JOURNAL READING

Effects of zinc or symbiotic on the duration of diarrhea in children

with Acute infectious diarrhea

Oleh:
Alya Annisa
NIM: 1911901005

Pembimbing :
dr. Cherlina, Sp.A, [Link]

KEPANITRAAN KLINIK SENIOR

BAGIAN ILMU ANAK RSUD BANGKINANG
FAKULTAS KEDOKTERAN UNIVERSITAS ABDURRAB
PEKANBARU
2020
Effects of zinc or synbiotic on the duration of diarrhea in
children with acute infectious diarrhea
BOWEL
Ahmet Sami Yazar1, Şirin Güven1, Ener Çağrı Dinleyici2
Department of Pediatrics, Ümraniye Training and Research Hospital, İstanbul, Turkey
1

Department of Pediatrics, Eskişehir Osmangazi University School of Medicine, Eskişehir, Turkey

2

ABSTRACT
Background/Aims: Probiotic effects on acute infectious diarrhea are strain(s) specific, and all
formulations should be evaluated by clinical trials. We aimed to evaluate the effect of a synbiotic
preparation on the duration of diarrhea in children compared to a zinc suspension.
Materials and Methods: We conducted a single-center, randomized, and controlled clinical trial in children with acute
infectious diarrhea. The first group received a synbiotic preparation containing Lactobacillus casei, L. plantarum, L.
rhamnosus, Bifidobacterium lactis and prebiotics; the second group received a zinc suspension (15 mg/day) for 5
days in addition to oral rehydration solution (ORS) and/or intravenous therapy. The third group received ORS and/or
intravenous therapy (control group). The primary endpoint was the duration of diarrhea (in hours). The secondary
endpoint was the percentage of children with diarrhea during each day of intervention.
Results: The duration of diarrhea was significantly reduced in the synbiotic and the zinc groups
compared to the control group (91.0±28.9 hours vs. 114.3±30.9 hours, p<0.001; 86.4±30.8 hours
vs. 114.3±30.9 hours, p<0.001, respectively). There was no significant difference in the duration of
diarrhea between the synbiotic and zinc groups (p>0.05). At 72 nd and 96th hours, the percentage of
children with diarrhea was lower in the zinc group than in the synbiotic group (p<0.05 for both).
Conclusion: Our study showed that zinc or synbiotic supplementation reduced the duration of diarrhea, with
better clinical outcomes at 72nd and 96th hours, and both can be used in children with acute diarrhea. To the
best of our knowledge, this was the first study to make a comparison between zinc and synbiotics.
Keywords: Synbiotics, zinc, acute diarrhea, children

Original Article
INTRODUCTION ducted meta-analyses are now available about the use
Acute infectious diarrhea still remains a leading cause of of probiotics for treatment of acute diarrhea; however,
morbidity and hospitalization in developed countries, the effects of probiotics on acute infectious diarrhea
and also a cause of mortality in low resource countries are strain-specific (4-8). There are several studies about
(1,2). Recent clinical studies and guidelines proposed the use of synbiotic preparations with different strains,
some complementary therapies for acute infectious and all of these combinations should be evaluated for
diarrhea, such as zinc and probiotics, in addition to their effectiveness (3,9-11). We aimed to evaluate the ef-
the mainstay treatment with oral rehydration solution fect of synbiotic preparations (containing Lactobacillus
(ORS) (3). There are contradictory results about the zinc casei, Lactobacillus rhamnosus, Lactobacillus plantarum,
supplementation for acute infectious diarrhea during Bifidobacterium lactis, and prebiotics) and zinc on the
childhood. The beneficial effects of zinc supplemen- duration of diarrhea in children.
tation have been shown in children aged >6 months
in developing countries; however, current European MATERIALS AND METHODS
guidelines suggest that zinc supplementation has no We conducted a single-center, randomized, parallel
effect on acute diarrhea when zinc deficiency is rare group, controlled, clinical trial in outpatient children (6–
(4). Many randomized, controlled studies and well-con- 120 months) with acute infectious diarrhea in Turkey.

Address for Correspondence: Ener Çağrı Dinleyici E-mail: timboothtr@[Link]

Received: August 9, 2016 Accepted: October 3, 2016
© Copyright 2016 by The Turkish Society of Gastroenterology • Available online at [Link] • DOI: 10.5152/tjg.2016.16396

537
 114.3±30.9 hours, p<0.001, respectively). The duration of
Yazar et al. Zinc or synbiotic effects on acute diarrhea was significantly re-duced (~28 hours) in the zinc
diarrhea
group compared to the control

The study protocol was approved by the local ethical commit-

tee. Informed consent was obtained from all parents.
Children with severe dehydration and/or requiring intensive
care unit stay were excluded. Other exclusion criteria were
the use of antibiotics or probiotics up to 8 weeks before
admission, mal-nutrition, and chronic underlying diseases. All
children were randomly assigned to 3 interventions
(synbiotic, zinc or control group) according to a computer-
generated randomization list.

The first group received synbiotic preparations (NBL Probiotic

ATP® sachet, Nobel İlaç, Turkey; one sachet per day)
contain-ing L. casei, L. rhamnosus, L. plantarum, B. lactis
(4.5×109 CFU in total), prebiotics such as fructose and
galactooligosaccharides and polydextrose (1996.57 mg),
Vitamin C, Vitamin E, ribofla-vin, pyridoxine, and thiamine for
5 days in addition to ORS with or without intravenous
therapy. The second group received a zinc suspension (15
mg per day for 5 days, Berko İlaç; Turkey) in addition to ORS
and/or intravenous therapy. The third group (controls)
received ORS and/or intravenous therapy only.

Upon admission, demographic and clinical findings (fever,

body weight, and degree of dehydration) of the patients
were recorded. A fluid/electrolyte replacement was
performed us-ing hypo-osmolar ORS based on the status
of each patient. The primary endpoint was the duration of
diarrhea. The secondary endpoint was the number of
children with diarrhea at the third day of intervention and
each day of the five-day intervention. Consistency and
Original Article

frequency of each stool were recorded. The duration of

diarrhea was defined as the time in hours from ad-mission
until cessation of diarrhea, which was defined as the first
normal stool. Stool evaluation was made according to the
Bristol score, where a score <5 was described as normal.
The forms were filled out by the parents.

Statistical Analysis
Statistical analysis was performed using the SPSS 16.0
software (SPSS Inc.; Chicago, IL, USA). Variables were
evaluated for nor-mal distribution, and comparisons were
tested using a t-test and χ2 or Fisher’s exact tests as
appropriate. Risk ratio and a 95% confidence interval were
used for comparisons between synbiotic group and controls,
and zinc group and controls. Risk difference and a 95%
confidence interval were used for com-parisons between the
synbiotic group and the zinc group. Sta-tistical significance
was set at p<0.05.

RESULTS
The study included 165 children (55 in synbiotic group, 55 in
zinc group, and 55 in the control group). The mean age and
sex of the children in the synbiotic, zinc, and control groups
were similar (p>0.05) (Table 1). Presence of dehydration was
similar in all three groups. The duration of diarrhea was
significantly reduced (~24 hours) in the synbiotic group
compared to the control group (91.0±28.9 hours vs.
 ours, p<0.001,
respec-tively). No statistical (p<0.05). At 96 hours of intervention, the percentage of
Turk J Gastroenterol 2016; 27: 537-
40 significance was observed between the synbiotic children with diarrhea was lower in the zinc group compared
and zinc groups (91.0±28.9 hours vs. 86.4±30.8 to the synbiotic group (p<0.05). There was no difference in
hours, p>0.05, respectively) (Table 1). the percentage of diarrhea-free children between the zinc and
gr
probiotic groups (p>0.05).
o
No effect on diarrhea was observed at 24 th hours of synbiotic
u Table 1. Demographic findings and duration of diarrhea in the stud
intervention. The effects of synbiotics (diarrhea-free percent-
p groups
age of children) started to be observed by 48 hours (Table 2).
(8 Synbiotic group Zinc group Controls
At Day 3, 61.8% of the children receiving synbiotics still had
6. (n=55) (n=55) (n=55)
wa-tery diarrhea while 83.6% of the controls had watery
4
diarrhea (p=0.01). At 96 and 120 hours of intervention, the Age (months) 36.4±32.7 54.9±44.3b 49.5±37.6
±
diarrhea-free percentage of children was still lower in the Sex (Girls/Boys) 24/31 28/27 28/27
3
synbiotic group than in the control group (p<0.01 for both)
0. Duration of diarrhea (hours) 91.0±28.9a 86.4±30.8b 114.3±30.9
(Table 2).
8 *Values of age, duration of diarrhea, and length of hospital/ER stay are expressed
h as mean±SD. ap<0.001; synbiotic vs. control group. bp<0.001; zinc vs. control group
The effects (diarrhea-free percentage of children) of
o
the zinc started to be observed at 48 hours of
ur Table 2. Percentage of children with diarrhea at Day 3 and
intervention (Table 3). After 48 hours, 81.8% of the
s Day 5 in the synbiotic and control groups
children receiving zinc still had wa-tery diarrhea while it
v Synbiotic group Control group
98% of the children in the control group still had watery
s. (n=55) (n=55) RR (95% CI) p
diarrhea (p=0.01). After 72, 96, and 120 hours, the
1 24th hour 54/55 (98.1%) 55/55 (100%) 0.98 (0.93–1.03) p>0.05
number of children receiving zinc who still had watery
1
di-arrhea was significantly lower compared to the 48th hour 45/55 (81.8%) 54/55 (98.1%) 0.83 (0.73–0.95) p<0.01
4.
control group (p<0.01 for all groups).
3 72nd hour 34/55 (61.8%) 46/55 (83.6%) 0.74 (0.58–0.94) p=0.01
± The effect of synbiotics and zinc was similar at 24 and 48 96th hour 15/55 (27.2%) 30/55 (54.5%) 0.50 (0.30–0.82) p<0.01
3 hours of intervention (p>0.05) (Table 4). At 72 hours, 45.4% 120th hour 4/55 (7.2%) 16/55 (29%) 0.25 (0.09–0.70) p<0.01
0. of children receiving zinc still had watery diarrhea, which was
9 RR: relative risk; CI: confidence interval
significantly lower than in the synbiotic group with 61.8%,
h

538

h
Turk J Gastroenterol 2016; 27: 537-40 DISCUSSION o
The initial therapy recommended for acute diarrhea is treat- ur
Table 3. Percentage of children with diarrhea at Day 3 and ment with oral fluids and use of ORS (4). However, ORS nei- s,
Day 5 in the zinc and control groups ther reduces the frequency of fluid loss or bowel movements wi
Zinc group Control group nor shortens the duration of diarrhea; therefore, further ad- th
(n=55) (n=55) RR (95% CI) p junctive therapy options have been extensively studied (3). In a
24th hour 55/55 (100%) 55/55 (100%) 1.00 (0.97–1.04) p>0.05 the present study, the synbiotic formulation reduced the b
duration of diarrhea for approximately 24 hours, with a simi- et
48th hour 46/55 (83.6%) 54/55 (98.1%) 0.85 (0.75–0.96) p=0.01
lar efficacy to other clinical studies and guidelines related to te
72nd hour 25/55 (45.4%) 46/55 (83.6%) 0.54 (0.40–0.74) p<0.001
other probiotic strains (3,4,8,12). Our study was the first to r
96th hour 8/55 (14.5%) 30/55 (54.5%) 0.27 (0.13–0.53) p<0.001 evaluate the effect of synbiotic preparations containing L. o
120th hour 6/55 (10.9%) 16/55 (29%) 0.38 (0.16–0.89) p<0.05 casei, L. plantarum L. rhamnosus, and B. lactis. These are ut
well-known and commonly studied bacterial strains as c
RR: relative risk; CI: confidence interval
probiotics for different clinical conditions; however, probiotic o
effects on acute infectious diarrhea are strain(s) specific, and m
Table 4. Percentage of children with diarrhea at Day 3 and all formula-tions should be evaluated by clinical trials (4). In e
Day 5 in the synbiotic and zinc groups
the present study, the effects of synbiotic preparations started at
Synbiotic group Zinc group Risk difference to be ob-served at 48 hours; and at 96 hours of intervention, 4
(n=55) (n=55) (95% CI) p the per-centage of diarrhea-free children was 73% while it 8
24th hour 54/55(98.1%) 55/55 (100%) -0.02 (-0.07–0.03) p>0.05 was 45% in the control group. Our previous study with a
48th hour 45/55(81.8%) 46/55 (83.6%) -0.02 (-0.16–0.12) p>0.05 another synbiotic preparation containing L. rhamnosus L. n
acidophilus, B. bifidum, B. longum, Enterococcus faecium d
72nd hour 34/55(61.8%) 25/55 (45.4%) 0.16 (-0.02–0.35) p<0.05
(2.5×109 CFU in total of live bacteria daily) and 625 mg
96th hour 15/55(27.2%) 8/55 (14.5%) 0.13 (-0.02–0.28) p<0.05 fructooligosaccharide for 5 days had also shown significant
120th hour 4/55(7.2%) 6/55 (10.9%) -0.04 (-0.14–0.07) p>0.05 reduction in the duration of di-arrhea. The duration was
reduced approximately 36 hours in children with acute
CI: confidence interval
infectious diarrhea, and the effects were visible after 24th
72 hours of intervention (9). Two studies conducted in ac
Yazar et al. Zinc or synbiotic effects on acute diarrhea
Belgium ut
e
(11) (Streptococcus thermophilus, L. rhamnosus, L B. lactis, B. infantis, and fructooligosaccharide) and Italy (10) di
acidophilus, (Lactobacillus paracasei B21060 with arabinogalactan and ar
xy-looligosaccharides) (4) also showed promising results rh
related to the effects of synbiotics on acute infectious ea
diarrhea. Cur-rent ESPID/ESPGHAN guidelines does not .
recommend any of the studied synbiotics (each combination
with only one clini-cal study) until further confirmatory studies
are available (4). For strong recommendation, further studies
are needed for the same synbiotic preparations in different
clinical settings.

Many studies have reported on the efficacy of zinc for treat-

ment of acute diarrhea during childhood, and contradictory re-
sults have been published concerning the geographical
region and age (3, 4). Zinc deficiency is a major determinant
factor of immunity and low weight in developing countries,
and both are related with the duration of diarrhea (13-15). The
adminis-tration of zinc was shown to reduce the duration of
the diarrhea as well as frequency and amount of the stool in
randomized controlled trials and reviews (16-18). The World
Health Orga-nization recommends routine use of zinc
supplementation, at a dosage of 20 mg per day for children
older than six months. In our study, we preferred to use a
standard dose of 15 mg per day with a liquid formulation. The
duration of diarrhea was sig-nificantly reduced in the zinc
group compared to the control group (approximately 28
hours). The effect of the zinc prepara-tion started to be
observed at 48 hours of intervention. At 72 and 96 hours, the
zinc group had less diarrhea compared to the control group
(45% vs. 86%, respectively). A meta-analysis (including 18
clinical trials with 6165 participants) showed that zinc
supplementation resulted in a shorter diarrhea duration in
acute diarrhea, and less diarrhea at Day 3 and Day 5, similar
to our results (17). In contrast to other studies, a recently
made double-blind randomized study about zinc
supplementation for acute diarrhea in Switzerland showed
that zinc treatment decreases the frequency and severity of
diarrhea in children aged 2 months to 5 years old, but not the
duration of diarrhea (20). In developing countries, zinc
supplementation might be useful in the treatment of acute
diarrhea for children older than 6 months. However, no benefit
from the use of zinc was docu-mented in regions where zinc
deficiency is rare (4).

We found no significant difference between the synbiotic and

zinc groups (91.0±28.9 hours vs. 86.4±30.8 hours); however,
it seems that zinc supplementation had a faster effect than
the synbiotic supplementation, and the percentage of
diarrhea-free children was significantly higher in the zinc
group than in the synbiotic group at 72 and 96 hours of
intervention. By the fifth day, the significance between the two
groups disappeared. There was also no significant difference
between the synbiotic and zinc groups in the duration of
diarrhea (91.0±28.9 hours vs. 86.4±30.8 hours, respectively).
To our knowledge, this was the first study to make a
comparison between zinc and synbiotics. Further studies with
larger cohorts are required to clarify the ef-fect of zinc and/or
synbiotics on fecal microbiota composition in children with
Original Article
539
Nutrition/European Society for Pediatric Infectious Diseases
Yazar et al. Zinc or synbiotic effects on acute evidence-based guidelines for the management of acute
diarrhea gastroenteritis in children in Europe: update 2014. J Pediatr
Gastroenterol Nutr 2014; 59: 132-52.
Our study had some limitations. We did not perform a stool
analysis for etiological causes of acute infectious diarrhea,
and had no chance to evaluate the effects of zinc or
synbiotics on different etiological causes of diarrhea. This
study was not a placebo-controlled study. Despite
randomization of three in-terventions, the children in the zinc
group were found to be older than the other groups, and we
had no chance to evaluate the age-specific effects of zinc on
the duration of diarrhea.

In children with acute diarrhea, our study showed that zinc

or synbiotic supplementation reduced the duration of
diarrhea. Children receiving zinc or synbiotics were more
likely to be diarrhea-free after the first 48 hours of
intervention, with better outcomes at 72 and 96 hours.
Zinc or synbiotic preparations containing Lactobacillus
rhamnosus, Lactobacillus casei, Lacto-bacillus plantarum,
Bifidobacterium lactis, and prebiotics may be used in
children with acute diarrhea.

Ethics Committee Approval: Ethics committee approval was

received for this study from the ethics committee of Clinical Trials
Ethical Com-mitee of Ümraniye Training and Research Hospital (24
March 2016).
Informed Consent: Written informed consent was
obtained from the parents of the patients who participated
in this study.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept - A.S.Y., S.G., E.C.D.; Design -
A.S.Y., S.G., E.C.D.; Supervision - E.C.D.; Funding - A.S.Y., S.G.;
Materials - A.S.Y., S.G.; Data Collection and/or Processing - A.S.Y.,
S.G.; Analysis and/or Inter-pretation - E.C.D.; Literature Review -
Original Article

A.S.Y., S.G., E.C.D.; Writer - A.S.Y., S.G., E.C.D.; Critical Review -

E.C.D.
Conflict of Interest: Ener Çağrı Dinleyici is a consultant
and speaker for Biocodex.
Financial Disclosure: The authors declared that this
study has re-ceived no financial support.

REFERENCES
1. Walker CL, Rudan I, Liu L, et al. Global burden of
childhood pneu-monia and diarrhoea. Lancet 2013; 381:
1405-16.
2. Leung DT, Chisti MJ, Pavia AT. Prevention and
Control of Child-hood Pneumonia and Diarrhea.
Pediatr Clin North Am 2016; 63: 67-79.
3. Pieścik-Lech M, Shamir R, Guarino A, Szajewska H.
Review article: the management of acute
gastroenteritis in children. Aliment Pharmacol Ther
2013; 37: 289-303.
4. Guarino A, Ashkenazi S, Gendrel D, Lo Vecchio A, Shamir
R, Sza-jewska H; European Society for Pediatric
Gastroenterology, Hepa-tology, and Nutrition; European
Society for Pediatric Infectious Diseases. European Society
for Pediatric Gastroenterology, Hepa-tology, and
 for Probiotic Use--2015 Update: Proceedings and Section on Gastroenterology, Hepatology, and Nutrition.
Turk J Gastroenterol 2016; 27: 537-
Consensus Opin-ion. J Clin Gastroenterol 2015; 49(Suppl Probiotics and pre-biotics in pediatrics. Pediatrics 2010; 126:
40
1): S69-73. 1217-31.
6. Cruchet S, Furnes R, Maruy A, et al. The use of 13. Black RE, Brown KH, Becker S. Malnutrition is a
5. Fl
probiotics in pe-diatric gastroenterology: a review of determining factor in diarrheal duration, but not
oc
the literature and recom-mendations by Latin- incidence, among young children in a longitudinal
h
American experts. Paediatr Drugs 2015; 17: 199-216. study in rural Bangladesh. Am J Clin Nutr 1984; 39:
M
7. Dinleyici EC; PROBAGE Study Group, Vandenplas Y. 87-94.
H,
Lactobacillus reuteri DSM 17938 effectively reduces the duration 14. Baqui AH, Sack RB, Black RE, Chowdhury HR, Yunus M,
W
of acute diar-rhoea in hospitalised children. Acta Paediatr 2014; Siddique AK. Cell-mediated immune deficiency and
al
103: e300-5. malnutrition are inde-pendent risk factors for persistent
ke
8. Dinleyici EC, Eren M, Ozen M, Yargic ZA, Vandenplas Y. diarrhea in Bangladeshi chil-dren. Am J Clin Nutr 1993; 58:
r
Effective-ness and safety of Saccharomyces boulardii for 543-8.
W
acute infectious diarrhea. Expert Opin Biol Ther 2012; 12: 15. Sandstead HH. Is zinc deficiency a public health
A,
395-410. problem? Nutri-tion 1995; 11: 87-92.
S
9. Dinleyici EC, Dalgic N, Guven S, et al. The effect of a 16. Trivedia SS, Chudasamab RK, Patel N. Effect of zinc
an
multispe-cies synbiotic mixture on the duration of supplementa-tion in children with acute diarrhea:
de
diarrhea and of hospital stay in children with acute Randomized double blind controlled trial. Gastroenterol Res
rs
diarrhea in Turkey. Eur J Ped 2013; 172: 459-64. 2009; 2: 168-74.
M
10. Passariello A, Terrin G, Cecere G, et al. Randomised 17. Lazzerini M, Ronfani L. Oral zinc for treating diarrhea
E,
clinical trial: efficacy of a new synbiotic formulation in children. Cochrane Database Syst Rev 2008:
et
containing Lactobacillus paracasei B21060 plus CD005436.
al.
arabinogalactan and xilooligosaccharides in children 18. Patel A, Mamtani M, Dibley MJ, Badhoniya N, Kulkarni H.
R
with acute diarrhoea. Aliment Pharm Ther 2012; 35: Thera-peutic value of zinc supplementation in acute and
ec
782-8. persistent di-arrhea: a systematic review. Plos One 2010; 5:
o
11. Vandenplas Y, De Hert SG; PROBIOTICAL-study e10386.
m
group. Ran-domised clinical trial: the synbiotic food 19. [Link]
m
supplement Probiotical vs. placebo for acute 20. Crisinel PA, Verga ME, Kouame KS, et al.
en
gastroenteritis in children. Aliment Pharma-col Ther Demonstration of the ef-fectiveness of zinc in diarrhea
da
2011; 34: 862-7. of children living in Switzerland. Eur J Pediatr 2015;
tio
12. Thomas DW, Greer FR; American Academy of Pediatrics 174: 1061-7.
ns
Com-mittee on Nutrition; American Academy of Pediatrics

540

EFEK ZINC DAN SINBIOTIK TERHADAP DURASI DIARE PADA ANAK

DENGAN DIARE INFEKSI AKUT

Ahmet Sami Yazar, Şirin Güven, Ener Çağrı Dinleyici

Abstrak

Latar Belakang/Tujuan: Efek probiotik terhadap diare infeksi akut bersifat spesifik untuk strain tertentu,
dan semua formulasi harus dievaluasi dengan uji klinis. Kami bertujuan untuk mengevaluasi efek preparat
simbiotik terhadap durasi diare pada anak-anak dan membandingkannya dengan suspensi zinc.
 
Bahan dan Metode: Kami melakukan uji klinis acak terkontrol single-center pada anak-anak dengan diare
infeksi akut. Kelompok pertama menerima preparat sinbiotik yang mengandung Lactobacillus casei, L.
plantarum, L. rhamnosus, Bifidobacterium lactis, dan prebiotik; kelompok kedua menerima suspensi zinc
(15 mg/hari) selama 5 hari di samping larutan rehidrasi oral/oral rehydration solution (ORS) dan/atau
terapi intravena. Kelompok ketiga menerima ORS dan/atau terapi intravena (kelompok kontrol). Titik
akhir primer adalah durasi diare (dalam jam). Titik akhir sekunder adalah persentase anak-anak yang
mengalami diare selama intervensi.
 
Hasil: Durasi diare berkurang secara signifikan pada kelompok sinbiotik dan zinc, dibandingkan dengan
kelompok kontrol (masing-masing 91,0 ± 28,9 jam vs 114,3 ± 30,9 jam, p <0,001; 86,4 ± 30,8 jam vs
114,3 ± 30,9 jam, p <0,001). Tidak ada perbedaan yang signifikan dalam durasi diare antara kelompok
sinbiotik dan zinc (p >0,05). Pada jam ke-72 dan ke-96, persentase anak-anak yang mengalami diare lebih
rendah pada kelompok zinc dibandingkan dengan kelompok sinbiotik (p <0,05).
 
Kesimpulan: Penelitian kami menunjukkan bahwa suplementasi zinc atau sinbiotik dapat mengurangi
durasi diare, dengan hasil klinis yang lebih baik pada jam ke-72 dan ke-96, dan keduanya dapat digunakan
pada anak-anak dengan diare akut. Sepengetahuan kami, studi ini adalah studi pertama yang membuat
perbandingan antara zinc dan sinbiotik.
 
Pendahuluan
 
Diare infeksi akut masih tetap menjadi penyebab utama morbiditas dan rawat inap di negara maju, dan
juga merupakan penyebab kematian di negara berkembang. Selain terapi dengan larutan rehidrasi oral/oral
rehydration solution (ORS), berbagai studi klinis terbaru dan pedoman yang telah diterbitkan telah
mengusulkan beberapa terapi komplementer untuk diare infeksi akut, seperti zinc dan probiotik. Hasil
penelitian mengenai suplementasi zinc untuk diare infeksi akut selama masa kanak-kanak masih bersifat
kontradiktif. Efek menguntungkan dari suplementasi zinc telah ditunjukkan pada anak-anak berusia >6
bulan di negara-negara berkembang; Namun, pedoman terbaru di Eropa menunjukkan bahwa suplementasi
zinc tidak memiliki efek pada diare akut, ketika defisiensi zinc jarang terjadi. Saat ini, terdapat berbagai uji
klinis acak terkontrol dan meta-analisis berkualitas tinggi mengenai penggunaan probiotik untuk
pengobatan diare akut yang telah diterbitkan; Namun, efek probiotik terhadap diare infeksi akut bersifat
spesifik strain. Ada beberapa studi mengenai penggunaan sediaan sinbiotik dengan strain yang berbeda-
beda, dan semua kombinasi ini harus dievaluasi efektivitasnya. Penelitian ini bertujuan untuk
mengevaluasi efek preparat sinbiotik (mengandung Lactobacillus casei, Lactobacillus rhamnosus,
Lactobacillus plantarum, Bifidobacterium lactis, dan prebiotik) dan zinc terhadap durasi diare pada anak-
anak.
 
Bahan dan metode
 
Kami melakukan uji klinis acak terkontrol dengan kelompok paralel single-center pada anak-anak yang
menjalani rawat jalan (6- 120 bulan) karena diare infeksi akut di Turki. Protokol penelitian telah disetujui
oleh komite etik lokal. Informed consent telah diperoleh dari seluruh orang tua partisipan. Anak-anak
dengan dehidrasi berat dan/atau membutuhkan perawatan intensive care unit akan dieksklusikan dari
studi. Kriteria eksklusi lainnya adalah penggunaan antibiotik atau probiotik hingga 8 minggu sebelum
masuk rumah sakit, malnutrisi, dan adanya penyakit kronis yang mendasari. Semua anak akan dibagi
menjadi 3 kelompok intervensi secara acak, yaitu (sinbiotic, zinc, atau kelompok kontrol) sesuai dengan
daftar pengacakan yang dihasilkan komputer.

Kelompok pertama menerima preparat sinbiotik (NBL Probiotik ATP® sachet, Nobel İlaç, Turki; satu
sachet per hari) yang mengandung L. casei, L. rhamnosus, L. plantarum, B. lactis (total 4,5 × 109 CFU),
prebiotik seperti fruktosa, galaktooligosakarida, dan polidekstrosa (1996,57 mg), serta Vitamin C, Vitamin
E, riboflavin, piridoksin, dan tiamin selama 5 hari, di samping ORS dengan atau tanpa terapi
intravena. Kelompok kedua menerima suspensi zinc (15 mg per hari selama 5 hari, Berko İlaç; Turki), di
samping ORS dan/atau terapi intravena. Kelompok ketiga (kontrol) hanya menerima ORS dan/atau terapi
intravena.

Saat mengunjungi rumah sakit, data demografis dan hasil pemeriksaan klinis (demam, berat badan, dan
tingkat dehidrasi) dari pasien akan dicatat. Penggantian cairan/elektrolit dilakukan menggunakan ORS
hipo-osmolar berdasarkan status dehidrasi setiap pasien. Titik akhir primer adalah durasi diare. Titik akhir
sekunder adalah jumlah anak yang mengalami diare pada intervensi hari ketiga dan setiap hari selama lima
hari intervensi. Konsistensi feses dan frekuensi diare akan dicatat. Durasi diare didefinisikan sebagai
waktu dalam jam dari masuk sampai penghentian diare, yang didefinisikan sebagai feses normal pertama
setelah diare. Evaluasi feses dilakukan sesuai dengan skor Bristol, di mana skor <5 menunjukkan feses
yang normal. Formulir diisi oleh orang tua. 
Analisis statistik
 
Analisis statistik dilakukan dengan menggunakan perangkat lunak SPSS 16.0 (SPSS Inc.; Chicago, IL,
USA). Uji normalitas akan dilakukan untuk seluruh variabel, dan perbandingan akan diuji menggunakan
uji-t dan χ2 atau uji Fisher exact. Risk ratio dan confidence interval 95% digunakan untuk perbandingan
antara kelompok sinbiotik dan kontrol, dan kelompok zinc dan kontrol. Risk difference dan confidence
interval 95% digunakan untuk perbandingan antara kelompok sinbiotik dan kelompok zinc. Nilai p <0,05
dinyatakan signifikan secara statistik.
 
Hasil
 
Penelitian ini melibatkan 165 anak-anak (55 pada kelompok sinbiotik, 55 pada kelompok zinc, dan 55
pada kelompok kontrol). Tidak terdapat perbedaan usia rata-rata dan jenis kelamin anak-anak antara
kelompok sinbiotik, zinc, dan kontrol (p >0,05) (Tabel 1). Ada/tidaknya dehidrasi juga serupa pada ketiga
kelompok. Durasi diare berkurang secara signifikan (~24 jam) pada kelompok sinbiotik dibandingkan
dengan kelompok kontrol (masing-masing 91,0 ± 28,9 jam vs 114,3 ± 30,9 jam, p <0,001). Durasi diare
berkurang secara signifikan (~28 jam) pada kelompok zinc dibandingkan dengan kelompok kontrol
(masing-masing 86,4 ± 30,8 jam vs 114,3 ± 30,9 jam, p <0,001). Tidak ditemukan perbedaan durasi diare
yang signifikan antara kelompok sinbiotik dan zinc (masing-masing 91,0 ± 28,9 jam vs 86,4 ± 30,8 jam, p
>0,05) (Tabel 1).

Tabel 1. Data demografis dan durasi diare pada kelompok studi

Tidak ada efek terhadap diare yang diamati pada 24 jam intervensi sinbiotik. Efek dari sinbiotik
(persentase anak yang bebas diare) mulai telihat setelah 48 jam (Tabel 2). Persentase anak-anak yang
masih mengalami diare cair pada hari ke-3 adalah 61,8% anak-anak pada kelompok sinbiotik vs 83,6%
anak pada kelompok kontrol (p = 0,01). Pada intervensi 96 dan 120 jam, persentase anak yang masih
mengalami diare pada kelompok sinbiotik lebih rendah daripada kelompok kontrol (p <0,01 untuk
keduanya) (Tabel 2).
Tabel 2. Persentase anak-anak yang mengalami diare pada Hari 3 dan Hari 5 pada kelompok sinbiotik dan
kontrol

 
Efek (persentase anak yang bebas diare) dari zinc mulai terlihat pada 48 jam intervensi (Tabel 3). Setelah
48 jam, 81,8% anak-anak yang menerima zinc masih mengalami diare cair vs 98% anak-anak dalam
kelompok kontrol (p = 0,01). Setelah 72, 96, dan 120 jam, jumlah anak yang menerima zinc yang masih
mengalamai diare cair secara signifikan lebih rendah dibandingkan dengan kelompok kontrol (p <0,01
untuk semua kelompok).

Tabel 3. Persentase anak-anak yang mengalami diare pada Hari 3 dan Hari 5 dalam kelompok zinc dan
kontrol

Efek sinbiotik dan zinc serupa pada intervensi 24 dan 48 jam (p >0,05) (Tabel 4). Pada 72 jam, persentase
anak-anak yang masih mengalami diare pada kelompok zinc secara signifikan lebih rendah daripada
kelompok sinbiotik, (45,4% vs 61,8%, p <0,05). Pada 96 jam intervensi, persentase anak-anak yang masih
mengalami diare lebih rendah secara signifikan pada kelompok zinc dibandingkan dengan kelompok
sinbiotik (p <0,05). Tidak ada perbedaan dalam persentase anak yang masih mengalami diare pada 120
jam intervensi antara kelompok zinc dan probiotik (p >0,05).
Tabel 4. Persentase anak-anak yang mengalami diare pada Hari 3 dan Hari 5 pada kelompok sinbiotik dan
zinc

 
Diskusi

Terapi awal yang direkomendasikan untuk diare akut adalah pemberian cairan secara oral dan penggunaan
terapi ORS (4). Namun, ORS tidak mengurangi frekuensi kehilangan cairan dan sakit perut, atau
memperpendek durasi diare. Oleh karena itu, opsi terapi tambahan lebih lanjut telah dipelajari secara
luas. Dalam penelitian ini, formulasi sinbiotik berhasil mengurangi durasi diare selama sekitar 24 jam,
dengan efikasi yang serupa dengan studi klinis lainnya dan pedoman yang berkaitan dengan strain
probiotik lainnya. Penelitian ini adalah penelitian pertama yang mengevaluasi efek preparat simbiotik yang
mengandung L. casei, L. plantarum L. rhamnosus, dan B. lactis. Beberapa probiotik tersebut adalah strain
bakteri yang telah diketahui dan banyak diteliti sebagai probiotik untuk kondisi klinis yang
berbeda; Namun, efek probiotik terhadap diare infeksi akut bersifat spesifik strain, dan semua formulasi
harus dievaluasi dengan uji klinis. Dalam penelitian ini, efek preparat sinbiotik mulai diamati pada 48
jam; dan pada 96 jam intervensi, persentase anak-anak yang bebas diare adalah 73% (vs 45% pada
kelompok kontrol). Penelitian kami sebelumnya dengan preparat simbiotik lain yang mengandung L.
rhamnosus, L. acidophilus, B. bifidum, B. longum, Enterococcus faecium (2,5 × 109 CFU total bakteri
hidup setiap hari) dan 625 mg fruktooligosakarida selama 5 hari juga menunjukkan penurunan yang
signifikan dalam durasi diare. Durasi berkurang sekitar 36 jam pada anak-anak dengan diare infeksi akut,
dan efeknya terlihat setelah 24 jam, dengan hasil yang lebih baik pada intervensi 48 dan 72 jam. Dua
penelitian yang dilakukan di Belgia (Streptococcus thermophilus, L. rhamnosus, L. acidophilus, B. lactis,
B. infantis, dan fruktooligosakarida) dan Italia (Lactobacillus paracasei B21060 dengan arabinogalaktgan
dan xylooligosakarida) juga menunjukkan hasil menunjukkan efek menguntungkan dari sinbiotik pada
diare infeksi akut. Pedoman ESPID/ESPGHAN terbaru tidak merekomendasikan kedua sinbiotik yang
telah diteliti tersebut (setiap kombinasi dengan hanya satu studi klinis) sampai studi konfirmasi lebih lanjut
tersedia. Untuk rekomendasi yang kuat, studi lebih lanjut diperlukan untuk preparat sinbiotik yang sama
dalam pengaturan klinis yang berbeda.
 
Banyak penelitian yang telah melaporkan efikasi zinc untuk pengobatan diare akut selama masa kanak-
kanak, namun hasil yang kontradiktif terkait wilayah geografis dan usia juga telah
dipublikasikan. Defisiensi zinc adalah faktor penentu utama imunitas dan berat badan rendah di negara
berkembang, dan keduanya terkait dengan durasi diare. Dalam beberapa uji coba acak terkontrol dan
beberapa systematic review, pemberian zinc terbukti mengurangi durasi dan frekuensi diare, begitu juga
dengan jumlah feses. World Health Organization merekomendasikan penggunaan rutin suplementasi zinc,
dengan dosis 20 mg per hari untuk anak-anak berusia >6 bulan. Dalam penelitian ini, kami lebih suka
menggunakan dosis standar 15 mg per hari dengan formulasi cair. Durasi diare berkurang secara signifikan
pada kelompok zinc dibandingkan dengan kelompok kontrol (sekitar 28 jam). Efek preparat zinc mulai
diamati pada 48 jam intervensi. Pada 72 dan 96 jam, persentase anak dalam kelompok zinc yang masih
mengalami diare lebih sedikit dibandingkan dengan kelompok kontrol (45% vs 86%). Sebuah meta-
analisis (18 uji klinis dengan 6.165 peserta) menunjukkan bahwa suplementasi zinc menghasilkan durasi
diare yang lebih pendek pada diare akut, dan lebih sedikit diare pada Hari 3 dan Hari 5, yang serupa
dengan hasil penelitian kami. Berbeda dengan penelitian lain, penelitian acak tersamar ganda yang baru-
baru ini dilakukan mengenai suplementasi zinc untuk diare akut di Swiss menunjukkan bahwa pemberian
zinc dapat menurunkan frekuensi dan tingkat keparahan diare pada anak usia 2 bulan hingga 5 tahun,
namun tidak menurunkan durasi diare. Di negara-negara berkembang, suplementasi zinc mungkin berguna
dalam pengobatan diare akut untuk anak-anak di atas 6 bulan. Namun, tidak ada manfaat dari penggunaan
zinc yang dilaporkan di daerah di mana defisiensi zinc jarang terjadi.
 
Kami tidak menemukan perbedaan yang signifikan antara kelompok sinbiotik dan zinc dalam durasi diare
(91,0 ± 28,9 jam vs 86,4 ± 30,8 jam); Namun, tampaknya suplementasi zinc memiliki efek yang lebih
cepat daripada suplementasi sinbiotik, dan persentase anak-anak yang mengalami diare secara signifikan
lebih tinggi pada kelompok zinc dibandingkan pada kelompok sinbiotik pada 72 dan 96 jam
intervensi. Pada hari ke-5, signifikansi perbedaan antara kedua kelompok tidak ditemukan. Sepengetahuan
kami, penelitian ini adalah penelitian pertama yang membandingkan zinc dan sinbiotik. Penelitian lebih
lanjut dengan kohort yang lebih besar diperlukan untuk mengklarifikasi efek zinc dan/atau sinbiotik
terhadap komposisi mikrobiota feses pada anak-anak dengan diare akut.
 
Penelitian kami memiliki beberapa keterbatasan. Kami tidak melakukan analisis feses untuk mengevaluasi
etiologi diare infeksi akut, dan tidak memiliki kesempatan untuk mengevaluasi efek zinc atau sinbiotik
terhadap etiologi diare yang berbeda. Penelitian ini bukan penelitian yang terkontrol plasebo. Meskipun
kami membagi partisipan ke dalam 3 kelompok intervensi secara acak, anak-anak dalam kelompok zinc
ditemukan berusia lebih tua dari kelompok lain, dan kami tidak memiliki kesempatan untuk mengevaluasi
efek spesifik usia dari zinc terhadap durasi diare.
 
Pada anak-anak dengan diare akut, penelitian kami menunjukkan bahwa suplementasi zinc atau sinbiotik
dapat mengurangi durasi diare. Anak-anak yang menerima zinc atau sinbiotik lebih mungkin bebas diare
setelah 48 jam pertama intervensi, dengan hasil yang lebih baik pada 72 dan 96 jam. Sediaan zinc atau
simbiotik yang mengandung Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus plantarum,
Bifidobacterium lactis, dan prebiotik dapat digunakan pada anak-anak dengan diare akut.