A Comparative Study between Zinc Alone and Zinc

with Racecadotril in AWD

Dr. Abu Sufian

FCPS (Paediatrics) PART- II

Mob: 01718762595

Session: January, 2023

Department of Paediatrics
Abdul Malek Ukil Medical College & Jononeta Nurul
Haque Adhunik Hospital, Noakhali

Submission date: ………………….

i
 Declaration

This primary data-based dissertation is submitted in partial fulfillment of the

requirements of the Fellowship of the College of Physicians and Surgeons
(FCPS) Paediatrics Part-II Examinations of Bangladesh College of
Physicians and Surgeons (BCPS). The research work was done during July
2021 to December 2021 in Abdul Malek Ukil Medical College & Jononeta
Nurul Haque Adhunik Hospital, Noakhali.

No portion of the work referred to in this dissertation has been submitted in

support of an application for another degree or qualification of this or any
other institution of learning.

Dr. Abu Sufian

FCPS-II Examinee (Paediatrics)

ii
 Forwarding

Certified that Dr. Abu Sufian carried out this research work titled “A
comparative study between zinc alone and zinc with racecadotril in
AWD” and prepared this dissertation under my direct supervision. I have
found the work and the dissertation satisfactory for partial fulfillment of the
requirements of the Fellowship of the College of Physicians and Surgeons
(FCPS) Paediatrics Part-II Examinations of Bangladesh College of
Physicians and Surgeons (BCPS).

Dr. Bimal Chandra Das

MBBS,MD(Paediatrics)
Associate Professor
Department of Paediatrics
Abdul Malek Ukil Medical College & Jononeta Nurul
Haque Adhunik Hospital, Noakhali.

iii
 Acceptance-I
Certified that this dissertation titled “A comparative study between zinc
alone and zinc with racecadotril in AWD” submitted by Dr. Abu Sufian has
been examined by me and found to be satisfactory for partial fulfillment of the
requirements of the Fellowship of the College of Physicians and Surgeons
(FCPS) Paediatrics Part- II Examination of Bangladesh College of Physicians
and Surgeons (BCPS).

…………………………
(Signature of the examiner)
…………………………
(Name)
…………………………

(Designation)

iv
 Acceptance-II
Certified that this dissertation titled “A comparative study between zinc
alone and zinc with racecadotril in AWD” submitted by Dr. Abu Sufian has
been examined by me and found to be satisfactory for partial fulfillment of the
requirements of the Fellowship of the College of Physicians and Surgeons
(FCPS) Paediatrics Part- II Examination of Bangladesh College of Physicians
and Surgeons (BCPS).

…………………………
(Signature of the examiner)
…………………………
(Name)
…………………………
(Designation)

v
Abstract
Background: Diarrhoea is one of the most common causes of morbidity and
mortality in children under 5 years in the developing world.Racecadotril is a
diesterified derivative of thiorphan. Once absorbed after oral administration, it is
converted to its parent compound (thiorphan) which acts to increase the half-life of
enterocyte methionine-enkephalin (a potent antisecretory agent).
Objective: To compare between zinc alone and zinc with racecadotril in AWD.
Materials and Method: Prospective comparative study was carried out in the
Department of Paediatrics, Abdul Malek Ukil Medical College & Jononeta Nurul
Hoque Adhunik Hospital, Noakhali during July 2021 to December 2021 total 86
Children aged between 3–60 months requiring admission for severe acute
gastroenteritis, as evidenced by a Modified Vesikari Score of >11 were included in
this study. Patients were divided in to two groups, Group A: Zinc with racecadotril
and Group B: Zinc alone. All the information were recorded in the fixed protocol.
Collected data were classified, edited, coded and entered into the computer for
statistical analysis by using SPSS-23.
Result: The mean age was found 16.5±8.3 months in group A and 15.7±9.6 months
in group B. Male patients were predominant in both groups, that was 24(55.8%) in
group A and 26(60.5%) in group B. More than three fourth (76.7%) patients given
complimentary food in group A and 35(81.4%) in group B. Mild malnutrition was
found in 24(55.8%) in group A and 11(25.6%) in group B. Good nutrition was
13(30.2%) and 17(39.5%) in group A and group B respectively. Moderate
malnutrition was 6(14.0%) in group A and 15(34.9%) in group B. The difference was
statistically significant (p<0.05) between two groups. At day 2 mean frequency of
diarrhoea was found 3.10±0.57 in group A and 3.42±0.62 in group B. At day 3 mean
frequency of diarrhoea was 0.75±0.41 and 1.52±0.35 in group A and group B
respectively. The difference was statistically significant (p<0.05) between two groups.
Mean duration of diarrhoea was found 35.32±9.25 hrs in group A and 31.57±11.38
hrs in group B. The mean duration of hospital stay was 30.39±16.10 hrs in group A
and 41.53±18.38 hrs in group B. Mean remission time was 49.7±23.22 hrs in group A
and 66.25±29.41 in group B. The difference was statistically significant between two
groups. Skin rashes was found 4(9.3%) in group A and 6(14.0%) in group B.
Angiooedema was 3(7.0%) and 1(2.3%) in group A and group B respectively.
Tonsilitis was 2(4.7%) in group A but found in group B. Convulsions was 2(4.7%) in
group A and 1(2.3%) in group B.

vi
Conclusion: The mean frequency of diarrhea was significantly low in Zinc with
racecadotril in comparison to Zinc alone group. The mean duration of hospital stay
and mean remission time also significantly lower in Zinc with racecadotril group. No
any significant difference was found in adverse events between both groups.

vii
 Table of contents

Page
CHAPTER 1: INTRODUCTION

1.1 Background

1.2 Rationale of the research

1.3 Research question

1.4 Objective

1.5 Review of literature

CHAPTER 2: MATERIALS AND METHODS

CHAPTER 3: RESULTS

CHAPTER 4: DISCUSSION

Limitations of the study

Conclusion

Recommendations
References Cited

Appendices

Appendix A : Data collection sheet

Appendix B : Consent form

viii
 List of tables
Sl. No. Title Page
3.1 Socio-demographic characteristics of the study patients
3.2 Distribution of the study patients by feeding history
3.3 Distribution of the study patients by sanitation status
3.4 Distribution of the study patients by nutritional status
3.5 Mean frequency of diarrhoea between two groups
3.6 Mean duration of diarrhoea before treatment between two
groups
3.7 Distribution of the study patients by degree of dehydration
3.8 Mean duration of hospital stay and remission between two
groups
3.9 Mean duration of hospital stay and remission between two
groups

ix
 Acknowledgements
All praises to Almighty the most Gracious and the most Merciful, whose blessings
enabled me to complete the dissertation.

It is my privilege to express my deepest gratitude to my honorable guide Dr. Bimal

Chandra Das, Associate Professor, Department of Paediatrics, Abdul MalekUkil
Medical College & Jononeta Nurul Haque Adhunik Hospital, Noakhali for his able
guidance, constant supervision, criticism and advice which has made this study
possible.

I acknowledge my heartiest gratitude to all my teachers, associate professors,

assistant professors, doctors, friends and colleagues in the department of
Department of Paediatrics, Abdul MalekUkil Medical College & Jononeta Nurul
Haque Adhunik Hospital, Noakhali for their inspiration, co-operation and valuable
suggestions.
My acknowledgements would remain incomplete if I do not offer my special gratitude
to the patients and their parents whose whole hearted co-operation has enabled me
to carry out this study successfully.

Date: Dr. Abu Sufian

FCPS-II Examinee (Paediatrics)

x
 Chapter: One

Introduction

1
1.1 Background

Diarrhea is a common problem in our country especially in children. There are many
treatment options for acute watery diarrhea in addition to oral rehydration saline for
reducing the severity of acute watery diarrhea.1

Diarrheal disorders in childhood accounts for a large proportion (18%) of childhood

deaths, with an estimated 1.5 million deaths per year globally, making it the second
most common cause of child deaths worldwide.2,3 The World Health Organization
(WHO) and UNICEF estimate that almost 2.5 billion episodes of diarrhea occur
annually in children <5 year of age in developing countries, with more than 80% of
the episodes occurring in Africa and South Asia (46% and 38%, respectively). Global
mortality may be declining, but the overall incidence of diarrhea remains unchanged
2
at about 3.6 episodes per child-year.

Currently WHO recommends treatment with oral rehydration salts (ORS) and
continued feeding for the prevention and treatment of dehydration, as well as zinc to
4
shorten the duration and severity of the episodes. Probiotics are not recommended
by WHO for the treatment of community-acquired acute diarrhea, though they are
5
becoming increasingly popular in some country. Probiotics are non-pathogenic live
microorganisms. When ingested, probiotics can survive passage through the
5
stomach and small bowel.

Racecadotril is a diesterified derivative of thiorphan.6 Once absorbed after oral

administration, it is converted to its parent compound (thiorphan) which acts to
increase the half-life of enterocyte methionine-enkephalin (a potent antisecretory
agent).7 Racecadotril has been in use for the past 20 years in Europe and has been
consistently useful in the management of diarrhoeal disease with an acceptable
adverse effect profile.8-10 Although zinc has been shown to significantly affect the
duration and severity of diarrhoea and forms part of the core treatment
recommendations by the WHO, none of the trials studying efficacy of racecadotril
have included it in their protocols.11,12

Racecadotril is an antisecretory agent with a unique mechanism of action

distinguishing it from other antidiarrheal agents. Racecadotril “decreases the
intestinal hypersecretion of water and electrolytes induced by the cholera toxin or

2
inflammation, and does not have effects on basal secretory activity. Racecadotril
exerts rapid antidiarrhoeal action, without modifying the duration of intestinal transit. 13
Racecadotril is a more recent addition to the armamentarium for the treatment of
acute diarrhea in children.14-15 It has been shown to inhibit rotavirus-induced
secretion in Caco-2 cells.16 Based on its anti-secretory activity against pathological
agents, racecadotril has been shown to mitigate castor oil-induced diarrhea in
healthy human volunteers. Accordingly, racecadotril did not alter E. coli content in
proximal jejunum and reduced it in stool of newborn piglets, whereas the
gastrointestinal motility inhibitor loperamide increased the E. coli content in jejunum
and reduced it in stool. Taken together, these pharmacological properties should
make racecadotril an effective agent for the treatment of acute diarrhea with little
potential for retention of infectious agent or rebound constipation. 17 The efficacy and
safety of racecadotril in the treatment of acute diarrhea in children has been the
subject of several reviews and meta-analysis.18-19 Based on such data, international
guidelines recommend racecadotril as a treatment option in children with acute
diarrhea.20

3
1.2 Rationale of the research

Oral rehydration treatment (ORT) is the cornerstone of treatment of acute

diarrhea and its widespread adoption has improved prognosis of the condition
over the past 30 years. Previously WHO recommended treatment with oral
rehydration salts (ORS), as well as Zinc to shorten the duration and severity
of the episodes. Although Zinc has been shown to significantly affect the
duration and severity of diarrhea and forms part of the core treatment
recommendation by the WHO, none of the trials studying efficacy of
racecadotril have included it in their protocol. Racecadotril is a research
based treatment option for acute diarrhea in children. Despite major advances
in treatment, acute diarrhea continues to be a public health problem in
children under five years. It is proven that zinc is highly effective in diarrhoea,
and there are few research worldwide that racecadotril is also effective in
diarrhea. but there is no research worldwide as well as our country on
combined effect of zinc with racecadotril in AWD. So such a study is
necessary.

4
1.3 Hypothesis
Zinc with racecadotril is more effective than zinc alone in the treatment of acute
watery diarrhea.

5
1.4 Objectives
General objective:

To see the efficacy between zinc alone and zinc with racecadotril in AWD

Specific objectives:
 To compare the number of stools in the first 48 hours in children with severe
gastroenteritis requiring admission and treated with either zinc with
racecadotril and zinc alone.
 To study the impact of racecadotril on duration of inpatient stay as well as
duration of diarrhoea.

6
 Chapter: Two

Literature Review

7
Literature Review

Diarrhea

Diarrhoea is defined as the passage of three or more loose or liquid stools per day
(or more frequent passage than is normal for the individual). Frequent passing of
formed stools is not diarrhoea, nor is the passing of loose, "pasty" stools by breastfed
babies.21

Diarrhoea is usually a symptom of an infection in the intestinal tract, which can be

caused by a variety of bacterial, viral and parasitic organisms. Infection is spread
through contaminated food or drinking-water, or from person-to-person as a result of
poor hygiene.21

Etiology of Diarrhoea22

Diarrhoea is a symptom of infections caused by a host of bacterial, viral and parasitic

organisms, most of which are spread by faeces-contaminated water. Infection is
more common when there is a shortage of adequate sanitation and hygiene and safe
water for drinking, cooking and cleaning. Rotavirus and Escherichia coli, are the two
most common etiological agents of moderate-to-severe diarrhoea in low-income
countries. Other pathogens such as cryptosporidium and shigella species may also
be important. Location-specific etiologic patterns also need to be considered.
Diarrhoeal disease can also spread from person-to-person, aggravated by poor
personal hygiene. Food is another major cause of diarrhoea when it is prepared or
stored in unhygienic conditions. Unsafe domestic water storage and handling is also
an important risk factor. Fish and seafood from polluted water may also contribute to
the disease.

Types of diarrhoea :

Acute watery diarrhea: This term refers to diarrhoea that begins acutely, lasts less
than 14 days (most episodes last less than 7 days), and involves the passage of
frequent loose or watery stools without visible blood.
Dysentery: This is diarrhoea with visible blood in the faeces. The main cause of
acute dysentery is Shigella; other causes are Campylobacterjejuni and, infrequently,

8
enteroinvasive E. coli or Salmonella. Entamoeba histolytica can cause serious
dysentery in young adults but is rarely a cause of dysentery in young children.
Persistent diarrhea: This is diarrhoea that begins acutely but is of unusually long
duration (at least 14 days). The episode may begin either as watery diarrhoea or as
dysentery. Marked weight loss is frequent.

Types and management of dehydration 23

Management
Two of the following signs: Lethargic Severe dehydration IV fluid
or unconscious Sunken eyes Not able Cholera Saline < 12
to drink or drinking poorly Skin pinch month 100 ml/kg
goes back very slowly. over 6 hours and >
12 months 100
ml/kg over 3 hours
Two of the following signs: Restless, Some dehydration ORS 75 ml /kg over
irritable Sunken eyes Drinks eagerly, 4 hours along with
thirsty Skin pinch goes back slowly. Zinc
Not enough signs to classify as some No dehydration ORS
or severe dehydration.

Complications:
 Dehydration ,
 Electrolyte imbalance
- Hyponatraemia
- Hypernatraemia
- Hypokalaemia
- Acidosis
 Shock
 Acute renal failure

Prevention:
 Promotion of Exclusive Breast Feeding
 Appropriate complementary feeding practices
 Improvement of water and sanitary facilities
 Improvement of domestic hygiene

9
  Rotavirus vaccination
 Improvement of case management strategy.
Zinc

The World Health Organization (WHO) and UNICEF recommend therapeutic zinc (20

mg), to be given daily for 10-14 days during diarrhea episodes, along with oral

rehydration salt (ORS) solution (given on diarrhea days).24

The zinc recommendation is based on studies that have shown that administration of

supplemental zinc results in a shorter duration of diarrhea, reduces the number of

stools and stool output, reduces the risk of persistent diarrhea, and may reduce the

risk of subsequent illness.25

Zinc can treat acute and chronic diarrhea by inhibiting three out of the four main

intracellular pathways of intestinal ion secretion, including cyclic adenosine

monophosphate (cAMP), calcium, and nitric oxide. Zinc decreases the concentration

of copper by inducing the synthesis of a copper-binding ligand in mucosal cells; this

sequesters copper, making it unavailable for serosal transfer in the GI tract.26

Zinc inhibits cAMP-induced, chloride-dependent fluid secretion by inhibiting

basolateral potassium (K) channels27,28 Zinc also improves the absorption of water

and electrolytes, improves regeneration of the intestinal epithelium, increases the

levels of brush border enzymes, and enhances the immune response, allowing for a

better clearance of the pathogens.29

Racecadotril

Racecadotril is an antisecretory agent with a different mechanism of action from

existing antidiarrhoeal agents. It functions by selective inhibition of the enzyme

neutral endopeptidase (also known as enkephalinase), a cell membrane peptidase

enzyme found most commonly on the epithelium of the small intestine. The enzyme

neutral endopeptidase degrades endogenous enkephalins in the intestinal mucosa

which normally exhibit pro-absorptive and antisecretory properties. Racecadotril

therefore aims to promote these antisecretory properties by prolonging the presence

10
of the enkephalins through the inhibition of neutral endopeptidase. Ultimately, the

hypersecretion of water and electrolytes is reduced without affecting intestinal

motility/transit.30

[3-acetylmercapto-2-benzylpropanoyl]–glycine, benzyl ester, is a lipophilic derivative

of thiorphan. Racecadotril is rapidly converted in the body to thiorphan, a potent

enkephalinase inhibitor. Enkephalins are endogenous opioid peptides secreted by

myenteric and sub mucosal neurons in the digestive tract. The enkephalins by

activating the δ opioid receptor, inhibit the secretion of Cl– and fluids thus reducing

the loss of fluids and electrolytes during diarrhea.31 The antisecretory mechanisms

are independent of effects on intestinal motility, differentiating this compound from μ-

opiate receptor agonists like loperamide and diphenoxylate. Experimental studies in

rodents and human volunteers demonstrated no delay on gastrointestinal transit or

increase in experimental bacterial proliferation in small bowel of germ free piglets

with racecadotril as compared to loperamide.31

11
Review of literature

A randomized controlled trial was conducted Sultana et al.1 they compared the
efficacy of zinc & probiotics combination therapy to zinc alone therapy in reducing the
severity of acute diarrhea. A total of 110 numbers of children ages 6 months to 5
years with acute watery diarrhea were enrolled those who were fulfilled the selection
criteria. They were divided into two groups. Group A (n=55) received zinc-probiotics
combination therapy and group B (n=55) received zinc only. Measurement of disease
severity was based on the frequency of diarrhea (times/day) and duration of diarrhea
(hours) after initial drug consumption. Among the study population 56% male &44%
female in group A and 58% male & 42% female in group B. Duration of acute watery
diarrhea was significantly reduced in group A than group B(56.22 versus 70.69 hours
respectively), (P-0.002)and frequency of stool also reduced in group A than group
B(3.92 versus 7.15 times/day) on day 2 (P-0.002). Consistency of stool also
improved in group A than group B[liquid stool12(21.8%) versus 25(45.5%), (P-0.015)
on day 1, semi-liquid stool 4 (8.2%) versus 16 (30.8%), (P-0.004) on day 2, formed
stool 29 (52.73%) versus 16(29.09%), P-0.004 on day 2 respectively]. Combination
therapy was more effective in reducing the severity of acute watery diarrhea than
zinc alone therapy in children.

An observational, prospective, open label, comparative study was conducted by

Ramadas and Chakraborty21. They conducted on 90 children after obtaining informed
consent from their guardian. The participants were allocated to one of three study
groups as follows; Group A: ORS & zinc Group, B: ORS, Zinc and lactic acid bacilli;
Group C: ORS, Zinc and combination of lactic acid bacilli acidophilus,
Bifidobacterium lactis and Saccharomyces boulardii. They were followed up for 72
hours after receiving the treatment and after 7 days. The outcome measures were
reduction in mean duration and mean frequency of diarrhea. The mean frequency of
diarrhea on day 1 in Group A, B and C were 5.87±1.23; 6.5±1.15 and 6.63±1.42
respectively. On day 2, in Group A it was 2.93±0.82; Group B, 3.23±0.99 and in
Group C, 2.73±0.89 respectively. On day 3, in Group A it was 1.33±0.47; Group B,
0.86±0.5 and in Group C, 0.53±0.5 respectively. The mean duration of diarrhea in
Group A, B and C were 4.5±0.76, 3.47±0.5 and 3.17±0.37 days respectively. There
was significant reduction in mean frequency and duration of diarrhea in Group B and
C compared to Group A (p˂0.05). Probiotics when used alone or in combination as

12
adjuvant to ORS and Zinc in the treatment of acute pediatric diarrhea results in
significant reduction in mean frequency and mean duration of diarrhea.

Gharial et al.22 compared the number of stools in the first 48 hours in children with
severe gastroenteritis requiring admission and treated with either racecadotril or
placebo. They also observed the impact of racecadotril on duration of inpatient stay
as well as duration of diarrhoea and to describe the side effect profile of racecadotril.
120 children were enrolled into the study. There were no differences in the
demographics or outcomes between the 2 groups. Stools at 48 hours: median (IQR)
of 5 (3–7) and 5 (2.5–7.5), respectively; p=0.63. The duration of inpatient stay:
median (IQR): 4 days (1.5–6.5) and 4.5 (1.8–6.3); p=0.71. The duration of illness: 3
days (2–4) and 2 days (1–3); p=0.77. The relative risk of a severe adverse event was
3-fold higher in the drug group but was not statistically significant (95% CI 0.63 to
14.7); p=0.16. Racecadotril has no impact on the number of stools at 48 hours, the
duration of hospital stay or the duration of diarrhoea in children admitted with severe
gastroenteritis and managed with ORS and zinc.

Dutta et al.23 compared the clinical efficacy of supplementation of zinc, zinc plus
vitamin A, and zinc plus combination of micronutrients and vitamins (iron, copper,
selenium, vitamin B12, folate, and vitamin A) on acute diarrhea in children. They
studied children with aged 6 to 24 months with diarrhea and moderate dehydration
were randomized to receive zinc plus placebo vitamin A (group 1), zinc plus other
micronutrients plus vitamin A (group 2), zinc plus vitamin A (group 3), or placebo
(group 4) as an adjunct to oral rehydration solution. Duration, volume of diarrhea, and
consumption of oral rehydration solution were compared as outcome variables within
the supplemented groups and with the placebo group. The 167 study subjects
included 41 in group 1, 39 in group 2, 44 in group 3, and 43 in group 4. All 3
supplemented groups demonstrated a significant reduction in outcome variables (P
<.0001) compared with the placebo group. Group 3 had the lowest reduction of
outcome variables and group 2 had a speedy recovery, but differences among the
supplemented groups were not statistically significant. Supplementation with a
combination of micronutrients and vitamins was not superior to zinc alone, confirming
the clinical benefit of zinc in children with diarrhea.

13
Cojocaru et al.10 measured the number of emergency department visits for acute
diarrhoea either the children received racecadotril or not. Racecadotril and
rehydration were compared with rehydration alone in children aged three months to
three years who had acute diarrhoea and were evaluated in the emergency
department (ED). One hundred and sixty-six children were alternatively randomized
to the treated and the control groups. There was no difference for age, degree of
dehydration and length of illness before the first visit between the groups. Whatever
type of rehydration (oral or IV), the treated group had a significant lower number of
stools (p<0.001) and a faster recovery (p<10–9). The children receiving racecadotril
needed less additional ED visits for the same episode (p<0.05). There was no
difference for the weight-gain on day 7. Their study demonstrates the efficacy of
racecadotril as adjuvant therapy to oral and IV rehydration in the treatment of acute
diarrhoea and a fewer emergency department second visit before recovery.

Rautenberg et al.13 performed cost utility (CU) and budget impact (BI) analyses
augmented by scenario analyses of critical model structure components to evaluate
racecadotril as adjuvant to oral rehydration solution (ORS) for children under 5 years
with acute diarrhea in Malaysia. According to the CU model, the intervention is less
costly and more effective than comparator for the base case with a dominant
incremental cost-effectiveness ratio of –RM 1,272,833/quality-adjusted life year (USD
–312,726/quality-adjusted life year) in favor of the intervention. According to the BI
analysis (assuming an increase of 5% market share per year for racecadotril+ORS
for 5 years), the total cumulative incremental percentage reduction in health care
expenditure for diarrhea in children is 0.136578%, resulting in a total potential
cumulative cost savings of –RM 73,193,603 (USD –17,983,595) over a 5-year period.
Results hold true across a range of plausible scenarios focused on critical model
components. Adjuvant racecadotril vs ORS alone is potentially cost-effective from a
Malaysian public payer perspective subject to the assumptions and limitations of the
model. BI analysis shows that this translates into potential cost savings for the
Malaysian public health care system. Results hold true at evidence-based base case
values and over a range of alternate scenarios.

Eberlin et al.17 observed Racecadotril is a guideline-recommended option for the

treatment of acute diarrhea in children but existing guidelines and previous reviews of
the field are based on a small fraction of published evidence. They have retrieved 58
trials, from nine countries including six in comparison to placebo, 15 in comparison to
various active treatments and 41 as add-on to various standard treatments (some

14
multi-armed studies allowing more than one comparison). Trials used 45 distinct
efficacy parameters, most often time to cure, % of cured children after 3 days of
treatment, global efficacy and number of stools on second day of treatment.
Racecadotril was superior to comparator treatments in outpatients and hospitalized
patients with a high degree of consistency as confirmed by meta-analysis for the five
most frequently used outcome parameters. For instance, it reduced time to cure from
106.2 h to 78.2 h (mean reduction 28.0 h; P < 0.0001 in 24 studies reporting on this
parameter). Tolerability of racecadotril was comparable to that of placebo (10.4% vs.
10.6% adverse events incidence) or that of active comparator treatments other than
loperamide (2.4% in both groups). Based on a comprehensive review of the existing
evidence, they conclude that racecadotril is more efficacious than other treatments
except for loperamide and has a tolerability similar to placebo and better than
loperamide. These findings support the use of racecadotril in the treatment of acute
diarrhea in children.

Sazawal et al.24 evaluated the effects of daily supplementation with 20 mg of

elemental zinc on the duration and severity of acute diarrhea. Among the children
who received zinc supplementation, there was a 23 percent reduction (95 percent
confidence interval, 12 percent to 32 percent) in the risk of continued diarrhea.
Estimates of the likelihood of recovery according to the day of zinc supplementation
revealed a reduction of 7 percent (95 percent confidence interval, -9 percent to +22
percent) in the risk of continued diarrhea during days 1 through 3 and a reduction of
38 percent (95 percent confidence interval, 27 percent to 48 percent) after day 3.
When zinc supplementation was initiated within three days of the onset of diarrhea,
there was a 39 percent reduction (95 percent confidence interval, 7 percent to 61
percent) in the proportion of episodes lasting more than seven days. In the zinc-
supplementation group there was a decrease of 39 percent (95 percent confidence
interval, 6 percent to 70 percent) in the mean number of watery stools per day (P =
0.02) and a decrease of 21 percent (95 percent confidence interval, 10 percent to 31
percent) in the number of days with watery diarrhea. The reductions in the duration
and severity of diarrhea were greater in children with stunted growth than in those
with normal growth. For infants and young children with acute diarrhea, zinc
supplementation results in clinically important reductions in the duration and severity
of diarrhea.

15
 Chapter: Two

Materials and Methods

16
MATERIALS AND METHODS

Study design: Prospective comparative study.

Place of study: The study was conducted in the Department of Paediatrics, Abdul
Malek Ukil Medical College & Jononeta Nurul Haque Adhunik Hospital, Noakhali

Study period: July 2021 to December 2021.

Study population: Children aged 3–60 months requiring admission for severe
acute gastroenteritis, as evidenced by a Vesikari score of >11.

Sample size:

The sample size is calculated by using following formula-

Z2pq
n=………………
d2
Here, Z is the confidence limit, ‘p’ is the prevalence rate and ‘q’ is ‘1- p’. ( or
proportion of persons not suffering from the disease), ‘d’ is the acceptable standard
error and ‘n’ is the required sample size.
Here,
Z =‘1.96’ standard normal deviate set at ‘1.96’ at 5% corresponds to 95% confidence
level.
P= anticipated prevalence of disease.
In unknown population
p=6%=0.06
q= 1-p=1-0.06. =0.94
d=0.05
n= the required sample size
(1.96)2×0.06×0.94
=……………………….
(0.05)2
=86 so estimated sample size was 86.

Sampling method: Purposive sampling.

17
Inclusion criteria:

Children aged 3–60 months requiring admission for severe acute

gastroenteritis, as evidenced by a Vesikari score of >11 with written parental
consent.

Exclusion criteria:
Children who had severe vomiting (scoring 3 on the Vesikari score for
maximum number of vomiting episodes per day); those with a clinical
diagnosis of dysentery or a known diagnosis of liver or renal failure; children
who had prescriptions of probiotics or any other antidiarrhoeal medication
(loperamide, attapulgite, activated charcoal, diphenoxylate and kaolin).

Main outcome variables:

Number of stools in the first 48 hours

Duration of inpatient stay.

Procedures of preparing & organizing materials

Sample selection by purposive sampling, taking consent -interview- result

collection -preparing for tabulation.

Procedures of collecting data:

The protocol was submitted for approval by the institutional ethical committee, and
written informed consent was obtained from parents of all participating children.
Inclusion criteria were children aged 3–60 months requiring admission for severe
acute gastroenteritis. Exclusion criteria were clinical diagnosis of dysentery or a
known diagnosis of liver or renal failure; children who had prescriptions of probiotics
or any other anti diarrhoeal medication. All children were admitted and started on
WHO recommended treatment by the attending physician. They received either
intravenous fluids as per WHO plan C (30 mL/kg followed by 70 mL/kg over 1 and 5
hours respectively, in infants and over 30 min and 2.5 hours for those over 12
months of age) or low osmolality ORS as per WHO plan B (75 mL/kg over 4 hours).
Zinc was prescribed at 10–20 mg/day. Participants were recruited within 24 hours of
admission after initial hydrations have been completed. This included the patients’
history up to and the examination at the time of admission. The test arm received
zinc and racecadotril at a dose recommended by the researcher: 10 mg for children

18
below 12 months of age and 30 mg for those over 12 months of age. This was
administered as granules dissolved in 10 mL of water and taken three times a day for
a maximum duration of 3 days. The control arm have zinc only preparation
administered in the same way. An initial dose of the racecadotril or zinc was given at
the time of enrolment. The parents were taught how to administer the drug at this
time and this was confirmed by return demonstration. The participants were followed
up using daily interviews asking about: the number of stools, the presence of blood in
stool, any new symptoms and the introduction of an anti-diarrhoeal or other
medication. Treatment was given either until the stools were formed or for a total of 3
days, whichever comes first. Children who were discharged before complete
resolution of symptoms were followed up by phone interviews until recovery. The
primary outcome measure was the number of stools in the first 48 hours after
introduction of the drug. The secondary outcomes were included the duration of
inpatient stay, the duration of illness and the number of adverse events associated
with racecadotril. All the data was collected with the above mentioned methods and
was entered in to SPSS version 23.

The patients were examined by the researcher for certain signs and those were
recorded in the check-list.

Investigations were done for supporting the diagnoses. According to the participants’
understanding level, sometimes the questions were described in the native language
so that the patients can understand the questions perfectly and answer accurately.

All the data was collected by the researcher own to avoid the errors. At very
beginning it was clarified that the participants have the right to refuse to answer of
any question during completing questionnaire. They can be withdrawn from the study
at any time and refusing to participate was not affected his/her treatment in any way.
It also clarified to all participants about the aim of the study. Participants were
ensured that any personal information was not published anywhere.
]

19
Procedure of data analysis:
Data was processed and analysed using SPSS (Statistical Package for Social
Sciences) software version 23. The chi- square test for qualitative variables and
student “t” test for quantitative variables was used to analyze the significance level of
p < 0.05. Continuous scale data was presented as mean ± standard deviation and
Categorical data was presented as number and percentage. The summarize data
was present in the table and chart.

Ethical implications:

In this study, keeping compliance with Helsinki Declaration for Medical Research
Involving Human Subjects 1964, the nature and purpose of the study was informed
in detail to all participants. Voluntary participations were encouraged. There was no
physical, psychological and social risk to the subjects. Informed and understood
written consent was taken from every parent of the participating children before
enrollment. Privacy, anonymity and confidentiality of data information identifying any
patient were maintained strictly. Each patient enjoyed every right to participate of
refuse or even withdrawn from the study at any point of time. Before starting this
study ethical clearance was taken from Institutional Review Board (IRB) of Abdul
Malek Ukil Medical College Hospital, Noakhali. Data taken from the participants
were coded and regarded as confidential and kept locked under investigator for
purposeful use only. No experimental new drug was administered and no placebo
was used here. This protocol has been primary selected by academic committee of
Department of Paediatrics, Abdul Malek Ukil Medical College Hospital & Jononeta
Nurul Haque Adhunik Hospital, Noakhali. Due respect was given to all the subjects.

20
 Chapter: Three

Results

21
RESULTS

Table 3.1: Socio-demographic characteristics of the study patients (n=86)

Variables Group A Group B P value

(n=43) (n=43)
n % n %
Age (months)
<6 11 25.6 12 27.9
6-24 19 44.2 21 48.8
25-48 10 23.3 8 18.6
>48 3 7.0 2 4.7
Mean±SD 16.5±8.3 15.7±9.6 0.680ns
Sex
Male 24 55.8 26 60.5
0.662ns
Female 19 44.2 17 39.5
Residence
Rural 27 62.8 31 72.1
0.357ns
Urban 16 37.2 12 27.9
Socioeconomic status
Average 19 44.2 22 51.2
Below average 11 25.6 8 18.6
0.718ns
Above average 4 9.3 6 14.0
Poor 9 20.9 7 16.3
Group A: Zinc with racecadotril
Group B: Zinc alone

ns=not significant
P value reached from unpaired t-test and Chi square test

Table 3.1 shows that majority patients belonged to age group 6-24 months in both
groups. The mean age was found 16.5±8.3 months in group A and 15.7±9.6 months
in group B. Male patients were predominant in both groups, that was 24(55.8%) in
group A and 26(60.5%) in group B. Majority patients came from rural area in both
groups, 27(62.8%) in group A and 31(72.1%) in group B. Most of the patients came
from average income group family, that was 19(44.2%) in group A and 22(51.2%) in
group B. The difference was not statistically significant (p>0.05) between two groups.

22
Table 3.2: Distribution of the study patients by feeding history (n=86)

Feeding history Group A Group B P value

(n=43) (n=43)
n % n %
Breast feeding only 3 7.0 5 11.6
Formula feeding 7 16.3 3 7.0 0.339ns
Complimentary food 33 76.7 35 81.4

ns=not significant
P value reached from Chi square test

Table 3.2 shows that more than three fourth (76.7%) patients given complimentary
food in group A and 35(81.4%) in group B. The difference was not statistically
significant (p>0.05) compared between two groups.

23
Table 3.3: Distribution of the study patients by sanitation status (n=86)

Sanitation status Group A Group B P value

(n=43) (n=43)
n % n %
Good 34 79.1 31 72.1
0.451ns
Poor 9 20.9 12 27.9

ns=not significant
P value reached from Chi square test

Table 3.3 shows that good sanitation was found in 34(79.1%) in group A and
31(72.1%) in group B. The difference was not statistically significant (p>0.05)
compared between two groups.

24
Table 3.4: Distribution of the study patients by nutritional status (n=86)

Nutritional status Group A Group B P value

(n=43) (n=43)
n % n %
Good 13 30.2 17 39.5
Mild malnutrition 24 55.8 11 25.6 0.010s
Moderate malnutrition 6 14.0 15 34.9

s= significant
P value reached from Chi square test

Table 3.4 shows that mild malnutrition was found in 24(55.8%) in group A and
11(25.6%) in group B. Good nutrition was 13(30.2%) and 17(39.5%) in group A and
group B respectively. Moderate malnutrition was 6(14.0%) in group A and 15(34.9%)
in group B. The difference was statistically significant (p<0.05) between two groups.

25
Table 3.5: Mean frequency of diarrhoea between two groups (n=86)

Mean frequency of Group A Group B P value

diarrhoea (n=43) (n=43)
mean±SD mean±SD
Day 1 6.40±1.29 5.92±1.17 0.074ns
Day 2 3.10±0.57 3. 42±0.62 0.014s
Day 3 0.75±0.41 1.52±0.35 0.001s

ns=not significant; s=significant

P value reached from unpaired t-test

Table 3.5 shows that at day 2 mean frequency of diarrhoea was found 3.10±0.57 in
group A and 3.42±0.62 in group B. At day 3 mean frequency of diarrhoea was
0.75±0.41 and 1.52±0.35 in group A and group B respectively. The difference was
statistically significant (p<0.05) between two groups.

26
Table 3.6: Mean duration of diarrhoea before treatment between two groups
(n=86)

Mean duration of Group A Group B P value

diarrhoea (hrs) (n=43) (n=43)
mean±SD mean±SD
Mean duration of diarrhoea 35.32±9.25 31.57±11.38 0.097ns
(hrs)

ns=not significant
P value reached from unpaired t-test

Table 3.6 shows that mean duration of diarrhoea was found 35.32±9.25 hrs in group
A and 31.57±11.38 hrs in group B. The difference was not significant (p>0.05)
between two groups.

27
Table 3.7: Distribution of the study patients by degree of dehydration (n=86)

Degree of dehydration Group A Group B P value

(n=43) (n=43)
n % n %
No sign of dehydration 16 37.2 13 30.2
Some sign of dehydration 25 58.1 29 67.4 0.625ns
Severe sign of dehydration 2 4.7 1 2.3

ns=not significant
P value reached from Chi square test

Table 3.7 shows that some sign of dehydration was found in 25(58.1%) in group A
and 29(67.4%) in group B. Severe sign of dehydration was 2(4.7%) in group A and
1(2.3%) in group B. No sign of dehydration was 16(37.2%) in group A and 13(30.2%)
in group B. The difference was not statistically significant (p>0.05) compared
between two groups.

28
Table 3.8: Mean duration of hospital stay and remission between two groups
(n=86)

Parameters Group A Group B P value

(n=43) (n=43)
mean±SD mean±SD
Duration of hospital stay (hrs) 30.39±16.10 41.53±18.38 0.003s
Remission time (hrs) 49.7±23.22 66.25±29.41 0.001s

s=significant
P value reached from unpaired t-test

Table 3.8 shows that mean duration of hospital stay was 30.39±16.10 hrs in group A
and 41.53±18.38 hrs in group B. Mean remission time was 49.7±23.22 hrs in group A
and 66.25±29.41 in group B. The difference was statistically significant between two
groups.

29
Table 3.9: Distribution of the study patients by adverse events (n=86)

Adverse events Group A Group B P value

(n=43) (n=43)
n % n %
Skin rashes 4 9.3 6 14.0 0.501ns
Angiooedema 3 7.0 1 2.3 0.305ns
Tonsilitis 0 0.0 2 4.7 0.152ns
Convulsions 2 4.7 1 2.3 0.556ns

ns=not significant
P value reached from Chi square test

Table 3.9 shows that skin rashes was found 4(9.3%) in group A and 6(14.0%) in
group B. Angiooedema was 3(7.0%) and 1(2.3%) in group A and group B
respectively. Tonsilitis was 2(4.7%) in group A but found in group B. Convulsions was
2(4.7%) in group A and 1(2.3%) in group B. The difference was not statistically
significant (p>0.05) between two groups.

30
 Chapter: Four
Discussion

31
DISCUSSION

In this study showed that majority patients belonged to age group 6-24
months in both groups. The mean age was found 16.5±8.3 months in group A
and 15.7±9.6 months in group B. Male patients were predominant in both
groups, that was 24(55.8%) in group A and 26(60.5%) in group B. Majority
patients came from rural area in both groups, 27(62.8%) in group A and
31(72.1%) in group B. Most of the patients came from average income group
family, that was 19(44.2%) in group A and 22(51.2%) in group B. The
difference was not statistically significant (p>0.05) between two groups.
Sultana et al.1 reported the mean age of month in Probiotics plus zinc group
(14.01±6.72) and Zinc alone group (13.31±8.02) were almost similar with in
this study. In group A male 56% & female 44% and in group B male 58% &
female 42%. Greater number of the patients was male in both groups (56.36%
vs. 58.18%). Ramadas et al.32 observed the mean age was 14±6.38 months
in group A and 11±5.19 months in group B. Male children was found
18(60.0%) in group A and 22(79.33%) in group B. Female was 40.0% and
26.67% in group A and group B respectively. In Ramadas et al.31 study,
95.56% subjects were below 2 years of age (mean age: 1.1±0.5). There was
another study done by Gharial et al.33 reported there was a statistically
significant predominance of girls in the drug group (p=0.04) despite an overall
male prevalence in the study. Aggarwal et al.34 where mean age was 19.18 ±
12.78 months & 20.02 ± 14.02 months in case & control group respectively.
This is consistent with the finding of other researchers that acute diarrhea is
more common in children less than 2 years of age. 35 Also, there was male
child preponderance in the study. Other researchers also mentioned that
number of male children were more in their study even though the gender
difference was not statistically significant.36 It was also found out that the
children belonged to low socioeconomic status without proper education
background. This is again consistent with the finding of other researchers that
acute diarrhea is more common in children belonging to low socioeconomic
status.35

32
In this study showed that more than three fourth (76.7%) patients given
complimentary food in group A and 35(81.4%) in group B. The difference was
not statistically significant (p>0.05) compared between two groups. Sultana et
al.1 reported breast feeding only was 1(1.81%) in group A (Zinc+Probiotics)
and 2(3.63%) in group B (Zinc). Formula feeding was 1(1.81%) in group A,
not found in group B. Complementary food was 53(96.36%) in group A and
53(96.36%) in group B.

Present study showed that good sanitation was found in 34(79.1%) in group A
and 31(72.1%) in group B. The difference was not statistically significant
(p>0.05) compared between two groups. Sultana et al.1 reported good
sanitation was 48(87.27%) in group A and 31(72.1%) in group B. Poor was
9(20.9%) and 12(27.9%) in group A and group B respectively.

In current study observed that mild malnutrition was found in 24(55.8%) in

group A and 11(25.6%) in group B. Good nutrition was 13(30.2%) and
17(39.5%) in group A and group B respectively. Moderate malnutrition was
6(14.0%) in group A and 15(34.9%) in group B. The difference was
statistically significant (p<0.05) between two groups. Gharial et al. 33 reported
Mild to moderate malnutrition was 28.0% in racecadotril group and 27.0% in
placebo group. Severe malnutrition was 15.0% and 27.0% in racecadotril
group and placebo group respectively. However, the mean weight of
participants in this study was 7.4 kg which was similar to a study carried out
by Savitha37 (as quoted in the Lehert et al.38 review). In both the Jean et al.39
and Savitha studies37, there was a significant improvement in the stool output
for children on racecadotril. Sultana et al.1 reported good malnutrition was
15(27.3%) in group A and 20(36.4%) in group B. Mild malnutrition was
32(58.2%) and 174(30.9%) in group A and group B respectively. Moderate
malnutrition was 8(14.5%) in group A and 18(32.7%) in group B.

In this study showed that at day 2 mean frequency of diarrhoea was found
3.10±0.57 in group A and 3.42±0.62 in group B. At day 3 mean frequency of
diarrhoea was 0.75±0.41 and 1.52±0.35 in group A and group B respectively.
The difference was statistically significant (p<0.05) between two groups.

33
Ramadas et al.32 reported the mean frequency of diarrhea on day 1 in Group
A was 5.87±1.23, Group B; 6.5±1.15 and Group C, 6.63±1.42 respectively.
There was no significant difference between the mean frequency of diarrhea
on day 1 in the three groups (p>0.05). In group A, the mean frequency of
diarrhea on day 1 was 5.87±1.23, day 2 was 2.93±0.82 and day 3; 1.33±0.47
respectively. In group B, the mean frequency of diarrhea on day 1 was
6.5±1.15, day 2 was 3.93±0.99 and day 3; 0.86±0.5 respectively. In group C,
the mean frequency of diarrhea on day 1 was 6.63±1.42, day 2 was 2.73±0.79
and on day 3 was 0.53±0.5 respectively. It was found that combination of
probiotics (group C) significantly reduced the mean frequency of diarrhea
when compared to group A and B respectively (p<0.05). Sultana et al.
observed the mean frequency of diarrhea before treatment was 37.78±22.62
times/day in group A and 39.30±19.93 times/day in group B.1

Present study showed that mean duration of diarrhoea was found 35.32±9.25
hrs in group A and 31.57±11.38 hrs in group B. The difference was not
significant (p>0.05) between two groups. Sultana et al. reported duration of
acute watery diarrhea was significantly reduced in group A than group B
(56.22 versus 70.69 hours respectively), (P-0.002). Aggarwal et al.34 reported
mean duration of diarrhea before treatment was 52.08 ± 30.48 hours in
probiotic group & 59.52 ± 30.72 hours in control group. Duration of diarrhea
before treatment was shorter than Aggarwal et al.34 study. Gharial et al.33
observed the duration from the time of introduction of the drug to the
appearance of ≤3 formed stools in 24 hours. This was noted to be lower in the
placebo group: median (IQR) of 2 days and 3 (2.5–3.5) days for the drug. The
results were not statistically significant (p=0.77). Ramadas et al.32 reported the
mean duration of diarrhea in Group A, B and C were 4.5±0.76, 3.47±0.5 and
3.17±0.37 days respectively. There was significant reduction in mean
frequency and duration of diarrhea in Group B and C compared to Group A
(p˂0.05).

In this study showed that some dehydration was found in 25(58.1%) in group
A and 29(67.4%) in group B. Severe dehydration was 2(4.7%) in group A and
1(2.3%) in group B. No dehydration was 16(37.2%) in group A and 13(30.2%)

34
in group B. The difference was not statistically significant (p>0.05) compared
between two groups. Sultana et al.1 reported In group A 20(36.36%),
35(63.64%) & 3(5.45%) children had no sign, some & severe dehydration
respectively. In group B, 17(30.90%), 37 (67.27%) & 1(1.81%) children had no
sign, some & severe dehydration respectively. Gharial et al. 33 observed the
difference in dehydration levels between the groups was not statistically
significant (p=0.25). It was noted that most children in the study were mild to
moderately dehydrated with severe dehydration present in only 15% of the
drug group and 27% of the placebo group. Similar results were found in the
study carried out by Schnadower et al.40

In current study showed that mean duration of hospital stay was 30.39±16.10
hrs in group A and 41.53±18.38 hrs in group B. Mean remission time was
49.7±23.22 hrs in group A and 66.25±29.41 in group B. The difference was
statistically significant between two groups. Sultana et al.1 showed that the
length of hospital stay was shorter in the combination group than in the zinc
group, which is similar to the findings of Gharial et al.33, who also reported a
shorter hospital stay in Racecadotril group.

In this study showed that skin rashes was found 4(9.3%) in group A and
6(14.0%) in group B. Angiooedema was 3(7.0%) and 1(2.3%) in group A and
group B respectively. Tonsilitis was 2(4.7%) in group A but found in group B.
Convulsions was 2(4.7%) in group A and 1(2.3%) in group B. The difference
was not statistically significant (p>0.05) between two groups. Gharial et al. 33
reported the proportion of patients experiencing any adverse event was
similar for the two groups (23%). There were four mortalities overall, two in
each group. Convulsions were noted in three children who were on the drug
(5%) but none in children on the placebo. All three children were investigated
for concurrent meningitis and this diagnosis was confirmed in one. Overall,
the proportion of children experiencing adverse reactions in the racecadotril
group was not statistically significant when compared to the placebo group.

35
Limitations of the study

1. The study population was selected from one selected hospital in Noakhali
city, so that the results of the study may not reflect the exact picture of the
country.

2. Small sample size was also a limitation of the present study. Therefore, in
future further study may be under taken with large sample size.

36
Conclusion

The mean frequency of diarrhea was significantly low in Zinc with racecadotril
in comparison to Zinc alone group. The mean duration of hospital stay and
mean remission time also significantly lower in Zinc with racecadotril group.
No any significant difference was found in adverse events between both
groups.

37
Recommendations

Further studies can be undertaken by including large number of patients.

38
Reference Cited

39
Reference

1. Sultana MM, Islam MS, Akhter S, Hossain MB, Mia MS. Comparative
Study of Zinc and Probiotics versus Zinc Alone Therapy in Children with
Acute Watery Diarrhea. TAJ: Journal of Teachers Association.
2017;30(2):32-8.
2. Bhutta ZA, Kliegman RM, Beharmen RE, Schor MF, Stanton BF.Acute
Gastroenteritis in Children. Nelson textbook of pediatrics, twentieth
edition. Philadelphia: WB Saunders 2016; Chapter 340; pp. 1854-1874.
3. Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, et al. Global,
regional, and national causes of child mortality: an updated systematic
analysis for 2010 with time trends since 2000. The Lancet. 2012 Jun
9;379(9832):2151-61.
4. WHO/UNICEF joint statement. Clinical management of acute diarrhea.
New York, NY, and Geneva, Switzerland: The United Nations Children’s
Fund/World Health Organization 2004: 1– 8.
5. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating
acute infectious diarrhoea. Cochrane Database of Systematic Reviews.
2010(11):CD003048.
6. Matheson AL, Noble S. Racecadotril. Drugs 2000;59:829–35.
7. Christophe F. Role of antidiarrhoeal drugs as adjunctive therapies for
acute diarrhoea in children. Int J Pediatr2013;2013:1–14.
8. Limited Abbot Health Products. SPC, Hidrasec Infant 10mg granules for
oral suspension. 2014. (Updated 9 April 2014) https://www.
medicines.org.uk/emc/medicine/27109/SPC/Hidrasec+Infant+10mg+gran
ules+for+oral+suspension/#PHARMACOKINETIC_PROPS (accessed 25
May 2014).
9. Lehert P, Chéron G, Calatayud GA, Cézard JP, Castrellón PG, Garcia
JM, et al. Racecadotril for childhood gastroenteritis: an individual patient
data meta-analysis. Digestive and Liver Disease. 2011 Sep 1;43(9):707-
13.
10. Cojocaru B, Bocquet N, Timsit S, Wille C, Boursiquot C, Marcombes F, et
al. Effect of racecadotril in the management of acute diarrhea in infants

40
 and children. Archives de pediatrie: organe officiel de la Societe
francaise de pediatrie. 2002 Aug 1;9(8):774-9.
11. Baumer P, Joulin Y. Pre- and post-marketing safety profiles of
racecadotril sachets, a “new” antidiarrhoeal drug. J
PediatrGastroenterolNutr 2009;48(Suppl 3):E99–E100.
12. World Health Organization DoCaAHaD. The treatment of diarrhoea, a
manual for physicians and other senior health workers—4th rev. Geneva:
World Health Organization, Department of Child and Adolescent Health
and Development, Development DoCaAHa, 2005.
13. Rautenberg TA, Zerwes U, Lee WS. Cost utility, budget impact, and
scenario analysis of racecadotril in addition to oral rehydration for acute
diarrhea in children in Malaysia. Clinico Economics and outcomes
research: CEOR. 2018;10:169-78.
14. Matheson AJ, Noble S. Racecadotril. Drugs. 2000;59(4):829–35.
15. Schwartz JC. Racecadotril: a new approach to the treatment of
diarrhoea. Int J Antimicrob Agents. 2000; 14(1):75–9.
16. Guarino A, Buccigrossi V, Armellino C. Colon in acute intestinal infection.
J PediatrGastroenterolNutr. 2009;48(Suppl 2):S58–62.
17. Eberlin M, Chen M, Mueck T, Däbritz J. Racecadotril in the treatment of
acute diarrhea in children: a systematic, comprehensive review and
meta-analysis of randomized controlled trials. BMC pediatrics. 2018
Dec;18(1):1-21.
18. Gordon M, Akobeng A. Racecadotril for acute diarrhoea in children:
systematic review and meta-analyses. Arch Dis Child. 2016;101(3):234–
40.
19. Wu B, Li J, Fb W, Tang Y. Meta-analysis of therapeutic efficacy of
racecadotril in the adjunctive treatment of acute infantile diarrhoea in
China. China Pharm. 2012;23(18):1687–9.
20. Castrellón PG, Allué IP, Lindo ES. Manejo de la gastroenteritis aguda en
menores de 5 años: un enfoque basado en la evidencia: Guía de
práctica clínica Ibero-Latinoamericana. In Anales de Pediatría 2010 Mar
1;72(3):220-e1).
21. Aik J, Ong J, Ng LC. The effects of climate variability and seasonal
influence on diarrhoeal disease in the tropical city-state of Singapore–A

41
 time-series analysis. International Journal of Hygiene and Environmental
Health. 2020 Jun 1;227:113517.
22. Jiwok, J.C., Adebowale, A.S., Wilson, I., Kancherla, V. and
Umeokonkwo, C.D., 2021. Patterns of diarrhoeal disease among under-
five children in Plateau State, Nigeria, 2013–2017. BMC Public
Health, 21(1), pp.1-9.
23. Kalu N, Lufesi N, Havens D, Mortimer K. Implementation of World Health
Organization Integrated Management of Childhood Illnesses (IMCI)
guidelines for the assessment of pneumonia in the under 5s in rural
Malawi. PLoS One. 2016 May 17;11(5):e0155830.
24. Barffour MA, Hinnouho GM, Wessells KR, Kounnavong S, Ratsavong K,
Sitthideth D, Bounheuang B, Sengnam K, Chanhthavong B, Arnold CD,
Brown KH. Effects of therapeutic zinc supplementation for diarrhea and
two preventive zinc supplementation regimens on the incidence and
duration of diarrhea and acute respiratory tract infections in rural Laotian
children: A randomized controlled trial. Journal of global health. 2020
Jun;10(1):1-14
25. Patel A, Mamtani M, Dibley MJ, Badhoniya N, Kulkarni H. Therapeutic
value of zinc supplementation in acute and persistent diarrhea: a
systematic review. PLoS One 2010;5(4):e10386-e10386.
26. Ischer PW, Giroux A, L'Abbé MR. The effect of dietary zinc on intestinal
copper absorption. Am J Clin Nutr. 1981 Sep;34(9):1670-5
27. Hoque KM, Rajendran VM, Binder HJ. Zinc inhibits cAMP-stimulated Cl
secretion via basolateral K-channel blockade in rat ileum. Am J
Physiol. 2005;288:G956–63
28. Hoque KM, Binder HJ. Zinc in the Treatment of Acute Diarrhea: Current
Status and Assessment. Gastroenterology. 2006;130:2201–05.
29. Zinc supplementation helps diarrhea symptoms. [last cited on 2010 Feb
6]. Available from: http://www.newsmedical.net / news / 2008 / 02 / 04 /
34888.aspx
30. Gordon M, Akobeng A. Racecadotril for acute diarrhoea in children:
systematic review and meta-analyses. Archives of disease in childhood.
2016 Mar 1;101(3):234-40.

42
31. Singh N, Narayan S. Racecadotril: A novel antidiarrheal. Medical Journal,
Armed Forces India. 2008 Oct;64(4):361.
32. Ramadas D, Chakraborty A. A Comparative Study of Probiotic Lactic
Acid Bacilli alone and in Combination with Bifidobacterium and
Saccharomyces as Adjuvants to ORS and Zinc in the Management of
Acute Pediatric Diarrhoea. International Archives of BioMedical and
Clinical Research 2016; 2(3): 47-50.

33. Gharial J, Laving A, Were F. Racecadotril for the treatment of severe

acute watery diarrhoea in children admitted to a tertiary hospital in
Kenya. BMJ open gastroenterology. 2017 Jan 1;4(1):e000124.
34. Aggarwal S, Upadhyay A, Shah D, Teotia N, Agarwal A & JaiswalV.
Lactobacillus GG for treatment of acute childhood diarrhea: An open
labelled, randomized controlled trial. Indian J Med Res. 2014; 139: 379-
385.
35. Faure C. Role of antidiarrheal drugs as adjunctive therapies for acute
diarrhea in children. International J Ped. 2013; :1-14.
36. Duggan C, Lasche J, McCarty M, Mitchell K, Dershewitz R, Lerman S J.
Oral rehydration solution for acute diarrhea prevents subsequent
unscheduled follow-up visits. Pediatrics 1999;104(3):e29.
37. Savita MR. Racecadotril—a novel drug for treatment of acute watery
diarrhea in Indian children. Karnataka Pedicon 2005; Karnataka, India:
Pediatric on call. 2005. (Updated 1 Jan 2006). http://www.
pediatriconcall. com/fordoctor/Conference_abstracts/racecadotrial.asp
(accessed 20 Sep 2013).
38. Lehert P, Chéron GA, Guillermo A. Racecadotril for childhood
gastroenteritis: an individual patient data meta-analysis. Dig Liver Dis.
2011;43:707–13.
39. Jean P, François D, Meyer M. Efficacy and tolerability of racecadotril in
acute diarrhea in children. Gastroenterology 2001;120:799–805.
40. Schnadower D, Tarr PI, Gorelick MH. Validation of the Modified Vesikari
Score in Children with Gastroenteritis in 5 U.S. Emergency Departments.
J Pediatr Gastroenterol Nutr. 2013;57:514–19.

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Appendices

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 Appendix-A
Data collection sheet

A. General information:
Date-
1. ID no…………………….. 2. Ward……………… Bed………………….
2. Date of admission………………………. Reg No…………………………
3. Name of the patient……………………..
4. Sex M=1, F=2 ………………………….
5. Date of birth ……………………………. 6. Age ……………yrs
7. Mother’s name ………………………….. 8. Age …………. yrs
9. Father’s name …………………………… 10. Age ………… yrs
11. Address : ……………………………………………………………………………

12. Phone no ………………………………

13. Residence: Urban =1, Rural =2, Urban slum= 3
14. Socioeconomic status: Average = 1, Below average =2, Above average=3,
Poor = 4

Study group : 1= Racecadotril 2= Placebo

FAMILY HISTORY

15. Birth issue : 1st issue-1 , 2nd issue -2, 3rd issue – 3, >3rd issue-4
16. Sib death: Yes = 1, No = 2
17. H/O similar illness in the family: Yes=1, No=2

History:
 H/O cough: 1= Yes 2=No /______/

 H/O breathing difficulty 1= Yes 2= No /______/

 H/O runny nose: 1= Yes 2= No /______/

 H/O fever: 1= Yes 2= No /______/

 H/O feeding difficulty: 1= Yes 2= No /______/

 H/O sleeping difficulty: 1= Yes 2= No /______/

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  H/O wheeze: 1= Yes 2= No /______/

 H/O congenital heart disease: 1= Yes 2=No /______/

 Previous H/O similar illness: 1= Yes 2= No /______/

 H/O consanguinity: 1= Yes 2= No /______/

 Previous H/O hospitalization: 1= Yes 2= No /______/

 Frequency of hospitalization: 1=<3 2=>3 /______/

 H/O atopy of patient/ family 1= yes 2= No /______/

Clinical Features
 Appearance: 1= Irritable 2= Playful /_______/

 Cyanosis: 1= Yes 2= No /_______/

 Temperature: ………….0F

 Nasal flaring: 1= Yes 2= No /_______/

 Respiratory Rate: 1 = <50/ min 2 = >50/ min /______/

 Chest indrawing : 1 = Yes 2 = No /______/
 Mediestinal shifting : 1 = Yes 2 = No /______/
 Breath sound: 1 = Vesicular with prolonged expiration
 2 = Bronchial 3= Others /_______/
 Ronchi: 1 = Yes 2 = No /______/
 Crepitation: 1= Yes 2= No / ______/
 Heart rate: < 160 beats per minute): 1 = Yes 0 = No
/______/
 Heart sound: 1 = Normal 2= Abnormal /_______/
 Murmer : 1= Yes 2 = No /_______/
 Hepatomegaly: 1= yes 2= No /________/
 Spleenomegaly: 1= Yes 2= No /_______/

Malnutrition: 1=None, 2= Mild 3= Moderate 4= Severe

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Duration of diarrhea: days

Number of stool:

Vomiting :

Number of vomiting per day:

Duration of vomiting :

Temperature

Dehydration : 1= Mild 2= Moderate 3= Severe

Adverse events

Skin rashes 1= Yes 2= No

Pruritus 1= Yes 2= No

Angiooedema 1= Yes 2= No

Tonsilitis 1= Yes 2= No

Mortality 1= Yes 2= No

Convulsions 1= Yes 2= No

(Principal Investigator)

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