A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and

Persistent Diarrhea
Marek Lukacik, MD
a
, Ronald L. Thomas, PhD

and !aco ". Aranda, MD, PhD

a
Department of Pediatrics, Children's Medical Center, Medical College of Georgia, Augusta,
Georgia
b
Department of Pediatrics, Wayne State Uniersity School of Medicine, and Children's !ospital of
Michigan, Detroit, Michigan, and "ational #nstitute of Child !ealth and !uman Deelopment,
Pediatric Pharmacology $esearch Unit "et%or&, Wayne State Uniersity, Detroit, Michigan
A#$TRA%T

'()*C+#,*- Children in deeloping countries are at a high ris&

for .inc
deficiency- Supplemental .inc has preiously been sho%n

to proide
therapeutic benefits in diarrhea- +he ob/ectie of

this study %as to e0amine
the efficacy and safety of supplemental

oral .inc therapy during recoery from
acute or persistent diarrhea-

M*+!'DS- We conducted a meta1analysis of randomi.ed, controlled

trials to compare the
efficacy and safety of supplementary oral

.inc %ith placebo in children %ith acute and persistent
diarrhea-

$esults %ere reported using a pooled relatie ris& or a %eighted

mean difference- A
total of 22 studies %ere identified for inclusion3

45 e0amined acute diarrhea 6n 7 48294:, and 5
e0amined persistent

diarrhea 6n 7 2;5<:-

$*SU=+S- Mean duration of acute diarrhea and persistent diarrhea

%as significantly lo%er for
.inc compared %ith placebo- Presence

of diarrhea bet%een .inc and placebo at day 4 %as not
significantly

different in acute diarrhea or persistent diarrhea trials- At

day 9, presence %as
significantly lo%er for .inc in persistent

diarrhea trials 6n 7 224: but not in acute diarrhea trials-

,omiting after therapy %as significantly higher for .inc in

44 acute diarrhea trials 6n 7 >>9<: and >
persistent diarrhea

trials 6n 7 2;5;:- +hose %ho receied .inc gluconate in comparison

%ith .inc
sulfate?acetate omited more fre@uently- 'erall,

children %ho receied .inc reported an 4<-<A
and 42-8A reduction

in aerage stool fre@uency, 48-BA and 48-8A shortening of diarrhea

duration, and a 4C-;A and 4<-BA probability of reducing diarrhea

oer placebo in acute and
persistent trials, respectiely-

C'"C=US#'"S- Dinc supplementation reduces the duration and seerity

of acute and persistent
diarrheaE ho%eer, the mechanisms by

%hich .inc e0erts its antidiarrheal effect hae not been
fully

elucidated-

&ey 'ords( diarrhea F .inc
Are)iations( W!'GWorld !ealth 'rgani.ation F '$SGoral rehydration solution F $$G
relatie ris& F WMDG%eighted mean difference F C#Gconfidence interal F cAMPG9',8'1cyclic
monophosphate F HGpotassium F CaGcalcium
Diarrheal diseases pose a significant public health problem

on a global scale and especially in
deeloping countries- #t

is estimated that there are 4-8 billion episodes of diarrhea

per year and
that diarrheal disease accounted for 24A of all

deaths in children %ho %ere younger than 8
years- +his is e@uialent

to 2-8 million deaths in the same age group-
4,2
+his compares more faorably %ith the results of a preious

study from 4;<2 in %hich on the
basis of a reie% of actie

sureillance data from studies conducted in the 4;8Bs, 4;5Bs,

and
4;CBs, it %as estimated that >-5 million children died annually

from diarrhea-
9
"e%er data from
the World !ealth 'rgani.ation

6W!': sho% that diarrheal disease accounts for 4<A of the 4B-5

million deaths in children %ho %ere younger than 8 years-
>
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D,$%+$$,O-
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'ne of the ma/or adances in the reduction of mortality from

diarrhea %as the introduction of
W!' oral rehydration solution

6'$S:
8
E ho%eer, W!' '$S does not significantly decrease stool

output and duration of diarrhea, and therefore other approaches

to add to or to enhance the
aailable '$S hae been sought-

Seeral ne%er approaches hae included the addition of .inc

to
the treatment regimen- Dinc is an essential micronutrient

and protects cell membranes from
o0idatie damage- Dinc is not

stored in the body, so the leel of .inc is determined by the

balance
of dietary inta&e, absorption, and losses- A .inc deficiency

state may e0ist in children %ith acute
diarrhea as a result

of intestinal loss- A comprehensie reie% on this sub/ect %as

recently
published-
5
An alternatie ie% is that .inc may be

%or&ing as a pharmacologic agent at the leel
of gene e0pression-
C
+he efficacy of .inc in the treatment of diarrhea is supported

by seeral
randomi.ed, controlled trials that sho%ed reduction

of diarrhea duration, stool output, and stool
fre@uency- Meta1analyses

on the therapeutic effects
<
of .inc in acute and persistent

diarrhea as
%ell as preention
;
of diarrhea %ith .inc supplementation

hae been preiously published- +he
published data so far hae

sho%n the efficacy of .inc in the treatment of acute and chronic

diarrhea- 'ur meta1analysis %as performed to include ne% studies

published since the last meta1
analysis and to e0amine the efficacy

and safety of .inc therapy during recoery from acute or
persistent

diarrhea-

MET*OD$

,nclusion %riteria
Studies that %ere selected for inclusion tested the same primary

hypotheses 6aerage duration of
diarrhea and presence of diarrhea

at days 4, 9, and 8: using similar patient
characteristics 6primarily

children aged bet%een 4 and 5B months:, %ith either
acute or

persistent diarrhea, including dysentery- Acute diarrhea %as

defined
as lasting up to 4> days, %ith persistent diarrhea lasting

I4> days- $andom
allocation to treatment groups and concealment

of allocation had to be met to
satisfy inclusion because inade@uate

allocation concealment, despite the use
of randomi.ation, allo%s

a ris& for selection bias- #nterention %ith oral .inc salt
supplementation, allo%ing for any .inc salt type or formulation

6sulfate,
gluconate, or acetate: if applied at 8 mg?day for

any length of duration, %as e0amined against a
control using

a placebo- All comparisons bet%een treatment groups had to be

free of confounding
by additional agents or co1interentions-

Study groups %ho, after randomi.ation, receied .inc
supplementation

and '$S or .inc supplemented %ith itamin A %ere e0cluded-

,dentification of Trials
+he search strategy used computeri.ed bibliographic searches

of Medline 64;55J2BB5:E the
Cochrane Central $egister

of Controlled +rials 62BB5:E *mbase 64;C>J2BB5:E =ilacs

64;<2J2BB5:E
C#"A!= 64;<2J2BB5:E Current Controlled

+rials 62BB5:E and abstracts published in Pediatric
Research

64;;4J2BB5: and the Kirst 6(oston, 2BBB: and Second 6Paris,

Krance, 2BB>: World
Congress of Pediatric Gastroenterology,

!epatology and "utrition- (oth published and
unpublished trials

%ere included in an effort to control for publication bias-

Citations of appropriate
studies %ere erified by reie%ing

the bibliographies and reference lists of identified trials-

#dentified titles of abstracts %ith potential releance %ere

do%nloaded, and full manuscripts %ere
then obtained for all

abstracts that %ere deemed releant on the basis of the inclusion

criteria-
+%enty1t%o trials met inclusion criteria3 45 published

studies relatie to the definition of acute
diarrhea and 5 relatie

to persistent diarrhea-

Primary and $econdary Outcomes
Data on < clinically releant outcome measures %ere collected-

We held aerage duration of
diarrhea and presence of diarrhea

episodes at days 4, 9, and 8 as our primary outcomes- Data
on

omiting fre@uency, omiting fre@uency by therapy type, stool

fre@uency reduction, and
probability of diarrhea continuation

%ere e0tracted as secondary outcomes- All 9 authors
independently

e0tracted data from the same articles using a data e0traction

sheet and
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subse@uently compared results for agreement- +he data

thus obtained %ere chec&ed for
consistency among authors, integrity

of randomi.ation, and concealment of allocation- Luestions
regarding

the interpretability of certain data alues %ere resoled by

all 9 authors- +he final
database entries %ere erified by the

statistician 6Dr +homas:- Ke% studies satisfied criteria for

inclusion on eery datum ariable- When necessary, authors of

selected studies %ere contacted
to erify e0tracted data alues

deried from graphs and?or to proide additional information

in a
scaling form that could be combined %ith other studies-

Where those instances occurred, they are
noted in +ables 4 and

2-

"ie/ this tale(
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TA#LE 0 Aerage Duration of Diarrhea 6Days:

"ie/ this tale(
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TA#LE 1 "umber of Children With Diarrhea at Days 4, 9, and 8

Definitions
Definitions of diarrhea aried some%hat in all included studies-

#n acute trials, generally, the
definitions stated for diarrhea

%ere the passage of 9 loose, %atery stools or 4 loose, %atery

stool %ith blood %ithin 2> hours for bet%een 9 and C days in

duration- #n persistent diarrhea trials,
the definitions %ere

similar, %ith the e0ception that they persisted up to 4> days

in duration-

Definitions for duration of diarrhea aried as %ell but %as

defined, generally, from the time of
enrollment into the study

until the first formed stool- Duration %as measured in either

days or
hours- Kor the purpose of this meta1analysis, hours

%ere conerted to days- After
enrollment?randomi.ation, either

the .inc treatment or the placebo %as assigned %ithin 2> hours-

$tatistical Analyses
Comprehensie Meta1Analysis,
4B
a stand1alone program, %as used

to synthesi.e data that %ere
obtained from the 22 trials identified

for inclusion3 45 acute and 5 persistent diarrhea trials-
(riefly,

the analysis soft%are produces a Korrest plot as a schematic

description of the meta1
analysis results- +he program is augmented

using accepted computational algorithms- Where
appropriate,

results %ere reported using a pooled relatie ris& 6$$:- Kor

continuous outcomes, the
%eighted mean difference 6WMD: %as

calculated- +he ;8A confidence interals 6C#s: %ere
reported

around the %eighted effect si.e-

*etero2eneity
Gien that studies that are selected for inclusion in a meta1analysis

%ill differ, the types of
ariability 6clinical, methodologic,

and?or statistical: that may occur among studies must be
inestigated-

+hese arious types of ariability are termed heterogeneity-

Meta1analysis should be
considered only %hen a group of trials

is sufficiently homogeneous 6as indicated in the inclusion
criteria:

in terms of participants, interentions, and outcomes to proide

a meaningful summary-
Strict adherence to the inclusion criteria

listed, such as blinding and concealment of allocation,
help

to control for clinical?methodologic heterogeneity- Still, statistical

heterogeneity can also
occur %hen ariability in the treatment

effects being ealuated in the different trials e0ists- +his

results %hen the obsered treatment effects are more different

from each other than %ould be
e0pected as a result of random

error 6chance: alone- Kollo%ing conention, statistical
heterogeneity

in the results of this meta1analysis are referred to simply

as heterogeneity-

Different approaches for identification and measurement of heterogeneity

%ere therefore
underta&en to e0amine the e0tent to %hich the

results of the studies included %ere consistent- C#s
for the

results of indiidual studies 6depicted graphically using hori.ontal

lines: %ere e0amined for
poor oerlap, a general indication

of presence of statistical heterogeneity- ,ariability
6heterogeneity:

among the obtained effects si.es %as formally operationali.ed

using a
2
test of
significance- +he formula for heterogeneity

assesses the dispersion of indiidual outcomes, is1O1
is

the combined effect, and denotes this alue using a Q statistic-
44
A lo% P alue 6or a large
2

statistic relatie to its degree

of freedom: proides eidence of heterogeneity of treatment

effects
6ariation in effect estimates beyond chance:-

(ecause some degree of clinical and methodologic diersity al%ays

occurs in a meta1analysis,
some statistical heterogeneity is

ineitableE therefore, the test for heterogeneity is irreleant

to the
choice of analysis3 heterogeneity %ill al%ays e0ist regardless

of %hether it can be detected using
a statistical test- Still,

methods hae been deeloped for @uantifying inconsistency across

studies
that moe the focus a%ay from testing %hether heterogeneity

is present to assessing its impact
on the meta1analysis- A useful

statistic for @uantifying inconsistency is I
2
, the percentage

of the
ariability in effect si.e estimates that is attributable

to heterogeneity rather than sampling error
6chance:-
42
A alue

I8BA may be considered substantial heterogeneity, and that

percentage
cutoff %as adopted and e0amined also in our analyses-

3ra)ity
Another more recent approach
49
proposed /ac&&nife resampling

to measure a concept termed
Pgraity-P #n any meta1analysis,

arguments hae focused on the inclusion or e0clusion of some

studies, %ith debate on %hich ones should be included or e0cluded

because studies are
commonly %eighted according to their sample

si.e and?or internal ariability- Gee
49
proposed that
/ac&&nife

resampling could be used to e0amine study influence and detect

outlier studies- +he
techni@ue recomputes the meta1analysis

once for each of k studies, %here each study is
indiidually

e0cluded- K results are then obtained- +he difference bet%een

the aerage of these k
results and each study's indiidual result

6%hen omitted: is ta&en as an inde0 of Pra% graity-P +his
difference,

diided by the SD of the k differences, is ta&en as a z score,

or Pstandardi.ed graity,P
%hich can be used to establish %hich

studies might be unusually influential- SPSS 48-B
4>
%as
used

to calculate standardi.ed graity alues-

.i4ed- or Random-Effects Model
Choice of %hether to interpret a fi0ed1effects or random1effects

model %as considered thoroughly-
Ki0ed1effect meta1analyses

ignore heterogeneity- +he fi0ed1effect estimate and its C# address

the
@uestion, PWhat is the best estimate of the treatment effectQP

+he random1effects estimate and its
C# address the @uestion,

PWhat is the aerage treatment effectQP +he ans%ers to these

@uestions
are analogous %hen no heterogeneity is present or

%hen the distribution of the treatment effects
is roughly symmetrical-

#f they are not, then the random1effects estimate may not reflect

the actual
effect in any population being studied- #n a fi0ed1effects

meta1analysis, a pooled1effect estimate is
termed, generally,

as the best estimate of the treatment effect- #t is for these

reasons that %e
chose a fi0ed1effects model for our meta1analysis,

along %ith the arious stated approaches to
e0amine heterogeneity

if found-

RE$+LT$

+he author, year, country, amount of .inc supplementation and

type, sample
si.e, and age for each of the 22 studies selected

for inclusion in the meta1
analysis are listed in +ables 9 and

>- Although all 22 studies %ere randomly
assigned clinical trials,

it seemed that 8
48J4;
%ere not double1blinded- Si0teen

of
these published studies met the definition for acute diarrhea

and 5 for
persistent diarrhea-

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"ie/ this tale(
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TA#LE 5 Characteristics of Acute Diarrhea +rials

"ie/ this tale(
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TA#LE 6 Characteristics of Persistent Diarrhea +rials

'erall, 85-9A 6; of 45: of acute diarrhea trials %ere conducted

in inpatient hospital settings, and
>9-CA 6C of 45: %ere conducted

in outpatient homes and communities- 'f the 5 persistent
diarrhea

trials, 55-CA 6> of 5: %ere inpatient and 99-9A 62 of 5: %ere

outpatient-

Mortality
Mortality %as originally a primary outcome in this meta1analysisE

ho%eer, of both acute and
persistent trials, only 9
48,2B,24
reported mortality outcome, ma&ing it difficult to compare across

all
included trials- +%o of these %ere acute diarrhea trials,
48,2B
and 4 %as a persistent diarrhea trial-
24
#n the largest acute

diarrhea outpatient trial
48
6n 7 <BCB:, 99 children 6B-BB<AE

99 of 9;C>: died in
the .inc1treated group and 9C 6B-BB;AE 9C

of >B;5: died in the placebo group- +hirty deaths %ere
attributed

to dro%ning, and the remaining %ere not in/ury related 6ie,

not attributable to .inc
interention:- When restricted to nonin/ury

deaths, there %ere 49 in the .inc1treated group and 2C
in the

placebo group- +he inestigators attributed the lo%er nonin/ury

death rate in the interention
group almost entirely to fe%er

deaths from diarrhea and acute lo%er respiratory infection-

Diarrhea and acute lo%er respiratory infection together accounted

for 4B deaths in the .inc
interention group and 2B deaths in

the placebo group- #n the other acute diarrhea trial,
2B
2
children

in the placebo group died of septicemia- #n the persistent diarrhea

trial,
24
the causes of
death %ere septicemia %ith diarrhea in

9 children, septicemia in 4 child, bronchopneumonia in 4
child,

and continued diarrhea in 4 child- (ecause acute and persistent

diarrhea are, most li&ely,
distinct disease entities, the outcomes

obtained are presented initially for acute diarrhea 6lasting

up to 4> days: and follo%ed by persistent diarrhea 6lasting

I4> days:-

Results for Acute Diarrhea Trials
Duration of Acute Diarrhea
#n 45 trials that e0amined the primary measure of aerage duration

of acute diarrhea
48J4C,4;,2B,22J92

6n 7 48294:,

those %ho receied .inc e0perienced a significantly lo%er aerage

duration of
diarrhea than those %ho receied a placebo 6WMD3

B-2>E S*3 B-B2E ;8A C#3 B-24JB-2CE P R -BB4E
+able

8, Kig 4: but also %ith the presence of statistically significant

heterogeneity 6Q 7 ;8-8<,
degrees of freedom MdfNQ 7 48, P R

-BB4, I
2
7 <>-9A:- Kigure 4 depicts a Korrest plot for these

results, in %hich eery study is displayed as a point estimate

%ith C#s-

"ie/ this tale(
Min this %indo%N
Min a ne% %indo%N

TA#LE 7 Mean Duration of Acute Diarrhea

"ie/ lar2er )ersion 694H:3
Min this %indo%N
Min a ne% %indo%N

.,3+RE 0 Mean difference in duration of acute
diarrhea- +he effect si.e inde0 in this plot is the
standard mean difference, so a point estimate of B-B
indicates no effect- ,alues RB-B reflect a better outcome
for the placebo group, and alues IB-B indicate a better
outcome for the .inc group- #f the point estimate and C#
fell aboe B-B, then the study %ould meet the criterion for
statistical significance 6 7 -B8:- #f the C# oerlapped B-B,
then the P alue %ould e0ceed -B8 and the study %ould
not be statistically significant-

*0amination of significant heterogeneity in the acute diarrhea

trials reealed 8 trials
4C,4;,2B,28,9B
%ith
insignificant differences

bet%een .inc and placebo groups in aerage duration of diarrhea-

P
alues ranged from ->C< to nonsignificant in sample si.es

that ranged from 8B to 248- Although
those %ho receied .inc

had a shorter aerage duration of diarrhea, the difference in

>
trials
4C,4;,2B,9B
%as ery small, %ith an aerage difference

of B-4< S B-4< days ranging from B-B> to
B->B days- 'ne

trial
28
found no difference at all bet%een treatment groups-

Participants in all 8
trials had been admitted for dehydration

secondary to diarrhea, although the seerity of
dehydration

ranged- Kour of the trials
4C,2B,28,9B
administered an '$S before

treatment assignment-
+hree trials receied .inc sulfate and

2 receied acetate- #n contrast, all acute diarrhea trials
29,94,92
that proided .inc gluconate and not .inc sulfate had a shorter

duration of diarrhea than placebo
6P -B<:- +%o trials
4C,2B
originated from #ndia, 2
28,9B
from (angladesh, and 4
4;
from

Australia- 'ne
trial
48
in %hich aerage duration %as significantly

lo%er 64-2 days lo%er: %ith .inc use also had a
tremendously

higher sample si.e 6n 7 <BCB: than all of the others-

+able 5 sho%s the effect si.es, calculated ra% graity alues,

standardi.ed graity alues, and
sample si.es for each study

%hen remoed- #t is clear that 4 study
48
had a great deal of

impact on
the strength and direction of the estimated effect

si.e alue found for aerage duration of acute
diarrhea among

all studies- When remoed, the reaeraged effect si.e obtained

6B-4<C: and
plotted standardi.ed graity alue 69-894E Kig 2:

%ere considered outlying alues in comparisons
%ith all others-

+his is largely attributed to the enormous sample si.e 6n 7

<BCB: used in the trial,
because een ery small differences

in mean duration of diarrhea %ould be statistically
significant-

"ie/ this tale(
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TA#LE 8 Acute Diarrhea3 Graity ,alues for Duration of Diarrhea

"ie/ lar2er )ersion 645H:3
Min this %indo%N
Min a ne% %indo%N

.,3+RE 1 Standardi.ed graity results-

Occurrence of Diarrhea at Day 0
Kie acute diarrhea trials
45,4;,2B,2C,92
reported the occurrence

of diarrhea at day 4 6n 7 94BB:- "o
statistically significant

difference in the occurrence of acute diarrhea at day 4 %as

found 6$$3
4-B4E ;8A C#3 B-;;J4-B9E P = B-9B:- Although

the ariability in effect si.es ranged from a lo% of
B-;5< to

4-5;8, significant heterogeneity did occur 6Q 7 4B-5B, dfQ 7

>, P = -B9, I
2
7 52-9A:-

Occurrence of Diarrhea at Day 5
Si0 acute diarrhea trials
45,4;,2B,29,2C,92
collected data for

occurrence of diarrhea at day 9- "o
statistically significant

differences occurred bet%een treatment groups in occurrence

of diarrhea
at day 9 6$$3 B-;CE ;8A C#3 B-;4J4-B9E P 7

-95:E ho%eer, the occurrence of statistically
significant heterogeneity

%as found 6Q 7 4B-<<B, dfQ 7 8, P = B-B8, I
2
7 8>-BA:- 'nly

4 trial
9B
found
a significantly 6P 7 -B4: lo%er occurrence of

diarrhea at day 9 %ith .inc 62C->A: than placebo
698->AE effect

si.e3 B-CC>:E ho%eer, the occurrence of statistically significant

heterogeneity %as
found 6Q 7 4B-<<B, dfQ 7 8, P = -B8, I
2
7

8>-BA:-

Occurrence of Diarrhea at Day 7
Similarly, in the same 5 acute diarrhea trials,
45,4;,2B,29,2C,92
no statistically significant differences
occurred bet%een treatment

groups in occurrence of diarrhea at day 8 6$$3 B-;>E ;8A C#3

B-<>J
4-B8E P 7 -25:- Similar to day 9 results, the occurrence

of statistically significant heterogeneity %as
found 6Q 7 4<-;8C,

dfQ 7 8, P = -BB2, I
2
7 C9-5A:-

"omitin2
#n 44 acute diarrhea trials
45,4C,4;,22J28,2;J92
6n 7 >>9<:, the proportion of participants %ho omited
after

the initial dose %as significantly higher %ith .inc 62C< M42-CAN

of 24;5: use than %ith placebo
64C4 MC-5AN of 22>2E $$3 4-88E

;8A C#3 4-9BJ4-<>E P B-BB4AE Q 7 28-8>, P = -BB>:-

"omitin2 After Administration of Zinc $ulfate or 3luconate
#n 9 acute diarrhea trials,
29,94,92
a significantly higher proportion

of patients %ho receied .inc
gluconate omited 645B M4>-5AN

of 4B;8: than .inc sulfate?acetate therapy
45,4C,4;,22,2>,28,2;,9B
644<
M4B-CAN of 44B4E $$3 4-4<E ;8A C#3 4-B8J4-94E P =

-BB5:-

$hortenin2 of Diarrhea Duration
*ight trials of acute diarrhea
48J4C,2B,28,25,2;,94
found

an aerage shortening of diarrhea duration of
48-BA for those

%ho receied .inc in comparison %ith placebo 6+able C:-

"ie/ this tale(
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TA#LE 9 *ffects of Dinc +herapy of Acute Diarrhea

Reduction in $tool .re:uency
Seen trials of acute diarrhea
4C,22,29,28,2;,94,92
found an

aerage reduction in stool fre@uency of
22-4A %ith .inc therapy

in comparison %ith placebo- 'ne single trial
45
found a 8-BA

higher stool
fre@uency using .inc than placebo-

$tool Out;ut
+hree trials of acute diarrhea
2>,25,9B
found an aerage lo%ering

of stool output of 9B-9A-

Proaility of Diarrhea Reduction
*ight acute diarrhea trials
2B,29J28,2C,2<,9B,92
measured

the probability of diarrhea reduction and found
a 4C-;A reduction

using .inc compared %ith placebo-

Results for Persistent Diarrhea Trials
Duration of Persistent Diarrhea
#n 8 persistent diarrhea trials
4<,24,99J98
6n 7 ><;:,

those %ho receied .inc also e0perienced a
significantly lo%er

aerage duration of diarrhea than the placebo group 6WMD3 B-9BE

S*3 B-B;E
;8A C#3 B-42JB-><E P R -BB4E +able <: but

%ithout significant heterogeneity 6Q = 9-B<, dfQ 7 >, P =
-8>>,

I
2
7 2;-;A:- Kigure 9 depicts the Korrest plot for these results-

"ie/ this tale(
Min this %indo%N
Min a ne% %indo%N

TA#LE < Mean Duration of Persistent Diarrhea

"ie/ lar2er )ersion 64>H:3
Min this %indo%N
Min a ne% %indo%N

.,3+RE 5 Mean difference in duration of persistent
diarrhea- +he effect si.e inde0 in this plot is the
standard mean difference, so a point estimate of B-B
indicates no effect- ,alues RB-B reflect a better outcome
for the placebo group, and alues IB-B indicate a better
outcome for the .inc group- #f the point estimate and C#
fell aboe B-B, then the study %ould meet the criterion for
statistical significance 6 7 -B8:- #f the C# oerlapped B-B,
then the P alue %ould e0ceed -B8 and the study %ould
not be statistically significant-

Occurrence of Diarrhea at Day 0
#n 2 trials of persistent diarrhea
9>,98
6n 7 224:, no statistically

significant differences occurred
bet%een treatment groups in

occurrence of diarrhea at day 4 6$$3 4-BBE ;8A C#3 B-;9J4-B<E

P 7 -
;<:, and no statistically significant ariability occurred

among the effect si.es 6Q 7 B-B4, dfQ 7 4, P
= -;9:-

Occurrence of Diarrhea at Day 5
#n 2 trials of persistent diarrhea
9>,98
6n 7 224:, a significantly

lo%er occurrence of diarrhea at day
9 occurred in those %ho

%ere treated %ith .inc in comparison %ith placebo 6$$3 B-CBE

;8A C#3
B-84JB-;>E P 7 -B2:- "o statistically significant

ariability occurred among the effect si.es 6Q 7
B-99, dfQ 7

4, P = -85:-

Occurrence of Diarrhea at Day 7
+his %as not e0aminedE fe%er than 2 studies reported-

"omitin2
#n > persistent diarrhea trials
4<,24,98,95
6n 7 2;5;:, a significantly

higher proportion omited on .inc
6>4 M2-<AN of 4><2: than %ith

placebo 62 MB-BB4AN of 4><CE $$3 9-5>E ;8A C#3 4-B2J49-B2E

P = -
B>CE Q 7 8-;4, P = -445:-

"omitin2 After Zinc $ulfate or 3luconate
#n > persistent diarrhea trials,
4<,24,98,95
those %ho receied

.inc gluconate
98,95
omited more
fre@uently 6>4 M9AN of 495C:

than did those %ho receied .inc sulfate?acetate 6B MBAN of

448E $$3
4-B;E ;8A C#3 B-;>J4-B;E P 7 -BC:-

$hortenin2 of Diarrhea Duration
#n > persistent diarrhea trials,
4<,24,9>,98
those %ho receied

.inc e0perienced a 48-8A aerage
shortening of diarrhea duration

than those %ho got a placebo 6+able ;:-

"ie/ this tale(
Min this %indo%N
Min a ne% %indo%N

TA#LE = *ffects of Dinc +herapy of Persistent Diarrhea

Reduction in $tool .re:uency
Kour trials of persistent diarrhea found that those %ho receied

.inc also e0perienced an aerage
of ;-<A reduction in fre@uency-

$tool Out;ut
Stool output %as not measured in the persistent trials-

Proaility of Diarrhea Reduction
+%o persistent diarrhea trials
99,95
that measured the probability

of diarrhea reduction found an
4<-BA reduction %hen .inc %as

used oer placebo-

D,$%+$$,O-

'n the basis of these findings, %hich no% add to the large body

of preiously published clinical
data and update preious meta1analyses

and systematic reie%s,
<,9C
.inc
therapy is useful for treating

both acute and persistent diarrhea and for their
prophyla0is-

Still, as e0tensiely addressed in a recent systematic reie%,
5
much information is lac&ing relatie to the mechanisms by %hich

.inc
physiologically e0erts its antidiarrheal effect- #n this

meta1analysis, 8 694-9A:
of 45 acute diarrhea studies
4C,4;,2B,28,9B
found no statistically significant
differences bet%een .inc

and placebo on the aerage duration of diarrhea 6at
least a

P -><:- Similarly, 2 6>B-BA: of 8 persistent diarrhea studies
24,99
also
found no statistically significant differences in aerage

duration of diarrhea bet%een treatments
6at least a P ->9:-

Still, the aerage stool fre@uency reductions, shortening of

diarrhea durations,
and probabilities of a shortening of diarrhea

duration reported %ere higher in studies %ith .inc
therapy in

comparison %ith placebo-

+o the ma/ority of indiiduals, diarrhea means an increased

fre@uency or decreased consistency
of bo%el moements- #n many

deeloped countries, the aerage number of bo%el moements is

9
per dayE ho%eer, diarrhea is associated %ith an increase

in stool %eight, mainly as a result of
e0cess %ater, %hich normally

ma&es up a large percentage of fecal matter- Gien this, diarrhea

is
distinguished from diseases that cause only an increase in

the number of bo%el moements or
fecal incontinence-

Determining the e0act causes of diarrhea can be difficult because

there are many different
diarrheal agents, %ith such a ariety

of infectious agents, including bacteria, parasites, and
iruses-

#dentification of specific diarrheal agents is complicated by

the lac& of access to
laboratory tests in many deeloping countries-

,iral gastroenteritis caused by rotairus is the
primary cause

of diarrhea among infants %orld%ide- 'ther causes include bacterial

pathogens
such as Vibrio cholerae, Shigella, and Salmonella-

Proto.oa such as Cryptosporidium parum
and !iardia lamblia

are 2 of the most common proto.oan diarrheal agents- +he primary

symptoms of rotairus infection are feer and omiting for seeral

days, follo%ed by nonbloody
diarrhea- Although not normally

fatal, the diarrhea caused by the irus can be @uite seere,

leading to potentially life1threatening dehydration- Although

easily treated %ith intraenous fluids
TOP
A#$TRA%T
MET*OD$
RE$+LT$
D,$%+$$,O-
RE.ERE-%E$
in deeloped nations,

these supplies are often unaailable in the deeloping %orld,

and the
dehydration that is caused by rotairus is a significant

cause of mortality-

#n fact, conclusions from these randomi.ed trials for the efficacy

of .inc treatment on diarrhea
duration included an improed

absorption of %ater and electrolytes by the intestine and @uic&er

regeneration of gut epithelium-
9<
#ncreased leels of brush

border 6apical: en.ymes suggesting a
.inc transporter for enterocytes
9;
and a stronger immune response that increased clearance of
pathogens

from the intestine
>B
%ere also described-

*fficacy of oral rehydration therapy in correcting dehydration

and reducing mortality led to
treatment modifications of '$S

%ith .inc therapy- Success %ith .inc therapy has generally been

attributed to a decrease in the olume of small intestinal fluid

and sodium absorption triggered by
.inc deliery- Still, the

mechanisms by %hich .inc improes fluid and electrolyte transportation

hae not been elucidated fully- +his includes the effect of

.inc on intestinal ion transport, %hether
.inc initiates or

increases cation absorption and?or suppresses anion secretion,

and %hether
deficiency enhances the li&elihood of secretory

diarrhea-

Most li&ely, the location of the effect of .inc is in the small

intestine, gien its inhibition of
adenosine 9',8'1cyclic monophosphate

6cAMP:1induced chloride1dependent fluid secretion-
+reatment

%ith '$S %ould hae its greatest effect on reducing fluid loss

by increasing small
intestine absorption- +hus, .inc therapy

after pretreatment %ith '$S may not hae sho%n a
beneficial

effect 6reduced aerage duration of diarrhea: oer placebo in

8 trials
4C,4;,2B,28,9B
of this
meta1analysis simply because

pretreatment %ith '$S had already ma0imi.ed the small intestine

absorption rate-

Dinc inhibits cAMP1induced chloride secretion by specifically

inhibiting basolateral potassium 6H:
channels %ith no bloc&age

effect on calcium 6Ca:1mediated H channels in in itro studies

%ith the
rat ileum-
>4
Dinc also inhibits cholera to0inJinduced

but not "scherichia coli heat1stable
enteroto0in1induced ion

secretion in cultured Caco12 cells- 'ne study
>2
sho%ed that

cAMP acted
as the intracellular effector of heat1labile enteroto0in1induced

fluid secretion- Guanosine 9',8'1
cyclic monophosphate mediates

heat1stableJinduced fluid secretion- #f substantiated,

then the
effectieness of .inc %ould be limited to heat1labileJinduced

diarrhea or to diarrhea mediated by
cAMP but not either 9',8'1cyclic

monophosphate or intracellular Ca- #t has been reported also
>9
that
a .inc1sensing receptor triggers the release of intracellular

Ca
2T
and regulates ion transport- A
micromolar concentration

of e0tracellular .inc set off a massie release of calcium from

intracellular pools in the colonocytic cell line- A sustained

increase in intracellular Ca leel may
augment H efflu0 and

a hyperpolari.ation of cell membrane potential, leading to an

adantageous
electrical gradient for chloride secretion-

Although the alternatie treatment of oral rehydration therapy

is more aailable, there are still
significant setbac&s in distributing

the therapy- An antisecretory drug accine %ould be a much
more

cost1effectie solution- An antisecretory drug accine could

induce immunity %ithout the
children's needing to go through

multiple infections and the ris&s associated %ith infections-

(y
preenting children from ac@uiring infection, a drug accine

could greatly reduce the number of
deaths as a result of diarrheal

diseases and greatly reduce the burden on the health system-

+he model for an antisecretory drug should perform by inhibiting

intestinal chloride and !C'9
secretion
5
in contrast to focusing

on decreasing gastrointestinal motility and regeneration and?or

restoration of gut epithelium- Accelerated research directed

to achieing a clearer understanding
of the biology, chemistry,

and pathobiology of .inc in the gastrointestinal system is necessary-

Does .inc maintain intestinal defense systemsQ What is the relationship

of .inc to intestinal fluid
balanceQ Definitiely %hat are the

lin&ages of intestinal .inc transporters to body .inc statusQ

#s
there a brush border 6apical: membrane .inc transporter for

enterocytesQ Ans%ers to these and
other @uestions %ill hopefully

drie the creation of a treatment drug that collectiely induces

cation
absorptionE inhibits anion secretionE reduces stool fre@uency

and outputE reduces diarrhea
durationE and is safe, tolerable,

and ine0pensie-

A%&-O'LED3ME-T$

We than& William D- =yman, PhD, for help and suggestions in

%riting this article-

.OOT-OTE$

Accepted )ul 2>, 2BBC-
Address correspondence to Mare& =u&aci&, MD, Children's Medical Center Department of
Pediatrics, Medical College of Georgia, 442B 48th St, Augusta, GA 9B;42- *1mail3
mlu&aci&Umcg-edu
+he authors hae indicated they hae no financial relationships

releant to this article to disclose-

RE.ERE-%E$

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