGRPL]DWLRQV RI VL[ 7KLV WDEOH ZDV NHSW E\ WKH
improve lung function and clinical score, while SULQFLSDOLQYHVWLJDWRU3,WRNHHSWKHVXEMHFWVEOLQGHG
lowering emergency department (ED) admission to their allocated group.
duration and hospital admission rates.8,9 Other studies 6XEMHFWV ZHUH JLYHQ HLWKHU  PJ VDOEXWDPRO
have also reported salbutamol-ipratropium bromide ZLWKPJLSUDWURSLXPEURPLGH&RPELYHQWŠRU
VXSHULRULW\ LQ SDWLHQWV ZLWK PRGHUDWH DWWDFNV PJVDOEXWDPRO9HQWROLQŠQHEXOL]DWLRQLQ
while studies on its use in patients with mild asthma POVDOLQH6XEMHFWVZHUHJLYHQWZRGRVHVE\XOWUDVRQLF
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nebulization has commonly been given to patients
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one Indonesian study to date has been published on
this subject.
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ipratropium nebulization with salbutamol alone in
pediatric patients with mild to moderate asthma
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and hospital admission rates of the two groups.
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minute interval between treatments. The duration
RI HDFK QHEXOL]HU WUHDWPHQW ZDV DERXW  PLQXWHV
$WHQUROOPHQWVXEMHFWV·EDVHOLQHGDWDZDVFROOHFWHG
including demographic characteristics (age, sex, and
nutritional status), asthma history, treatment history,
asthma comorbidities (allergic rhinitis or sinusitis),
duration of current symptoms, and asthma severity.
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Methods
This study was designed as a single-blind, randomized,
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saturation by pulse oxymetry (Oxy3, OneMed).
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until 2 hours post-nebulization, including the same
parameters measured at baseline. For patients with
PRGHUDWHDWWDFNVZHSODQQHGWRDOVRPHDVXUHEORRG
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compared the effects of nebulization with salbutamol-
ipratropium combination to those of salbutamol
alone.
3DWLHQWV DJHG  \HDUV ZKR YLVLWHG WKH ('
ZLWK PLOG WR PRGHUDWH DVWKPD DWWDFNV FODVVLILHG
JDVDQDO\VLV%*$WZLFHDWEDVHOLQHDQGDWKRXUV
DIWHUWUHDWPHQWWKRXJKPRVWSDWLHQWVGHFOLQHG3)5
was measured by forced expiration maneuver (patient
twice performed forced expiration after maximal
inspiration with at least a 5-second interval between
forced expiration). Only the best value was recorded.
3DWLHQWV ZLWK LQDGHTXDWH FOLQLFDO UHVSRQVH DIWHU 
hours post-treatment were admitted to the hospital.
DFFRUGLQJ WR 6FKXK·V DVWKPD FOLQLFDO VFRUH9 were
HOLJLEOH IRU HQUROOPHQW :H H[FOXGHG SDWLHQWV ZLWK
signs of respiratory failure, need of intensive care
management, heart abnormality, pneumonia or other
respiratory disorders altering lung function, ocular
disorder altering intraocular pressure or pupillar res-
ponse DV GLDJQRVHG E\ KLVWRU\WDNLQJ DQG SK\VLFDO
examination), hypersensitivity to ipratropium or
salbutamol, and those who had received ipratropium
,I WKH SULQFLSDO LQYHVWLJDWRU 3, ZDV DEVHQW
ZKHQ DQ DVWKPD DWWDFN SDWLHQW FDPH WR (' WKH
clinical score at baseline was measured by a research
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DVXEMHFWHQUROOHGWKH3,ZDVFDOOHGE\SKRQHIRUVWXG\
group random allocation instructions. By the time the
VHFRQGQHEXOL]DWLRQZDVILQLVKHGWKH3,ZRXOGKDYH
arrived at the ED to continue data measurements.
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Paediatr Indones, Vol. 52, No. 4, July 2012 ‡201
Matahari Harumdini et al:6DOEXWDPROLSUDWURSLXPEURPLGHQHEXOL]DWLRQFRPSDUHGWRVDOEXWDPRODORQHLQDVWKPDDWWDFNV

FOLQLFDO VFRULQJ ZDV DVVHVVHG E\ FRPSDULQJ WKH 3,·V Results

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Individual severity scores were summed and divided $WRWDORISDWLHQWVZHUHHQUROOHGDIWHUSDWLHQWV
LQWRWKUHHVHYHULW\JURXSVDVIROORZVPLOGWRWDOVFRUH ZHUHH[FOXGHGGXHWRVHYHUHDVWKPDDWWDFNSDWLHQWV
²PRGHUDWHWRWDOVFRUH²RUVHYHUHWRWDOVFRUH had received ipratropium bromide within the prior
² Table 1). Interrater reliability was measured  KRXUV  SDWLHQWV RU KDG D KHDUW DEQRUPDOLW\
XVLQJWKHVHVHYHULW\VXEJURXSVZLWK.DSSD  SDWLHQW2IWKHVXEMHFWVKDGPLOGDVWKPD
The primary outcome was nebulization efficacy,
measured by several parameters including decreased
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saturation, decreased respiratory rate, and decreased
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DV WKH SHUFHQWDJH LQFUHDVH IURP EDVHOLQH 3)5
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from baseline. The proportion of patients with
DWWDFNVSDWLHQWVZHUHDOORFDWHGWRHDFKJURXS
ZKLOH  SDWLHQWV KDG PRGHUDWH DVWKPD DWWDFNV 
were allocated to each group). All baseline parameters
were similar between the two groups (Table 2).
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clinical scores decreased more in the experimental
group, but they were not statistically or clinically
GLIIHUHQWIURPWKHFRQWUROJURXSE\0DQQ:KLWQH\WHVW
3)5 UHYHUVLELOLW\ LQ HDFK JURXS ZDV DOVR UHFRUGHG
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after treatment, and side effects of medications.
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a formula of mean difference of two independent
groups, with A  DQG SRZHU RI  6LQFH D
previous study showed that the standard deviation
of mean change in clinical asthma score between the
salbutamol-ipratropium and salbutamol groups was
9 the clinically significant difference was set at
7KHUHIRUHSDWLHQWVSHUVWXG\JURXSRUDWRWDO
of 32 patients, were needed for this study.
(Table 3,QVXEMHFWVZLWKPRGHUDWHDWWDFNVQ 
we found an apparent difference in the mean decrease of
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difference between the two groups seemed substantial,
but statistical significance could not be established
EHFDXVHRILQDGHTXDWHVDPSOHVL]HTable 3).
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experimental group than in the control group. The
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'LIIHUHQFHV LQ FOLQLFDO VFRUHV 3)5V R[\JHQ WR3 DQGWKHPHGLDQGLIIHUHQFHV
saturation, and respiratory rates between groups were DW   DQG  PLQXWHV ZHUH DOO  GDWD
DQDO\]HGE\LQGHSHQGHQWWWHVWRU0DQQ:KLWQH\WHVW was abnormally distributed) (Table 4 6WDWLVWLFDO
if the data had an abnormal distribution. Differences in VLJQLILFDQFH ZDV REVHUYHG RQO\ DW WKH PLQXWH
3)5UHYHUVLELOLW\KRVSLWDODGPLVVLRQDQGVLGHHIIHFWV WLPHSRLQW3 ,QPLOGDWWDFNVXEMHFWVDORQH
ZHUH DQDO\]HG E\ &KLVTXDUH WHVW RU )LVKHU·V H[DFW Q ZHIRXQGPHDQGLIIHUHQFHRIDW
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This study was approved by The Medical WKDQPHDQGLIIHUHQFHDWWKHEHJLQQLQJDQGILQDO
Research Ethics Committee, Faculty of Medicine, observation, but statistical analysis could not be
University of Indonesia. performed (Table 4).

Table 1. Schuh’s clinical asthma score 9

Score Accessory muscle score Wheeze score Dyspnea score
0 No retractions No wheeze and moving air well Dyspnea absent
1 Intercostal retractions 'PFGZRKTCVQT[YJGG\GU 0QTOCN CEVKXKV[ CPF URGGEJ OKPKOCN
dyspnea
2 Intercostal and suprasternal retractions 2CPGZRKTCVQT[ KPURKTCVQT[YJGG\GU &GETGCUGF CEVKXKV[  YQTF UGPVGPEGU
moderate dyspnea
3 0CUCNƀCTKPI Wheezes audible without stethoscope %QPEGPVTCVG QP DTGCVJKPI  YQTF
UGPVGPEGUUGXGTGF[URPGC
/KNFCVVCEMVQVCNUEQTGOQFGTCVGCVVCEMVQVCNUEQTGUGXGTGCVVCEMVQVCNUEQTG

202‡Paediatr Indones, Vol. 52, No. 4, July 2012

Matahari Harumdini et al:6DOEXWDPROLSUDWURSLXPEURPLGHQHEXOL]DWLRQFRPSDUHGWRVDOEXWDPRODORQHLQDVWKPDDWWDFNV

Table 2. Subjects’ baseline demographics, asthma history and clinical parameters

Parameters Control (n= 23) 'ZRGTKOGPVCN
P
Mean age, years (SD) 11.39 (2.56) 11.07 (3.29)
Male gender, n 12 11
Obese, n 1 2
1PUGVQHCUVJOC [GCTUCIQP 13 13
#UVJOCUGXGTKV[KPHTGSWGPVCVVCEMGRKUQFGUP 14 15
Asthma attack severity: mild attack, n 16 16
/GFKCPFWTCVKQPQHEWTTGPVU[ORVQOUFC[U
TCPIG 2 (1-7) 1 (1-7)
2TGXKQWURTQRJ[NCZKUP 2 3
Current non-steroid, non- ipratropium inhalant use, n 10 7
Current steroid use, n 2 2
Asthma comorbidities (allergic rhinitis and/or sinusitis), n 8 5
Median initial clinical score, (range) 2 (1-4) 3 (1-6)
/GFKCPKPKVKCNRGCMƀQYTCVGNKVGTUOKP (range) 175 (50-350) 100 (50-300)
/GFKCPKPKVKCNQZ[IGPUCVWTCVKQP
TCPIG 97 (96-99) 98 (96-99)
/GCPKPKVKCNTGURKTCVQT[TCVGZOKP
5& 28.76 (6.24) 29.42 (7.11)
/GCPKPKVKCNJGCTVTCVGZOKP
5& 102.19 (12.54) 103.74 (20.03)

Table 3. Comparative median/mean decreases in clinical score

Decrease in clinical score
Subjects 6KOGCVGXCNWCVKQP Control (n= 23) 'ZRGTKOGPVCN
P P 95% CI
median (range) median (range)
Mild to 20 minutes 2 (1-4) 2 (1-4) 0.560 -0.40 to 0.57
moderate 40 minutes 2 (1-5) 3 (1-6) 0.775 -0.55 to 0.81
attack 60 minutes 2 (1-5) 3 (1-6) 0.524 -0.42 to 1.12
120 minutes 2 (1-5) 3 (1-6) 0.414 -0.34 to 1.29
Control (n= 7) 'ZRGTKOGPVCN
P
mean (SD) mean (SD)
Moderate 20 minutes 2.14 (0.90) 2.43 (0.98) Statistical analysis was not
attacks only 40 minutes 3.57 (0.98) 4.14 (1.07) RGTHQTOGFFWGVQKPCFGSWCVG
60 minutes 3.71 (0.95) 4.86 (1.07) PWODGTQHUWDLGEVU
120 minutes 3.71 (0.95) 5.29 (0.76)
%+OGCUWTGFD[CHQTOWNCWUKPIOGCPXCNWG

:HREVHUYHGDKLJKHUSURSRUWLRQRIVXEMHFWVZLWK needed. There were no differences in oxygen saturation

3)5 UHYHUVLELOLW\ LQ WKH H[SHULPHQWDO JURXS  EHWZHHQWKHWZRJURXSV:HDOVRIRXQGQRVLJQLILFDQW
VXEMHFWVWKDQLQWKHFRQWUROJURXSVXEMHFWV difference in the decrease of respiratory rates between
DW  PLQXWHV 7KH GLIIHUHQFH EHWZHHQ JURXSV ZDV the two groups (Table 6,QPRGHUDWHDVWKPDDWWDFN
&,WR3 $WWR VXEMHFWVDORQHQ WKHUHZDVDJUHDWHUGHFUHDVH
minutes, there were similarly no significant differences in respiratory rates in the experimental group. These
LQSURSRUWLRQVRIVXEMHFWVZLWK3)5UHYHUVLELOLW\Table GLIIHUHQFHVZHUH[PLQXWHVDWDQGPLQXWHV
5,QVXEMHFWVZLWKPLOGDWWDFNVDORQHQ WKHUH DQG[PLQXWHVDWDQGPLQXWHVZKLFKZHUH
was also no difference between groups (Table 5), while FOLQLFDOO\ TXLWH DSSDUHQW Table 6) but statistical
LQ VXEMHFWV ZLWK PRGHUDWH DWWDFNV DORQH Q  
reversibility tended to be higher in the experimental
group, but the sample size was too small to analyze
(Table 5).
Before intervention, all subjects had oxygen
VDWXUDWLRQ!WKHUHIRUHR[\JHQWKHUDS\ZDVQRW
DQDO\VHVZHUHQRWSHUIRUPHGGXHWRODFNRIVXEMHFWV
7ZR SDWLHQWV ZLWK PRGHUDWH DVWKPD DWWDFN
IURP WKH FRQWURO JURXS UHVSRQGHG LQDGHTXDWHO\ DW
PLQXWHVUHTXLULQJKRVSLWDODGPLVVLRQ7KHVH
subjects were given ipratropium bromide nebulization
and intravenous steroids. They were analyzed in
Paediatr Indones, Vol. 52, No. 4, July 2012 ‡203
Matahari Harumdini et al:6DOEXWDPROLSUDWURSLXPEURPLGHQHEXOL]DWLRQFRPSDUHGWRVDOEXWDPRODORQHLQDVWKPDDWWDFNV

the control group, since we used intention-to-treat LQ WKH H[SHULPHQWDO JURXS  VXEMHFWV EXW WKLV
analyses. The number of hospital admissions was GLIIHUHQFHZDVQRWVWDWLVWLFDOO\VLJQLILFDQW3 
KLJKHU LQ WKH FRQWURO JURXS  VXEMHFWV WKDQ (Table 7).

Table 4. Comparative median PFR percentage increase

6KOGCV Control (n=21) 'ZRGTKOGPVCN
P
Subjects
evaluation % increase, (range) % increase, (range) P* 95% CI
Mild to 20 minutes 14.28 (0-100) 33.33 (8.33-200) 0.012 1.80 to 47.18
moderate attack 40 minutes 25 (7.14-100) 50 (8.33-200) 0.114 1.61 to 54.17
60 minutes 25 (11.1-100) 50 (8.33-300) 0.115 4.46 to 83.59
120 minutes 25 (11.1-100) 50 (8.33-200) 0.115 4.46 to 83.61
Control (n=16) 'ZRGTKOGPVCN
P
P* 95% CI
% increase, (range) % increase, (range)
Mild attacks 20 minutes 13,39 (0-57,14) 29,16 (8,33-100) 0.058 1.05 to 30.31
only 40 minutes 22,5 (7,14-60) 50 (8,33-100) 0.234 -2.5 to 40.96
60 minutes 25 (11,11-100) 50 (8,33-200) 0.531 -10.56 to 49.46
120 minutes 25 (11,11-100) 50 (8,33-200) 0.531 -10.56 to 49.46
Control (n=5) 'ZRGTKOGPVCN
P
% increase, (range) % increase, (range)
Moderate 20 minutes 16,7 (0-100) 66,7 (20-200) Statistical analyses was not
attacks only 40 minutes 50 (16,7-100) 100 (20-200) RGTHQTOGFFWGVQNCEMQHUWDLGEVU

60 minutes 50 (16,7-100) 166,7 (60-300)

120 minutes 50 (16,7-100) 166,7 (60-300)
/CPP9JKVPG[VGUV%+YCUOGCUWTGFD[HQTOWNCWUKPIOGCPXCNWG

Table 5. %QORCTCVKXG RTQRQTVKQPU QH 2(4 TGXGTUKDKNKV[

FGHKPGF CU 2(4 KPETGCUG > HTQO
baseline)
Control 'ZRGTKOGPVCN
Reversibility at P* 95% CI
(n=21) (n= 19)
Mild to moderate 20 minutes 13 17 0.069S 0.026 to 0.524
attacks 40 minutes 19 17 1S -0.409 to 0.431
60 minutes 20 17 0.596S -0.107 to 0.223
120 minutes 20 17 0.596S -0.107 to 0.223
Control 'ZRGTKOGPVCN
P
(n=16) (n= 14)
Mild attacks only 20 minutes 10 12 0,226a Not measured
40 minutes 14 12 1b
60 minutes 15 12 0,586b
120 minutes 15 12 0,586b
Control 'ZRGTKOGPVCN
(n=5) (n= 5)
Moderate attacks 20 minutes 3 5 Statistical analysis was not
only 40 minutes 5 5 RGTHQTOGFFWGVQNCEMQH
subjects
60 minutes 5 5
120 minutes 5 5
C%JKUSWCTGVGUVD(KUJGTŏUGZCEVVGUV

204‡Paediatr Indones, Vol. 52, No. 4, July 2012

Matahari Harumdini et al:6DOEXWDPROLSUDWURSLXPEURPLGHQHEXOL]DWLRQFRPSDUHGWRVDOEXWDPRODORQHLQDVWKPDDWWDFNV

Table 6. Comparative median respiratory rate decrease

Control 'ZRGTKOGPVCN
6KOGCVGXCNWCVKQP P* 95% CI
(n=23) (n= 23)
Mild to moderate attacks 20 minutes 4 (2-18) 4 (0-8) 0,907 
40 minutes 6 (4-20) 8 (1-16) 0,585 
60 minutes 6 (4-20) 8(1-16) 0,602 
120 minutes 6 (4-20) 8(1-16) 0,602 
Control 'ZRGTKOGPVCN
(n=7) (n= 7)
Moderate attacks only 20 minutes 4 (4-16) 8 (4-8) Statistical analysis was not
40 minutes 6 (4-16) 10 (8-12) RGTHQTOGFFWGVQNCEMQH
subjects
60 minutes 6 (4-18) 12 (8-12)
120 minutes 6 (4-18) 12 (8-12)
/CPP9JKVPG[VGUV%+OGCUWTGFD[HQTOWNCWUKPIOGCPXCNWG

Table 7.%QORCTCVKXGRTQRQTVKQPQHJQURKVCNK\CVKQP +RZHYHUWKHRWKHUHIILFDF\SDUDPHWHUV3)5R[\JHQ

Control 'ZRGTKOGPVCN saturation, respiratory rate, and proportion of hospital
(n= 23) (n= 23) DGPLVVLRQZHUHREMHFWLYHO\PHDVXUHG$OVRWKH3)5
Hospitalization 2 0 FRXOGQRWEHPHDVXUHGLQSDWLHQWVEXWWKHUHPDLQLQJ
No hospitalization 21 23
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2
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DQDO\VHV,QDGGLWLRQZHSODQQHGWRPHDVXUH%*$LQ
DOOVXEMHFWVZLWKPRGHUDWHDWWDFNVEXWPRVWVXEMHFWV
2I  SDWLHQWV ZLWK PRGHUDWH DWWDFNV RQO\  UHIXVHGWKHDUWHULDOSXQFWXUH6LQFH&DUUXWKHUVet al.
FRQVHQWHG WR %*$ H[DPLQDWLRQ 7KH ILUVW SDWLHQW VKRZHGWKDWUHVSLUDWRU\IDLOXUHZDVXQOLNHO\LQSDWLHQWV
agreed to arterial puncture after the intervention, and ZLWKR[\JHQVDWXUDWLRQ!%*$ZDVQRWQHFHVVDU\
the second patient agreed before the intervention. unless otherwise clinically indicated.
In both subjects, we found decreased pressure of In our study, interrater reliability could only be
R[\JHQLQDUWHULDOEORRG3D22DQGPP+J PHDVXUHGEHWZHHQWKH3,DQGDUHVHDUFKDVVLVWDQWRQ
UHVSHFWLYHO\ DQG ORZ +&23  DQG  PPRO/ SDWLHQWVGXHWROLPLWDWLRQVRIWLPHDQGVDPSOHVL]H
respectively) ZKLOHS+3D22 and oxygen saturation
were still normal.
:H IRXQG WKH VLGH HIIHFW RI PRXWK PXFRVDO
dryness to be of similar proportions in both groups.
The unilateral decrease of light pupillar response was
IRXQGLQSDWLHQWVIURPWKHH[SHULPHQWDOJURXSDW
PLQXWHVEXWVSRQWDQHRXVO\UHVROYHGDWPLQXWHV
The proportion of subjects with tachycardia was
KLJKHVW DW  PLQXWHV EXW GLG QRW GLIIHU EHWZHHQ
groups. Tachycardia resolved with time.
Discussion
This study had some limitations. In this single-blinded
study, investigators were not blinded, but subjects were.
Ideally, the study should be double-blinded, since we
used a subjective parameter of efficacy (clinical score).
2XU.DSSDZDVZDVFRQVLGHUHGVXIILFLHQW
The same clinical score was used by previous studies
ZLWK.DSSDYDOXHVUDQJLQJIURPWRVLPLODUWR
that of our study.
7KH UHTXLUHG PLQLPDO VDPSOH VL]H ZDV 
subjects, but at the end of the study, we had more
VXEMHFWVWREHDQDO\]HG:HDWWHPSWHGWRVXEJURXS
DQDO\VHVIRUGLIIHUHQWDWWDFNVHYHULWLHV+RZHYHUD
subanalysis could only be performed on subjects with
PLOGDWWDFNVGXHWRLQVXIILFLHQWQXPEHURIVXEMHFWV
ZLWKPRGHUDWHDWWDFNV7KHUHIRUHZHDQDO\]HGGDWD
RI PLOG DQG PRGHUDWH DWWDFN VXEMHFWV DV D ZKROH
while trying to demonstrate clinical differences in
HDFK VXEJURXS 7KH ORZ QXPEHU RI DVWKPD DWWDFN
patients at our public facilities may be due to
increasing numbers of private health centers with
nebulization facilities as well as better maintenance
treatment for asthma patients.
Paediatr Indones, Vol. 52, No. 4, July 2012 ‡205
Matahari Harumdini et al:6DOEXWDPROLSUDWURSLXPEURPLGHQHEXOL]DWLRQFRPSDUHGWRVDOEXWDPRODORQHLQDVWKPDDWWDFNV

Demographic and clinical parameters that EH\RQGPLQXWHV7KLVUHVXOWZDVFRQVLVWHQWZLWK

may influence the clinical response to nebulization previous studies which showed more profound
treatment were assessed at baseline, and found to be differences of lung function parameters at the end
VLPLODULQWKHWZRJURXSV:HREVHUYHGDQLQVLJQLILFDQW of the observations, due to the slower onset of
difference in clinical scored throughout the study ipratropium bromide compared to that of salbutamol.
EHWZHHQWKHWZRJURXSVPHGLDQGLIIHUHQFHRISRLQW 6LPLODUO\LQDPHWDDQDO\VLVRQVXEMHFWVZLWKPRGHUDWH
6LPLODUO\ 5D\QHU et al. reported that ipratropium WRVHYHUHDWWDFNV5RGULJRet al. found a difference of
bromide given after beta2-agonist resulted in a reduced LQIRUFHGH[SLUDWRU\YROXPHDWPLQXWH)(9)
V\QHUJLVWLF HIIHFW )XUWKHUPRUH .XPDUDWQH et al. PHDVXUHGE\VSLURPHWU\6KDUPDet al. also found a
UHSRUWHGWKDWLQ\RXQJVXEMHFWVPRQWKV\HDUV KLJKHU3)5LQFUHDVHSHUFHQWDJHLQWKHH[SHULPHQWDO
assumed to have a predominant bronchospasm on JURXSDWPLQXWHVWRKRXUVDIWHUQHEXOL]DWLRQLQ
peripheral small bronchi, ipratropium bromide was DVWXG\RQVXEMHFWVZLWKPRGHUDWHDWWDFNV
less effective. ,Q VXEMHFWV ZLWK PRGHUDWH DWWDFNV DORQH ZH
In our analysis of subjects with moderate IRXQGDODUJHUGLIIHUHQFHLQ3)5LPSURYHPHQW!
DWWDFNVDORQHZHIRXQGDJUHDWHUGHFUHDVHLQFOLQLFDO DWWRPLQXWHVEXWVWDWLVWLFDODQDO\VHVFRXOGQRW
score in the experimental group than in the control EHSHUIRUPHG6FKXKet al.9 reported that differences
JURXSPHDQGLIIHUHQFHSRLQWVWKRXJKIXUWKHU
statistical analyses could not be performed due to
LQVXIILFLHQWVXEMHFWV3UHYLRXVVWXGLHVE\6FKXKet al.,9
6KDUPDet al.,.DUWLQLQLQJVLKet al., and Qureshi
et al.8 also demonstrated a larger decrease in clinical
score in their experimental groups. Those studies
included children of younger age and greater numbers
RIVXEMHFWVZLWKPRGHUDWHO\VHYHUHDWWDFNV2XUVWXG\
LQFOXGHGPRVWO\VXEMHFWVZLWKPLOGDVWKPDDWWDFNVLQ
in FEV  LQFUHDVHG DV DWWDFN VHYHULW\ LQFUHDVHG
1RQHWKHOHVVDVLJQLILFDQWGLIIHUHQFHLQ3)5LQFUHDVH
was reported by Rayner et al., who gave ipratropium
EURPLGHVHTXHQWLDOO\DIWHUVDOEXWDPRODQG4XUHVKLet
al.8ZKRFRPSOHWHG3)5PHDVXUHPHQWVLQRQO\
of their subjects.
:H DOVR IRXQG D JUHDWHU SURSRUWLRQ RI 3)5
UHYHUVLELOLW\DWPLQXWHVLQWKHH[SHULPHQWDOJURXS
7KHGLIIHUHQFHLQSURSRUWLRQZDVRQO\&,
which less cholinergic activity occurs. On the other
KDQG LQ VXEMHFWV ZLWK PRGHUDWH DWWDFNV ZH IRXQG
a larger difference in the decrease in clinical scores.
This difference might have been more profound if
WKH QXPEHU RI VXEMHFWV ZLWK PRGHUDWH DWWDFNV ZDV
larger.
 WR  3  LQ FRQWUDVW WR SUHYLRXV
studies which showed better efficacy at the end of the
observation periods. Our study included mostly
SDWLHQWVZLWKPLOGDWWDFNVDQGOHVVEURQFKRFRQVWULFWLRQ
thus the synergistic effect of ipratropium-salbutamol
ZDVREVHUYHGDWMXVWPLQXWHV$WWKHVXEVHTXHQW
7KH *OREDO ,QLWLDWLYH IRU $VWKPD *,1$
recommends lung function tests to confirm diagnoses
and to evaluate asthma severity, as well as asthma
DWWDFNVHYHULW\ Lung function tests generally comprise
VSLURPHWU\ DQG SHDN IORZ PHWHU H[DPLQDWLRQV :H
FKRVH WR XVH SHDN IORZ PHWHUV GXH WR WKHLU JUHDWHU
DYDLODELOLW\ 7KH UHIHUHQFH GDWD IRU SUHGLFWLQJ 3)5
time points, the proportion of reversibility did not
further increase because maximal bronchodilatation
KDGDOUHDG\RFFXUUHGDWPLQXWHV
.DUWLQLQLQJVLKHWDO and Qureshi et al.8 found
significant differences in oxygen saturation between
their groups, in subjects with moderate to severe
DWWDFNV ,Q FRQWUDVW PRVW RI RXU VXEMHFWV KDG PLOG
values for age, sex, and body mass index in patients DWWDFNV ZLWK KLJK R[\JHQ VDWXUDWLRQ  DW
DJHG\HDUVLQ,QGRQHVLDZDVLQVXIILFLHQWVRZH baseline, thus clinical improvement could not be
JDXJHG3)5UHVSRQVHWREHWKHSHUFHQWDJHRILQFUHDVH shown. Ducharme et al. also reported no significant
IURPEDVHOLQHDQGWKHSURSRUWLRQRISDWLHQWVZLWK3)5 difference in oxygen saturation in subjects with mild
increase of !IURPEDVHOLQH3)5UHYHUVLELOLW\ WRPRGHUDWHDWWDFNV
:HIRXQGDGLIIHUHQFH&,WR :HREVHUYHGQRVLJQLILFDQWGLIIHUHQFHLQGHFUHDVHG
3 LQ3)5EHWZHHQWKHJURXSVDWPLQXWHV UHVSLUDWRU\UDWHVEHWZHHQWKHWZRJURXSV+RZHYHU
%H\RQGPLQXWHVZHDOVRIRXQGGLIIHUHQFHVRI LQPRGHUDWHDWWDFNVXEMHFWVDORQHZHRQO\IRXQGD
EXWWKH\ZHUHQRWVLJQLILFDQW+RZHYHUWKHLQFUHDVLQJ WHQGHQF\RIGLIIHUHQFHEHWZHHQWKHJURXSV6WXGLHVE\
confidence interval suggested relevant differences 6KDUPDet al. and Qureshi et al. reported a greater

206‡Paediatr Indones, Vol. 52, No. 4, July 2012

Matahari Harumdini et al:6DOEXWDPROLSUDWURSLXPEURPLGHQHEXOL]DWLRQFRPSDUHGWRVDOEXWDPRODORQHLQDVWKPDDWWDFNV
decrease in respiratory rate in the experimental groups,
LQVXEMHFWVZLWKPRGHUDWHDWWDFNVDQGVXEMHFWVZLWK
VHYHUHDWWDFNVUHVSHFWLYHO\2XUFRQWUDVWLQJUHVXOWV
may be due to the smaller number of subjects with
PRGHUDWHDWWDFNVLQRXUVWXG\
Many previous studies on subjects with moderate
WRVHYHUHDWWDFNVUHSRUWHGORZHUKRVSLWDODGPLVVLRQ
rates in the ipratropium bromide group. The difference
in admission rates between groups was greatest in
WKHPRVWVHYHUHFDVHV:HIRXQGDVPDOOGLIIHUHQFHLQ
KRVSLWDODGPLVVLRQVLQWKHFRQWUROJURXSYV
in the experimental group), but it was not statistically
al., and Rodrigo et al. also reported no significant
differences in side effects with the addition of
ipratropium bromide.Despite the study limitations,
we conclude that salbutamol-ipratopium bromide
nebulization showed better efficacy compared to
salbutamol alone in patients with mild to moderate
DVWKPD DWWDFNV 7KH 3)5 SHUFHQWDJH LQFUHDVH DQG
3)5UHYHUVLELOLW\DWPLQXWHVZDVEHWWHUFOLQLFDOO\
IRUWKHH[SHULPHQWDOJURXS+RZHYHURWKHUFOLQLFDO
parameters of efficacy (clinical scores, oxygen
saturation, respiratory rates, and hospital admission
rates) were not different between groups. In subjects
VLJQLILFDQW3 0RVWRIRXUVXEMHFWVKDGPLOG
DWWDFNVDQGDVVXFKZHUHOHVVOLNHO\WREHKRVSLWDOL]HG
Furthermore, our sample size was too small to detect
any differences in hospitalization rates.
 $Q DVWKPD DWWDFN SDWLHQW PD\ LQLWLDOO\
K\SHUYHQWLODWH WR LQFUHDVH R[\JHQ XSWDNH WKXV
decreasing carbon dioxide levels. If the obstruction
continues, the ventilation-perfusion mismatch can no
longer be overcome by hyperventilation, thus resulting
in hypoxemia and hypercapnia. Carruthers et
al. reported that the respiratory failure rate was
only 4.2% among patients with oxygen saturation
!,QFRQWUDVWLQSDWLHQWVZLWKR[\JHQVDWXUDWLRQ
  KDG UHVSLUDWRU\ IDLOXUH ,Q RXU VWXG\
ERWK VXEMHFWV WKDW ZH SHUIRUPHG %*$ RQ KDG
hypocapnia and normal oxygen saturation, consistent
with previous studies. The relatively low value
RI +&23 revealed a tendency towards metabolic
acidosis which can be caused by the increase of plasma
lactate due to increased respiratory muscle activity
under hypoxic conditions. Beta2-agonist receptor
stimulation may also generate gluconeogenesis,
glycolyis and lipolysis, producing lactate.23 The two
VXEMHFWV ZKR KDG %*$ DVVHVVHG LQ WKLV VWXG\ GLG
not show clinical signs of metabolic acidosis, despite
WKHORZYDOXHRI+&23, thus they did not need any
additional specific management.
There were 2 patients with pupil abnormalities
in the experimental group. These side effects were
reversible. Mouth mucosal dryness did not differ
between the groups. Tachycardia was also similar
between the groups, and resolved with time.
Tachycardia was not only due to side effects of
medications, but was also a physiologic response to
mismatched ventilation-perfusion, resolving as clinical
condition improved. Qureshi et al.,8 Ducharme et
ZLWKPRGHUDWHDWWDFNVDORQHZHREVHUYHGDWHQGHQF\
to better efficacy with the addition of ipratropium
EURPLGHEDVHGRQFOLQLFDOVFRUH3)5DQGUHVSLUDWRU\
rate. Nevertheless, further studies with a larger
VDPSOH VL]H IRU VXEMHFWV ZLWK PRGHUDWH DWWDFNV DUH
necessary.
Acknowledgment
:HWKDQN%RHKULQJHU,QJHOKHLPIRUVXSSRUWLQJWKHVWXG\DVZHOO
DV(0'DGL6X\RNR0'3DUWLQL37ULKRQR0'$QWRQLXV+
3XGMLDGL 0' DQG :DOGL 1XUKDP]DK 0' IRU WKHLU YDOXDEOH
DGYLFHV :H DOVR WKDQN RXU UHVHDUFK DVVLVWDQW +DUL 1XJURKR
MD and all staff of the Respirology Division of the Department
RI &KLOG +HDOWK DW &LSWR 0DQJXQNXVXPR +RVSLWDO WKH &LSWR
0DQJXQNXVXPR+RVSLWDO('WKH0+7KDPULQ6DOHPED+RVSLWDO
('DQGWKH&RPPXQLW\+HDOWK&HQWHURI7HEHW'LVWULFW
References
 $NLQEDPL/-6FKRHQGRUI.&7UHQGVLQFKLOGKRRGDVWKPD
SUHYDOHQFHKHDOWKFDUHXWLOL]DWLRQDQGPRUWDOLW\3HGLDWULFV

 5DKDMRH16XSUL\DWQR%6HW\DQWR'%3HGRPDQQDVLRQDO
DVPDDQDN-DNDUWD8..5HVSLURORJL33,NDWDQ'RNWHU$QDN
,QGRQHVLDS
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WRIUHTXHQWKLJKGRVHDOEXWHUROWKHUDS\LQVHYHUHFKLOGKRRG
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 5RGULJR *- &DVWUR5RGULJXH] -$ $QWLFKROLQHUJLFV
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DVWKPD D V\VWHPDWLF UHYLHZ ZLWK PHWDDQDO\VLV 7KRUD[

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DVWKPD$UFK'LV&KLOG
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