Jan 1, 2018 - 6. Departemen Kesehatan 5I. Epidemiologi dan etiologi ... Direktorat Jenderal Pemberantasan Penyakit Menular dan. 3enyehatan Lingkungan ...
Paediatrica Indonesiana January
VOLUME 49
NUMBER 1
Original Article
Efficacy of dioctahedral smectite in infants with acute diarrhea: a double blind randomized controlled trial A. A. Made Widiasa, Soetjiningsih, Putu Gede Karyana
Abstract Background Acute diarrhea is a sudden diarrhea which lasts less than seven days on babies and children. The standard treatment by WHO in managing acute diarrhea is still not satisfactory for parents whose infants and children suffering from the disease. Dioctahedral smectite is expected to decrease the volume, frequency, and duration of diarrhea. Objective To assess the clinical effects of dioctahedral smectite in infants with acute diarrhea. Methods$GRXEOHEOLQGUDQGRPL]HGFOLQLFDOFRQWUROOHGWULDOZDV SHUIRUPHGRQVL[WRPRQWKVROGLQIDQWVZKRZHUHKRVSLWDOL]HG in Sanglah Hospital, Denpasar due to acute diarrhea.The subjects were divided into two groups. The treatment group was given standard management with adjuvant dioctahedral smectite while and control group was given standard management with placebo. Results)URPLQIDQWVHQUROOHGLQWKLVVWXG\WKHPHDQGXUDWLRQ of diarrhea was significantly shorter in treatment group compared WR SODFHER JURXS > KRXUV 6' YV KRXUV 6' PHDQGLIIHUHQFH &, WR 3 @ 7KH555ZDVDQG$55ZDV .DSODQ0HLHUVXUYLYDO analysis showed that duration of acute diarrhea was shorter in WUHDWPHQWJURXS>KRXUV 6' YHUVXVKRXUV 6' PHDQ GLIIHUHQFH &, WR ORJ UDQN WHVW 3 @,QPXOWLYDULDWH&R[UHJUHVVLRQDQDO\VLVLWZDVIRXQG that dioctahedral smectite influenced the duration of diarrhea LQLQIDQWVZLWKDFXWHGLDUUKHD>25 &, WR 3 @ Conclusion Dioctahedral smectite can shorten the duration of acute diarrhea. [Paediatr Indones. 2009;49:48-53]. Keywords: acute diarrhea, dioctahedral smectite, diarrhea duration
48Paediatr Indones, Vol. 49, No. 1, January 2009
D
iarrhea is still a children health problem LQ ,QGRQHVLD ZKHUH ZKR VXIIHUV from diarrhea are under five years old.1 In WKHLQFLGHQFHRIGLDUUKHDLQ%DOLZDV )URPOLVWRIFRQVXOWDWLRQWRSULPDU\KHDOWKFDUH RXWSDWLHQWFOLQLFDQGKRVSLWDOL]HGSDWLHQWVGLDUUKHDLV always on top three diseases in their monthly census. In pediatric outpatient clinic, Sanglah Hospital, there ZHUHSDWLHQWVZLWKGLDUUKHDLQ3 ,Q :+2SXEOLVKHGDUDWLRQDOPHGLFDWLRQ in management of acute diarrhea for infants and children.4 Oral rehydration effort and early solid food intake has a positive impact for recovery of diarrhea. However, parents whose children sufferred from the disease tend to expect for drugs to shorten the period of diarrhea. Therefore, nowadays, numerous researches have been done to study types of drugs which can be given along with oral rehydration effort. Hypersecretion is a problem in diarrhea. Dioctahedral smectite (DS) as an anti-secretoric has been studied in many countries and most of the results
From the Department of Child Health, Medical School, Udayana University, Sanglah Hospital, Denpasar, Bali, Indonesia. Reprint request to: A.A. Md Widiasa, MD, Department of Child Health, Medical School, Udayana University, Sanglah Hospital, Jl. Pulau Nias, 'HQSDVDU%DOL,QGRQHVLD7HO)D[(PDLO ika_unud@ yahoo.com
A. A. Made Widiasa et al: Efficacy of dioctahedral smectite on acute diarrhea
had stated that DS are safe, effective and efficient. DS has a role in reducing cAMP level and reduce the leakage of fluid and electrolyte, binds with potential agents that can cause diarrhea, reduces membrane permeability, increases amount of mucous area, and decreases the recovery time of intestine injury in chronic diarrhea.7 DS has more benefits in decreasing VHFUHWLRQ LQFUHDVLQJ DEVRUSWLRQ DQG QRUPDOL]LQJ intestine peristaltic. Based on this mechanism, we were interested in researching cheap, affordable, effective, and safe medication which can be added to standard medication that might accelerate the recovery time of diarrhea.
Methods $ GRXEOH EOLQG UDQGRPL]HG FOLQLFDO WULDO ZDV conducted on Gastroenterology Division, Child Health Department of Udayana University, from -DQXDU\ WR -XO\ (OLJLEOH SDWLHQWV ZHUH FKRVHQ using consecutive sampling. The study had been approved by the Ethical Clearance from the Ethics Committee of Medical School, Sanglah Hospital, Denpasar, and informed consent was obtained from parents. The inclusion criteria were patients with mild to moderate dehydration due to acute diarrhea, aged PRQWKVROGDQGWKHGXUDWLRQRIGLDUUKHDEHIRUH KRVSLWDOL]DWLRQ ZDV WZR GD\V RU OHVV ,QIDQWV ZLWK complicated diarrhea, diarrhea with complication, and infants whose parents refused to participate in this study were excluded. Acute diarrhea was defined as defecation frequency for more than three times per day or more than the usual habit accompanied by changes in feces consistency, with or without blood and or mucous, lasting for less than seven days.4 Recovery time was the time needed until the frequency of defecation was equal to or less than three time per day with normal stool consistency without any complication. 1,4 Diarrhea with complication was defined as diarrhea episode accompanied by direct effect of acute diarrhea such as severe dehydration, metabolic DFLGRVLVVHL]XUHDQGLOHXVSDUDO\WLF Complicated diarrhea was defined as acute diarrhea with severe malnutrition, severe dysentery, respiratory infection, and anemia. Dehydration status was assessed
according to the WHO standard,4 while nutritional status was determined based on Z score of weight for length.9 Patients who did not take either oral DS or control in the first twelve hours and discharged by request, were considered as drop-out case. Patients who had treatment failure were defined as patients who failed to recover on the fifth day of treatment, or those who had experienced any complication before day five, or had co-infection or adverse events affecting the duration of diarrhea, or patients who passed away. 4XHVWLRQQDLUHVZHUHXVHGWRUHFRUGWKHEDVHOLQH characteristics of clinical and duration of diarrhea in the hospital, frequency of defecation, consistency of feces, complication, and adverse events. Total study VXEMHFWV ZHUH LQIDQWV WKH HVWLPDWLRQ ZDV EDVHG on A SRZHU7KH\ZHUHUDQGRPL]HGLQWR two groups; the treatment group who had standard diarrhea therapy with DS, while the control group who received standard diarrhea therapy with placebo. 7KH UDQGRPL]DWLRQ SURFHVV ZDV GRQH ZLWK EORFN UDQGRPL]DWLRQ DQG WKH FRGHV ZHUH NHSW LQ FORVHG envelopes. The envelopes were kept at Beaufour Ipsen PT Combiphar and opened after the study was finished. All subjects were managed according to the standard therapy recommended by WHO for acute diarrhea, with rehydration. All medicines prescribed before admission was discontinued. All study subjects were followed-up until the subjects recovered. To asses the outcome, we performed evaluation and measurement of dehydration status, frequency of defecation, stool consistency, adverse events, and complications every KRXUVZKLOHHYDOXDWLRQDQGPHDVXUHPHQWRIERG\ weight, compliance of taking DS and placebo, were GRQH HYHU\ KRXUV ,Q WKLV VWXG\ GURS RXW DQG treatment failure rates were accepted if the rate was EHOORZ 6XEMHFWV WKDW FRQVLGHUHG DV GURS RXW FDVHVRUWUHDWPHQWIDLOXUHVZHUHDQDO\]HGZLWKLQWKH group and treated afterward. Study procedures are shown in Figure 1. 'DWDZHUHDQDO\]HGXVLQJFRPSXWHUSURJUDP7KH mean difference of recovery time was examined using student’s t test. Additional variables (complications or DGYHUVHHYHQWVRQVWXG\GXUDWLRQ ZHUHDQDO\]HGXVLQJ x test. The primary outcome result was the difference in duration of diarrhea between groups showed by
Paediatr Indones, Vol. 49, No. 1, January 200949
A. A. Made Widiasa et al: Efficacy of dioctahedral smectite on acute diarrhea Survival Functions Typess onf intervention
DS Placebo
Cum Survival
Kaplan-Meier curve. Differences in duration of diarrhea between two groups were tested using log-rank test. Risk of treatment failure between the two groups was compared with relative risk reduction (RRR) and absolute risk reduction (ARR). We made adjustment of external variables to duration of diarrhea between two groups using cox-regression analysis. P value of ZLWK FRQILGHQFHLQWHUYDOZHUHFRQVLGHUHG as statistically significant.
Results
During the study period, there were 144 infants aged PRQWKVROGDGPLWWHGWR6DQJODK+RVSLWDOGXHWR acute diarrhea. Seventy-six infants with acute diarrhea accompanied with other problems or co-infections (three infants had severe malnutrition, six infants had bronchopneumonia, four infants had anemia, LQIDQWV KDG DFXWH UKLQRSKDU\QJLWLV LQIDQWV had acute tonsilo-pharyngitis, one infant had acute otitis media, seven infants had acute bronchiolitis, and eight infants refused to participate in the study. +HQFH WKHUH ZHUH LQIDQWV ZKR ZHUHHOLJLEOHIRU this study.
Table 1. $CUGNKPGEJCTCEVGTKUVKEUQHKPHCPVUYKVJCEWVGFKCTTJGCKP VTGCVOGPVCPFEQPVTQNITQWRU 6TGCVOGPV )TQWR
P #IG OQPVJ OGCPU 5& 5GZDQ[U +FGCN DQF[ YGKIJV ITCO OGCP
5& 0WVTKVKQPCNUVCVWU )QQF /QFGTCVGOCNPWVTKVKQP &KGVKPVCMG $GCUVHGGFKPI (QTOWNC $( (QTOWNC $( (QTOWNC OKNMRQTTKIFG (QTOWNC OKNMRQTTKFIG 2TGJQURKVCNFKCTTJGC
JQWTU OGCP 5& 2TGJQURKVCNFKCTTJGCHTGSWGPE[ OGCP 5& #PVKDKQVKEDGHQTGCFOKUUKQP 1$9 ITCO OGCP 5& %JCTCEVGTKUVKE
2NCEGDQ )TQWR
P
50Paediatr Indones, Vol. 49, No. 1, January 2009
Duration of diarrhea (hour)
Figure 2-CRNCPŌ/GKGTUWTXKXCNEWTXGQHFWTCVKQP QHFKCTTJGCKPVJGVTGCVOGPVITQWRCPFEQPVTQNITQWR QPFC[UVWF[
Mean age of infants in treatment group was 9.9 6' PRQWKVZKLOHLQWKHFRQWUROJURXSZDV 6' PRQWKV%DVHOLQHFKDUDFWHULVWLFVRIWKHWZR groups are shown in Table 1. Reduction in frequency of defecation was VLJQLILFDQWO\ RFFXU LQ WKH WUHDWPHQW JURXS KRXU 6' YHUVXV KRXUV 6' PHDQ GLIIHUHQFH RI > &, WR 3 @ 5HFRYHU\ RI VWRRO FRQVLVWHQF\ ZDV significantly had shorter duration in the treatment JURXS ^ KRXUV 6' YHUVXV KRXUV 6' PHDQGLIIHUHQFHRI> &, WR 3 @ Mean duration of diarrhea as a primary result was significantly shorter in the treatment group compared WRWKDWLQFRQWUROJURXS KRXUV 6' YHUVXV KRXUV 6' PHDQGLIIHUHQFH> &, WR 3 @%DVHGRQ.DSODQ0HLHU analysis, duration of diarrhea was significantly shorter in treatment group compared to that in control group ORJUDQNWHVW3 3ULPDU\RXWFRPHLVVKRZHG on Figure 2. There were two infants who failed in control group due to bronchopneumonia and acute otitis media on GD\WZRDQGGD\WKUHHKRVSLWDOL]DWLRQDQGRQHLQIDQWLQ treatment group was also considered as a drop-out case. The differences of treatment failure between two groups ZHUHH[SUHVVHGDV555RIDQG$55RI
A. A. Made Widiasa et al: Efficacy of dioctahedral smectite on acute diarrhea Table 2+PVGTXCTKCDNGUEQPPGEVKQPUVJCVCHHGEVGFCEWVGFKCTTJGCFWTCVKQPKPVTGCVOGPVITQWRXUEQPVTQN ITQWR (TGG8CTKCDNG #IG &KGVKPVCMG 0WVTKVKQPUVCVWU 2TGJQURKVCNFKCTTJGCFWTCVKQP #PVKDKQVKEUDGHQTGCFOKUUKQP &5
B
5'
2
'ZR $
In this study, there were no significant difference in the body weight gain between treatment and control groups at the time of admission and discharged from KRVSLWDO 6' YHUVXV 6' PHDQ GLIIHUHQFHZDV &,WR 3 From multivariate analysis (Cox regression), it was proven that only DS significantly affected the GXUDWLRQ RI GLDUUKHD >25 &, WR 3 @ Table 2). In this study, we found no adverse events caused by DS.
Discussion Several studies in many countries about DS as an adjunctive medication in management of diarrhea showed a significant result in shortening the duration of diarrhea and nursing time in the hospital. A meta-analysis study by Zue-Shenyen et al IURP 5&7ZLWKLQIDQWVUHSRUWHGWKDW'6VWDWLVWLFDOO\ significant to reduce the length of diarrhea. Our study revealed that the defecation frequency was significantly decreased in the treatment group KRXUV 6' YHUVXV WKH FRQWURO JURXS KRXUV 6' 0RVWO\RQWKHVHFRQGGD\RI KRVSLWDOL]DWLRQIUHTXHQF\RIGLDUUKHDKDGGHFUHDVHG to less than three times per day, cumulatively there ZHUH LQIDQWV YHUVXVVL[LQIDQWV This study result was consistent with the finding from Vivatvakin study group.11 Vivatvakin study showed that frequency of diarrhea reduced on day two of KRVSLWDOL]DWLRQLQLQIDQWV IURPLQIDQWVLQ WKHWUHDWPHQWJURXSYHUVXVLQIDQWV LQFRQWURO JURXS7KLVVWXG\DOVRUHYHDOHGTXLFNHUWLPHLH KRXUV 6' LQ IHFHV FRQVLVWHQF\ WR EHFRPH normal, soft, and formed in the treatment group FRPSDUHGWRFRQWUROJURXSKRXUV 6' WKH PHDQGLIIHUHQFHZDV3 2QGD\WZRRI
%+ HQT'ZR $ VQ VQ VQ VQ VQ VQ
KRVSLWDOL]DWLRQWKHWUDQVIRUPDWLRQRIIHFDOFRQVLVWHQF\ to normal was cumulatively significant in 31 infants ZLWKLQWKHWUHDWPHQWJURXSFRPSDUHGWRVHYHQ LQIDQWV LQ FRQWURO JURXS /H[RPERRQ et al reported that transformation of fecal consistency to QRUPDORQGD\WZRRIKRVSLWDOL]DWLRQZHUHREVHUYHGLQ LQIDQWV LQWKHWUHDWPHQWJURXSFRPSDUHGWR LQIDQWV LQFRQWUROJURXS%DVHGRQWZRVWXGLHV above, we conclude that recovery process of acute diarrhea in infants was faster in the treatment group if compared to the control group. In this study, we also had a result that duration of diarrhea in hospital was VKRUWHULQWKHWUHDWPHQWJURXS KRXUV 6' YHUVXVKRXUV 6' 3 This study result was also similar to Vivatvakin et al11LQLQIDQWVDJHGEHWZHHQRQHWRPRQWKV7KH duration of diarrhea in the treatment group was 43.3 KRXUV 6' FRPSDUHGWRKRXUV 6' LQ control group. The results were statistically significant. In study by Madkour et al13ZLWK LQIDQWVDJHGEHWZHHQ WKUHHWRPRQWKVWKHUHVXOWVZHUHKRXUV 6' LQWUHDWPHQWJURXSYHUVXV KRXUV 6' LQFRQWURO group. Study by Narkeviciute et al14ZLWKLQIDQWVDQG FKLOGUHQDJHGEHWZHHQVL[WRPRQWKVUHYHDOHGWKDW the duration of diarrhea was 43.3 hours in the treatment JURXSYHUVXVKRXUVLQFRQWUROJURXS Recovery of acute diarrhea is determined by intestinal mucosa recovery. In acute diarrhea, patients treated with DS have a quicker small intestine mucosal recovery through mucous interaction, cells regeneration stimulation, and differentiation of mucosal intestine resulting in less fluid excretion, increased absorption, and intestinal peristaltic recovery. Dupont et al reported recovery of small LQWHVWLQHVWUXFWXUHGHSHQGVRQVL]HRIDGDPDJH6HYHUH damage would need four days to recover and the function of absorbing water, electrolyte, and nutrition will be improved in 1.3 days time.
Paediatr Indones, Vol. 49, No. 1, January 200951
A. A. Made Widiasa et al: Efficacy of dioctahedral smectite on acute diarrhea
There was no significant difference between ERWKJURXSVDIWHULQWHUYHQWLRQ> 6' YHUVXV 6' @ DOWKRXJK ZHLJKW JDLQ WHQGHG WR be slightly higher in control group. This result was probably due to rehydration factor because DS did not show any influence in weight gain in short period of time. Similar study was done by Madkour et al13 which found that there was no statistically significant GLIIHUHQFHLQZHLJKWJDLQEHWZHHQFRQWUROJURXS gram) and treatment group (94.9 gram). Vivatvakin et al11 reported that there was a significant difference LQLQFUHPHQWRIERG\ZHLJKWJUDPVERG\ZHLJKW LQ WKH WUHDWPHQW JURXS FRPSDUHG WR JUDPV LQ the control group. Both studies were influenced by different period of monitoring. In Vivatvakin11, the PRQLWRULQJWLPHZDVRQWKHth day after treatment, whereas in our study, it was only performed when the SDWLHQWZDVKRVSLWDOL]HG ,Q WKLV VWXG\ 555 VKRZHG GHFUHDVH RU $55RI GHFUHDVHLQLQWHUYHQWLRQJURXSFRPSDUH to control group. Based on covariate analysis (cox regression), DS only affected the duration of diarrhea episode. Other factors such as age, nutrition status, nutrition type, duration of diarrhea prior to admission, and antibiotic intervention were not statistically significant to influence the duration of diarrhea. Adverse effects and complications were not encountered in our study. Meta-analysis study by 6]DMHZVNDet al showed that there was no adverse effects, which was caused by gut inability to absorb DS into the systemic circulation, found in nine UDQGRPL]HGFRQWUROOHGWULDOVZLWKSDUWLFLSDQWV To strengthen its validity, the calculation on intention to treat analysis was also included in this study. We included the drop-out and failure-totreatment subjects in our final analysis, with the worst assumption of subject’s results as expected. The weakness in our study was that there was no further investigation on the cause of diarrhea especially rotavirus, which had been known as the most common causeof diarrhea in children less than two years old. Due to the study limitation, its etiology remained unknown. In conclusion, DS could be used as an alternative therapy on treating acute diarrhea in infants. However, the standard procedure of acute diarrhea recommended by WHO remained to be the main protocol. Based on its safety, DS is considered to be a treatment used in
52Paediatr Indones, Vol. 49, No. 1, January 2009
management of acute diarrhea in infants routinely in gastroenterology division of child health in Udayana University, Sanglah Hospital, Denpasar.
Acknowlegments Our respect and gratitude to Head of Beafour IPSEN International PT. Combiphar for his support and assistance in accommodating DS, particularly Smecta and Smecta without DS as a control. Our respect and gratitude to all staffs and paramedic Department of Child Health, Udayana University, Sanglah Hospital, Denpasar. Also to all patients and their family who were admitted, especially to those participating in this study.
Conflict of Interest Beafour IPSEN International PT. Combiphar provided DS and Placebo. This study was not ordered or belonged to Beafour IPSEN International PT. Combiphar. The researchers did not receive any stipend or allowance in any form.
References 1. 3. 4.
Sudigbia. Pengobatan biotika. Semarang: Buletin IKA FK 81',3 'LQDV.HVHKDWDQ3URSLQVL%DOL5HJLVWUDVL30Denpasar: 'LQDV.HVHKDWDQ3URSLQVL%DOL S Registrasi Kunjungan Poliklinik Anak Rumah Sakit Sanglah 7DKXQ Suraatmaja S. Kapita selekta gastroenterologi. Diare Akut. 'HQSDVDU 60),.$).818' S .DQGXQ ,1HGLWRU 8SD\D 3HQFHJDKDQ GLDUH GLWLQMDX GDUL DVSHNNHVHKDWDQPDV\DUDNDW3URFHHGLQJRIWKHQG1DWLRQDO Congress of Badan Koordinasi Gastroenterologi Anak Indonesia %.*$, -XO\ %DQGXQJ,QGRQHVLD 'HSDUWHPHQ .HVHKDWDQ 5, (SLGHPLRORJL GDQ HWLRORJL diare. Buku ajar diare. Jakarta: Departemen Kesehatan RI, Direktorat Jenderal Pemberantasan Penyakit Menular dan 3HQ\HKDWDQ/LQJNXQJDQ3HPXNLPDQ 'LWMHW30 3/3 S /H[RPERRQ8+DULNXO6/RUWKRORU\2&RQWUROUDQGRPL]HG study of rehydration with dioctahedral smectite in ambulatory 7KDLLQIDQWVZLWKDFXWHGLDUUKHD1(QJO-0HG
A. A. Made Widiasa et al: Efficacy of dioctahedral smectite on acute diarrhea ,VPDLO5HGLWRU'LDUHEHUPDVDODK 6KLJHORVLVProceeding of the QG1DWLRQDO&RQJUHVVRI%DGDQ.RRUGLQDVL*DVWURHQWHURORJL $QDN ,QGRQHVLD %.*$, -XO\ %DQGXQJ ,QGRQHVLD 9. Soetjiningsih, IKG Suandi, Dwi Lingga Utama. Tumbuh NHPEDQJ JL]L'HQSDVDU %DJ60),OPX.HVHKDWDQ$QDN )DNXOWDV.HGRNWHUDQ818'566DQJODK S =XL6KHQ
