Paediatrica Indonesiana VOLUME 51
January
NUMBER 1
Original Article
Comparison of zinc-probiotic combination therapy to zinc therapy alone in reducing the severity of acute diarrhea Muhammad Hatta, Supriatmo1, Muhammad Ali1, Atan Baas Sinuhaji1, Berlian Hasibuan2, Fera Luna Nasution2
Abstract Background Although the incidence of diarrhea in Indonesia has declined in the last five years, the mortality rate in children under five years old is still high. Therefore, appropriate and comprehensive management of diarrhea is essential. There have been many studies on the role of zinc therapy and probiotic therapy in reducing the severity of acute diarrhea, but not many studies have compared the use of a combination of the two therapies to zinc therapy alone. Objective To compare the efficacy of zinc-probiotic combination therapy to zinc alone in reducing the severity of acute diarrhea. Methods We conducted a randomized, open-label, controlled WULDO IURP -XO\ WR -DQXDU\ LQ $GDP 0DOLN +RVSLWDO DQG3LUQJDGL+RVSLWDO0HGDQ&KLOGUHQDJHGEHWZHHQPRQWK and 5 years who met the criteria were divided into two groups. *URXS,UHFHLYHG]LQFVXOSKDWH DJHG PRQWKV PJGD\ DJHG PRQWKV PJGD\ FRPELQHG ZLWK KHDWNLOOHG Lactobacillus acidophilus [&)8GD\ IRUGD\V*URXS,,UHFHLYHGRQO\ zinc sulphate at the same dosage as group I. Measurement of disease VHYHULW\ZDVEDVHGRQWKHIUHTXHQF\RIGLDUUKHD WLPHVGD\ DQGWKH GXUDWLRQRIGLDUUKHD KRXUV DIWHULQLWLDOGUXJFRQVXPSWLRQ Results Eighty subjects were enrolled, randomised, and divided HTXDOO\LQWRWZRJURXSVFKLOGUHQUHFHLYHG]LQFSURELRWLFLQ FRPELQDWLRQ JURXS , DQG WKH UHPDLQGHU JURXS ,, UHFHLYHG zinc alone. We observed significant differences in frequency of GLDUUKHD YVWLPHVGD\3 &,WR DQGGXUDWLRQRIGLDUUKHD YVKRXUV3 &, WR LQWKHWZRJURXSV Conclusion &RPELQDWLRQ RI ]LQFSURELRWLF WKHUDS\ ZDV PRUH effective in reducing the severity of acute diarrhea than zinc therapy alone in children under five years of age. [Paediatr Indones. 2011;51:1-6]. Keywords: acute diarrhea, zinc, probiotic, Lactobacillus acidophilus
'
iarrhea is defined as the passage of unusually loose or watery stools, at least three times LQ D KRXU SHULRG DFFRPSDQLHG E\ changes in stool consistency, with or without blood or mucus in the stool, sometimes accompanied by vomiting.1 Episodes of diarrhea are generally acute, and in certain circumstances may last IRUZHHNVDFRQGLWLRQWHUPHGSHUVLVWHQWGLDUUKHD In Indonesia, diarrhea remains a leading cause of death in infants and children. Based on the +RXVHKROG +HDOWK 6XUYH\ 6.57 GLDUUKHD ZDV UDQNHG WKLUG RI FDXVHV RI GHDWK LQ FKLOGUHQ under five years of age.3 There have been many studies conducted on treatment of acute diarrhea in the last few years, especially involving the use of zinc and probiotics. Zinc has been shown to significantly reduce the frequency, severity, and morbidity of acute diarrhea.4-67KH:RUOG+HDOWK2UJDQL]DWLRQ :+2 UHFRPPHQGV]LQFWKHUDS\IRUDFXWHGLDUUKHD
This study has been presented at 4th$QQXDO6FLHQWLILF0HHWLQJRI&KLOG +HDWOK0HGDQ)HEUXDU\nd²th )URP WKH 'HSDUWPHQW RI &KLOG +HDOWK 0HGLFDO VFKRRO 8QLYHUVLW\ RI 1RUWK6XPDWUD$GDP0DOLN+RVSLWDO0HGDQ1 )URPWKH'HSDUWPHQW RI&KLOG+HDOWK3LUQJDGL+RVSLWDO0HGDQ 5HSULQWUHTXHVWWR 0XKDPPDG+DWWD0''HSDUWPHQWRI&KLOG+HDOWK Medical School, University of North Sumatra$GDP0DOLN+RVSLWDO-O %XQJD/DX1R0HGDQ7HO ²)D[ E-mail:
[email protected]
Paediatr Indones, Vol. 51, No. 1, January 2011 1
Muhammad Hatta et al:&RPSDULVRQRI]LQFSURELRWLFWR]LQFDORQHWKHUDS\LQDFXWHGLDUUKHD
DWDGRVHRIPJIRUFKLOGUHQ PRQWKVDQG PJ IRU FKLOGUHQ PRQWKV IRU WR GD\V *LYLQJSURELRWLFV /DFWREDFLOOXVVS KDVDOVRSURYHG to be effective for treatment of acute diarrhea. The combination of both zinc and probiotics in the diets of children aged less than 1 year has been shown to significantly reduce the severity and duration of diarrhea. =LQF DQG SURELRWLFV ZRUN E\ GLIIHUHQW PHFKD nisms to reduce the severity of acute diarrhea, EXWLWLVQRWNQRZQZKHWKHUDFRPELQDWLRQRIERWKLV more effective than zinc alone in reducing the severity of acute diarrhea. This study was designed to compare the efficacy of zinc-probiotic combination therapy with zinc therapy alone in reducing the severity of acute diarrhea.
Methods We conducted an open, randomized, controlled trial IURP-XO\ XQWLO-DQXDU\LQWKHSHGLDWULF ZDUGRI$GDP0DOLN+RVSLWDODQG3LUQJDGL+RVSLWDO Medan, North Sumatra. We included children aged 1 month to 5 years with acute diarrhea. We excluded those with severe malnutrition, encephalitis, meningitis, sepsis, bronchopneumonia, immunocompromised state, or those who had been JLYHQSURELRWLFVRU]LQFLQWKHODVWGD\V6XEMHFWV were divided into two groups by simple randomization using random tables. Group I received zinc sulfate PJGD\IRUDJH PRQWKVDQGPJGD\IRU PRQWKV DQGKHDWNLOOHG/DFWREDFLOOXVDFLGRSKLOXV [ &)8GD\ RUDOO\ IRU GD\V *URXS ,, received zinc sulfate at a the same dose as Group I. 7KHSURELRWLFVZHUHPL[HGLQWRPLONRUERLOHGZDWHU Zinc sulfate tablets were dissolved in 5 ml of boiled water. Both doctors and parents were aware of the therapies given. We did not perform stool examination because of the high cost required. The cause of diarrhea was GLVWLQJXLVKHGRQO\E\WKHVWRROFRQVLVWHQF\'\VHQWHU\ was characterized by acute diarrhea mixed with blood, while cholera and diarrhea caused by rotavirus was characterized by acute watery diarrhea. We suspected FKROHUD LI V\PSWRPV RFFXUUHG GXULQJ NQRZQ GLDUUKHDO RXWEUHDNV LQYROYLQJ FKLOGUHQ DQG DGXOWV RU IUHTXHQWYROXPLQRXVORRVHVWRROVTXLFNO\OHG
2Paediatr Indones, Vol. 51, No. 1, January 2011
WRVHYHUHGHK\GUDWLRQZLWKK\SRYROHPLFVKRFN RU severe dehydration occurred and antibiotics shortened the duration of diarrhea. Monitoring of the duration and frequency of diarrhea was done during hospitalization and after the patient was discharged. Toxicity and side effects relating to the administration of zinc and probiotics were also observed (nausea, vomiting, abdominal pain, DQGVHSVLV :HGHILQHGUHFRYHU\IURPGLDUUKHDDV KRXUVDIWHUSDVVDJHRIIRUPHGVWRRODQGRUGLVFKDUJHRI WKHSDWLHQW+RPHPRQLWRULQJZDVGRQHE\FRQWDFWLQJ the parents or caregivers by telephone. This study was DSSURYHG E\ WKH 0HGLFDO (WKLFV &RPPLWWHH RI WKH Medical School, University of North Sumatra. We used SPSS version 15 for data analysis. Independent t-test was used to assess the relationship between zinc-probiotic combination therapy and zinc alone as nominal scale with the duration and IUHTXHQF\RIGLDUUKHDDVQXPHULFDOVFDOH'LIIHUHQFHV were considered significant at a probability value of 3 DQG &,2XUVWXG\ZDVDQLQWHQWLRQWR treat analysis-based study.
Results 7KHUHZHUHFKLOGUHQZKRPHWWKHLQFOXVLRQFULWHULD :H GLYLGHG WKHP LQWR WZR JURXSV RI VXEMHFWV each: those who received zinc-probiotic combination WKHUDS\ *URXS, DQGWKRVHZKRUHFHLYHG]LQFWKHUDS\ DORQH *URXS,, Figure 1 ϴϴĞůŝŐŝďůĞƉĂƌƚŝĐŝƉĂŶƚƐ ;ůůŵĂŶĂŐĞĚǁŝƚŚt,KĚŝĂƌƌŚĞĂůŐƵŝĚĞůŝŶĞƐ͕ϮϬϬϱͿ
ŶƌŽůůĞĚĐŚŝůĚƌĞŶ ŶсϴϬ E с ϴϬ
ŝŶĐͲWƌŽďŝŽƚŝĐ;ŐƌŽƵƉ/Ϳ ŶсϰϬ
Completed intervention and included for final analysis n = 40
ϴǁĞƌĞĞdžĐůƵĚĞĚ͗ ϯƐĞǀĞƌĞŵĂůŶƵƚƌŝƚŝŽŶ ϭƉĞƌƐŝƐƚĞŶƚĚŝĂƌƌŚĞĂ ϮĞŶĐĞƉŚĂůŝƚŝƐ ϮŶŽƉĂƌĞŶƚĂůĐŽŶƐĞŶƚ
ŝŶĐĂůŽŶĞ;ŐƌŽƵƉ//Ϳ ŶсϰϬ
Completed intervention and included for final analysis n = 40
Figure 1. Study algorithm.
Muhammad Hatta et al:&RPSDULVRQRI]LQFSURELRWLFWR]LQFDORQHWKHUDS\LQDFXWHGLDUUKHD
The mean frequency of diarrhea before treatment ZDVWLPHVGD\LQWKHFRPELQDWLRQJURXSDQG WLPHVGD\LQWKH]LQFJURXS7KHGXUDWLRQRIGLDUUKHD EHIRUH WUHDWPHQW ZDV KRXUV GD\V LQ WKH FRPELQDWLRQJURXSDQGKRXUV GD\V LQWKH zinc group. (Table 1
'XULQJ WUHDWPHQW WKHUH ZHUH VLJQLILFDQW differences in diarrheal frequency in the two groups from the first to fourth days. (Table 2 1RSDUHQWV or caregivers in either group reported recurrent diarrhea or complained of toxicity or side effects often associated with zinc and probiotics.
Table 1. Baseline characteristics Characteristic Mean age, month (SD) Sex, n Male Female Degree of dehydration, n None Mild-moderate Severe Parental education Father, n Elementary School Junior High School Senior High School Undergraduate Graduate Mother, n Elementary School Junior High School Senior High School Undergraduate Graduate Parental Income/month Father, n < Rp. 500.000 Rp. 500.000 – Rp. 1.000.000 Rp. 1.000.000 – Rp. 3.000.000 > Rp. 3.000.000 Mother, n < Rp. 500.000 Rp. 500.000 – Rp. 1.000.000 Rp. 1.000.000 – Rp. 3.000.000 > Rp. 3.000.000 Mean frequency of diarrhea before treatment, times/day (SD) Mean duration of diarrhea before treatment, hours (SD)
Zinc-Probiotic n=40 27.4 (21.04)
Zinc n=40 21.5 (16.57)
23 17
21 19
0 40 0
0 40 0
4 2 22 10 2
1 4 19 14 2
3 7 22 8 0
0 5 28 3 4
2 15 18 5
0 22 18 0
26 8 6 0 8.2 (3.19)
27 9 4 0 9.2 (2.41)
62.4(18.67)
56 (23.05)
Table 2. Frequency of diarrhea, times/day Day of Intervention
1st 2nd 3th 4th 5th 6th 7th
day day day day day day day
Group I (Zinc-Probiotic) mean (SD) 7.2 (2.72) 4.6 (2.38) 2.1 (1.66) 0.8 (1.44) 0.2 (0.54) 0.0 (0.00) 0.0 (0.00)
Group II (Zinc) mean (SD) 8.8 (2.44) 6.6 (2.59) 3.8 (2.30) 1.8 (2.03) 0.7 (1.47) 0.3 (1.00) 0.0 (0.15)
95% CI
P
- 2.72 to - 0.42 - 3.40 to - 1.19 - 2.59 to - 0.80 - 1.86 to - 0.28 - 0.97 to 0.21 - 0.56 to 0.67 - 0.75 to 0.02
0.008 0.001 0.001 0.008 0.60 0.120 0.320
Paediatr Indones, Vol. 51, No. 1, January 2011 3
Muhammad Hatta et al:&RPSDULVRQRI]LQFSURELRWLFWR]LQFDORQHWKHUDS\LQDFXWHGLDUUKHD
In this study, the frequency and duration of diarrhea, as well as length of hospital stay were lower in the combination group than in the zinc group 3 Table 3
acidophilus, as it may be just as effective and may have fewer side effects compared to live probiotics. There was no standard dose of probiotic administration for acute diarrhea. Often the provisions of probiotic
Table 3. Frequency and duration of diarrhea, and length of hospital stay
Frequency of diarrhea (times/day) Duration of diarrhea (hours) Length of stay (hours)
Group I (Zinc-Probiotic) mean (SD) 2.1 (1.04) 52.1 (22.54) 56.7 (19.39)
Group II (Zinc) mean (SD) 3.1 (1.44) 72.6 (23.99) 98.5 (23.82)
95% CI
P
- 1.62 to - 0.49 - 30.91 to - 10.18 - 51.49 to - 32.15
0.001 0.001 0.001
Where does 2.1 and 3.1 in table 3 come from?
Discussion The mean age of children with acute diarrhea was PRQWKV LQ WKH FRPELQDWLRQ JURXS DQG months in the zinc group. There were more males in HDFKJURXS 7DEOH 3UHYLRXVHSLGHPLRORJLFDOVWXGLHV found that children with acute diarrhea caused by URWDYLUXVZHUHDJHGWRPRQWKV15,16 The majority of previous studies did not analyze the difference in diarrhea incidence between sexes. One study of GLDUUKHDLQKRVSLWDOL]HGFKLOGUHQDJHGWRPRQWKV found that the incidence of acute diarrhea was higher in boys, but did not discuss possible theories for this occurrence. In children under five years old, acute diarrhea is usually caused by rotavirus infection. Previous studies using live Lactobacillus acidophilus reported a significant benefit in reducing the severity of diarrhea caused by rotavirus infection.+RZHYHU,QGRQHVLDQV RIWHQGLVVROYHPLONRUIRRGLQKRWZDWHUWKXVNLOOLQJ the Lactobacillus acidophilus. This habit may not be DSUREOHPDVVHYHUDOVWXGLHVIRXQGWKDWKHDWNLOOHG Lactobacillus acidophilus is still able to stimulate gastrointestinal immunity.)XUWKHUPRUHRQHVWXG\ IRXQGWKDWKHDWNLOOHG/DFWREDFLOOXVDFLGRSKLOXVZDV even more effective in reducing symptoms of persistent diarrhea than live Lactobacillus acidophilus. It is thought that in addition to improving gastrointestinal LPPXQLW\KHDWNLOOHG/DFWREDFLOOXVDFLGRSKLOXVFDQ also prevent the adhesion of enteropathogens to enterocytes. Also, occurrence of sepsis in premature infants, the elderly, and immunocompromised patients has been reported after live, probiotic administration. )RUWKHVHUHDVRQVZHXVHGKHDWNLOOHG/DFWREDFLOOXV
4Paediatr Indones, Vol. 51, No. 1, January 2011
manufacturers were used. In our study, we gave SURELRWLFV RQFH SHU GD\ DW D GRVH RI [ &)8 for ten days to coincide with the duration of zinc administration. =LQFWR[LFLW\PD\RFFXULIPRUHWKDQJUDPVSHU day is consumed for long periods. Manifestations of zinc toxicity are nausea, vomiting, abdominal pain and fever.:HJDYHPJPJRI]LQFSHUGD\7KH possibility of zinc toxicity in our subjects was small, but it would be difficult to attribute symptoms (nausea, YRPLWLQJDEGRPLQDOSDLQDQGIHYHU WR]LQFWR[LFLW\ during the diarrheal illness. Previous studies assessed the severity of diarrhea based on the frequency, duration, and stool FRQVLVWHQF\,QRXUVWXG\ZHDVVHVVHGWKHVHYHULW\RI GLDUUKHDEDVHGRQIUHTXHQF\ WLPHVGD\ DQGGXUDWLRQ KRXUV $VVHVVPHQWRIWKHVWRROFRQVLVWHQF\ZDVQRW included because it was subjective and difficult to agree to a standard assessment scale. We found a significant difference in the decrease in diarrheal severity in the two groups. Shamir et al. reported similar results, but with shorter duration and lower frequency. A possible reason for this difference is their use of live, multi-strain probiotics (Streptococcus thermophilus, Bifidobacterium lactis, DQG/DFWREDFLOOXVDFLGRSKLOXV ZKLFKPD\EHPRUH HIIHFWLYHWKDQDVLQJOHVWUDLQRIKHDWNLOOHG/DFWREDFLOOXV acidophilus. One in vitro study concluded that live Lactobacillus acidophilus improved the transport of electrolytes in intestinal epithelial cells better than KHDWNLOOHG /DFWREDFLOOXV DFLGRSKLOXV +RZHYHU KHDWNLOOHG SURELRWLFV DUH VWLOO XVHIXO LQ WKH WKHUDS\ of acute diarrhea in children, because they are still effective even if mixed with hot water, and they are less expensive than live, multi-strain probiotics.
Muhammad Hatta et al:&RPSDULVRQRI]LQFSURELRWLFWR]LQFDORQHWKHUDS\LQDFXWHGLDUUKHD
We found no obvious reasons why the frequency of diarrhea in the fifth to seventh days of therapy did not differ in both groups. Anggarwal et al. used zinc supplementation and found that the duration of diarrhea after therapy was 3 days.4 We had similar results in our study. Length of hospital stay cannot be used as an indicator of therapeutic success due to many other factors that affect the length of patient hospitalization, such as time delays in hospital discharge caused by the parents’ requests or payment issues. In our study, ZHPRQLWRUHGWKHUHVXOWVRQO\XSWRGD\VEHFDXVH QR GLDUUKHD ZDV SUHVHQW E\ WKH WK GD\ RI WKHUDS\ +RZHYHUWKHUDS\ZDVJLYHQIRUGD\V,WDSSHDUV that intestinal recovery in acute diarrhea occurs ZLWKLQWRGD\V Limitations of this study were that the etiology RIGLDUUKHDZDVXQNQRZQDQGWKLVZDVQRWDGRXEOH blind study, although randomization was done to reduce bias. We conclude that a combination of zinc and probiotic therapy is more effective than zinc therapy alone in reducing the severity of acute diarrhea in children under five years.
11.
Acknowledgements :HWKDQN37.DOEH)DUPDIRUWKHSURYLVLRQRI]LQFVXOIDWHDQG probiotic preparations in this study. All authors have no conflict of interest on the data and conclusion reported in this paper.
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cholera in Bangladesh: randomised controlled trial. BMJ. 6XU'*XSWD'10RQGDO6.*KRVK60DQQD%5DMHQGUDQ .HWDO,PSDFWRI]LQFVXSSOHPHQWDWLRQRQGLDUUKHDOPRUELGLW\ DQGJURZWKSDWHUUQRIORZELUWKZHLJKWLQIDQWVLQ.RONDWD India: a randomized, double-blind, placebo-controlled, FRPPXQLW\EDVHGVWXG\3HGLDWULFV :+27KHWUHDWPHQWRIGLDUUKHDDPDQXDOIRUSK\VLFLDQV DQGRWKHUVHQLRUKHDOWKZRUNHUVWKUHYLVLRQ*HQHYD :+2 3UHVV SDJH""" 9DQ1LHO&:)HXGWQHU&*DUULVRQ00&KULVWDNLV'$ Lactobacillus therapy for acute infectious diarrhea in FKLOGUHQ DPHWDDQDO\VLV3HGLDWULFV 6KDPLU50DNKRXO,5(W]LRQL$6KHKDGHK1(YDOXDWLRQ of a diet containing probiotics and zinc for the treatment of mild diarrheal illness in children younger than one year of DJH-$P&ROO1XWU $UPLQ6$=DWJL]LPLNUR]LQNGDULDVSHNPROHNXOHUVDPSDL SDGDSURJUDPNHVHKDWDQPDV\DUDNDW6XSOHPHQW 35. Wapnir RA. Zinc deficiency, malnutrition and the JDVWURLQWHVWLQDOWUDFW-1XWU 6 6 $OWDI:3HUYHHQ65HKPDQ.87HLFEHUJ69DQFXURYD, +DUSHU5*HWDO=LQFVXSSOHPHQWDWLRQLQRUDOUHK\GUDWLRQ solutions: experimental assessment and mechanisms of DFWLRQ-$P&ROO1XWU +RTXH.05DMHQGUDQ90%LQGHU+-=LQFLQKLELWVF$03 VWLPXODWHG&OVHFUHWLRQYLDEDVRODWHUDO.FKDQQHOEORFNDGH in rat ileum. Am J Physiol Gastrointest Liver Physiol. * ,VRODXUL(.LUMDYDLQHQ396DOPLQHQ63URELRWLFV DUROHLQ WKHWUHDWPHQWRILQWHVWLQDOLQIHFWLRQDQGLQIODPPDWLRQ"*XW LLL 1JX\HQ 79 /H 9DQ 3 /H +X\ & :HLQWUDXE $ 'LDUUKHD caused by rotavirus in children less than 5 years of age in +DQRL9LHWQDP-&OLQ0LFURELRO ² .KDQ6$$KPHG$.KDOLG60'LDUUKHDGXHWRURWDYLUXV and probability of sewage contamination. J Islamic Acad Sci. +XVVHLQ $0 +DVVDQ 0. 5RWDYLUXV LQIHFWLRQ DPRQJ hospitalized children with acute watery diarrhea in Basrah ²,UDT%DKUDLQ0HG%XOO $OEHUW0-)DUXTXH$6*)DUXTXH606DFN5%0DKDODQLV % &DVH FRQWURO VWXG\ RI HQWHURSDWKRJHQV DVVRFLDWHG ZLWK FKLOGKRRGGLDUUKHDLQ'KDND%DQJODGHVK-&OLQ0LFURELRO 6XSULDWPR (IIHFWLYLW\ RI OLYH YHUVXV KHDW NLOOHG SURELRWLF LQ FKLOGUHQ ZLWK DFXWH GLDUUKRHD 0DM .HGRNW 1XV
Paediatr Indones, Vol. 51, No. 1, January 2011 5
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