A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and Persistent Diarrhea Marek Lukacik, Ronald L.

Thomas and Jacob V. Aranda Pediatrics 2008;121;326-336 DOI: 10.1542/peds.2007-0921

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/121/2/326

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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ARTICLE

A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and Persistent Diarrhea
Marek Lukacik, MDa, Ronald L. Thomas, PhDb, Jacob V. Aranda, MD, PhDb
a

Department of Pediatrics, Childrens Medical Center, Medical College of Georgia, Augusta, Georgia; bDepartment of Pediatrics, Wayne State University School of Medicine, and Childrens Hospital of Michigan, Detroit, Michigan, and National Institute of Child Health and Human Development, Pediatric Pharmacology Research Unit Network, Wayne State University, Detroit, Michigan

The authors have indicated they have no nancial relationships relevant to this article to disclose.

ABSTRACT
OBJECTIVE. Children in developing countries are at a high risk for zinc deciency. Supplemental zinc has previously been shown to provide therapeutic benets in diarrhea. The objective of this study was to examine the efcacy and safety of supplemental oral zinc therapy during recovery from acute or persistent diarrhea. METHODS. We conducted a meta-analysis of randomized, controlled trials to compare

www.pediatrics.org/cgi/doi/10.1542/ peds.2007-0921 doi:10.1542/peds.2007-0921

Key Words diarrhea, zinc Abbreviations WHOWorld Health Organization ORS oral rehydration solution RRrelative risk WMDweighted mean difference CI condence interval cAMP3 ,5 -cyclic monophosphate Kpotassium Ca calcium
Accepted for publication Jul 24, 2007 Address correspondence to Marek Lukacik, MD, Childrens Medical Center Department of Pediatrics, Medical College of Georgia, 1120 15th St, Augusta, GA 30912. E-mail: mlukacik@ mcg.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2008 by the American Academy of Pediatrics

the efcacy and safety of supplementary oral zinc with placebo in children with acute and persistent diarrhea. Results were reported using a pooled relative risk or a weighted mean difference. A total of 22 studies were identied for inclusion: 16 examined acute diarrhea (n 15 231), and 6 examined persistent diarrhea (n 2968).
RESULTS. Mean duration of acute diarrhea and persistent diarrhea was signicantly

lower for zinc compared with placebo. Presence of diarrhea between zinc and placebo at day 1 was not signicantly different in acute diarrhea or persistent diarrhea trials. At day 3, presence was signicantly lower for zinc in persistent diarrhea trials (n 221) but not in acute diarrhea trials. Vomiting after therapy was signicantly higher for zinc in 11 acute diarrhea trials (n 4438) and 4 persistent diarrhea trials (n 2969). Those who received zinc gluconate in comparison with zinc sulfate/acetate vomited more frequently. Overall, children who received zinc reported an 18.8% and 12.5% reduction in average stool frequency, 15.0% and 15.5% shortening of diarrhea duration, and a 17.9% and 18.0% probability of reducing diarrhea over placebo in acute and persistent trials, respectively.

CONCLUSIONS. Zinc supplementation reduces the duration and severity of acute and persistent diarrhea; however, the mechanisms by which zinc exerts its antidiarrheal effect have not been fully elucidated.

IARRHEAL DISEASES POSE a signicant public health problem on a global scale and especially in developing countries. It is estimated that there are 1.5 billion episodes of diarrhea per year and that diarrheal disease accounted for 21% of all deaths in children who were younger than 5 years. This is equivalent to 2.5 million deaths in the same age group.1,2 This compares more favorably with the results of a previous study from 1982 in which on the basis of a review of active surveillance data from studies conducted in the 1950s, 1960s, and 1970s, it was estimated that 4.6 million children died annually from diarrhea.3 Newer data from the World Health Organization (WHO) show that diarrheal disease accounts for 18% of the 10.6 million deaths in children who were younger than 5 years.4 One of the major advances in the reduction of mortality from diarrhea was the introduction of WHO oral rehydration solution (ORS)5; however, WHO ORS does not signicantly decrease stool output and duration of diarrhea, and therefore other approaches to add to or to enhance the available ORS have been sought. Several newer approaches have included the addition of zinc to the treatment regimen. Zinc is an essential micronutrient and protects cell membranes from oxidative damage. Zinc is not stored in the body, so the level of zinc is determined by the balance of dietary intake, absorption, and losses. A zinc deciency state may exist in children with acute diarrhea

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TABLE 1 Average Duration of Diarrhea (Days)

Reference Patel et al20 (2005) Valery et al19 (2005) Fischer Walker et al16 (2006)
Data are means

Zinc 4.34 3.26 4.93 2.28 3.31 3.90

Placebo 4.41 3.30 4.49 1.98 5.21 3.17

SD. Data previously obtained during the course of the study.

as a result of intestinal loss. A comprehensive review on this subject was recently published.6 An alternative view is that zinc may be working as a pharmacologic agent at the level of gene expression.7 The efcacy of zinc in the treatment of diarrhea is supported by several randomized, controlled trials that showed reduction of diarrhea duration, stool output, and stool frequency. Meta-analyses on the therapeutic effects8 of zinc in acute and persistent diarrhea as well as prevention9 of diarrhea with zinc supplementation have been previously published. The published data so far have shown the efcacy of zinc in the treatment of acute and chronic diarrhea. Our meta-analysis was performed to include new studies published since the last meta-analysis and to examine the efcacy and safety of zinc therapy during recovery from acute or persistent diarrhea. METHODS Inclusion Criteria Studies that were selected for inclusion tested the same primary hypotheses (average duration of diarrhea and presence of diarrhea at days 1, 3, and 5) using similar patient characteristics (primarily children aged between 1 and 60 months), with either acute or persistent diarrhea, including dysentery. Acute diarrhea was dened as lasting up to 14 days, with persistent diarrhea lasting 14 days. Random allocation to treatment groups and concealment of allocation had to be met to satisfy inclusion because inadequate allocation concealment, despite the use of randomization, allows a risk for selection bias. Intervention with oral zinc salt supplementation, allowing for any zinc salt type or formulation (sulfate, gluconate, or acetate) if applied at 5 mg/day for any length of duration, was examined against a control using a placebo. All comparisons between treatment groups had to be free of confounding by additional agents or co-interventions. Study groups who, after randomization, received zinc supplementation and ORS or zinc supplemented with vitamin A were excluded. Identication of Trials The search strategy used computerized bibliographic searches of Medline (1966 2006); the Cochrane Central Register of Controlled Trials (2006); Embase (1974 2006); Lilacs (19822006); CINAHL (19822006); Current Con-

trolled Trials (2006); and abstracts published in Pediatric Research (19912006) and the First (Boston, 2000) and Second (Paris, France, 2004) World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. Both published and unpublished trials were included in an effort to control for publication bias. Citations of appropriate studies were veried by reviewing the bibliographies and reference lists of identied trials. Identied titles of abstracts with potential relevance were downloaded, and full manuscripts were then obtained for all abstracts that were deemed relevant on the basis of the inclusion criteria. Twenty-two trials met inclusion criteria: 16 published studies relative to the denition of acute diarrhea and 6 relative to persistent diarrhea. Primary and Secondary Outcomes Data on 8 clinically relevant outcome measures were collected. We held average duration of diarrhea and presence of diarrhea episodes at days 1, 3, and 5 as our primary outcomes. Data on vomiting frequency, vomiting frequency by therapy type, stool frequency reduction, and probability of diarrhea continuation were extracted as secondary outcomes. All 3 authors independently extracted data from the same articles using a data extraction sheet and subsequently compared results for agreement. The data thus obtained were checked for consistency among authors, integrity of randomization, and concealment of allocation. Questions regarding the interpretability of certain data values were resolved by all 3 authors. The nal database entries were veried by the statistician (Dr Thomas). Few studies satised criteria for inclusion on every datum variable. When necessary, authors of selected studies were contacted to verify extracted data values derived from graphs and/or to provide additional information in a scaling form that could be combined with other studies. Where those instances occurred, they are noted in Tables 1 and 2. Denitions Denitions of diarrhea varied somewhat in all included studies. In acute trials, generally, the denitions stated for diarrhea were the passage of 3 loose, watery stools or 1 loose, watery stool with blood within 24 hours for between 3 and 7 days in duration. In persistent diarrhea trials, the denitions were similar, with the exception that they persisted up to 14 days in duration. Denitions for duration of diarrhea varied as well but was dened, generally, from the time of enrollment into the study until the rst formed stool. Duration was measured in either days or hours. For the purpose of this meta-analysis, hours were converted to days. After enrollment/randomization, either the zinc treatment or the placebo was assigned within 24 hours.

TABLE 2 Number of Children With Diarrhea at Days 1, 3, and 5

Reference Valery et al19 (2005) Fischer Walker et al16 (2006) Zinc Day 1 98/107 (91.6%) 538/554 (97.1%) Placebo Day 1 100/108 (92.6%) 526/556 (94.6%) Zinc Day 3 55/107 (51.4%) 391/554 (70.6%) Placebo Day 3 55/108 (50.9%) 385/556 (69.2%) Zinc Day 5 22/107 (20.6%) 226/554 (40.8%) Placebo Day 5 20/108 (18.5%) 204/556 (36.7%)

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Statistical Analyses Comprehensive Meta-Analysis,10 a stand-alone program, was used to synthesize data that were obtained from the 22 trials identied for inclusion: 16 acute and 6 persistent diarrhea trials. Briey, the analysis software produces a Forrest plot as a schematic description of the meta-analysis results. The program is augmented using accepted computational algorithms. Where appropriate, results were reported using a pooled relative risk (RR). For continuous outcomes, the weighted mean difference (WMD) was calculated. The 95% condence intervals (CIs) were reported around the weighted effect size. Heterogeneity Given that studies that are selected for inclusion in a meta-analysis will differ, the types of variability (clinical, methodologic, and/or statistical) that may occur among studies must be investigated. These various types of variability are termed heterogeneity. Meta-analysis should be considered only when a group of trials is sufciently homogeneous (as indicated in the inclusion criteria) in terms of participants, interventions, and outcomes to provide 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 when variability in the treatment effects being evaluated in the different trials exists. This results when the observed treatment effects are more different from each other than would be expected as a result of random error (chance) alone. Following convention, statistical heterogeneity in the results of this meta-analysis are referred to simply as heterogeneity. Different approaches for identication and measurement of heterogeneity were therefore undertaken to examine the extent to which the results of the studies included were consistent. CIs for the results of individual studies (depicted graphically using horizontal lines) were examined for poor overlap, a general indication of presence of statistical heterogeneity. Variability (heterogeneity) among the obtained effects sizes was formally operationalized using a 2 test of signicance. The formula for heterogeneity assesses the dispersion of individual outcomes, vis-a-vis the combined effect, and denotes ` this value using a Q statistic.11 A low P value (or a large 2 statistic relative to its degree of freedom) provides evidence of heterogeneity of treatment effects (variation in effect estimates beyond chance). Because some degree of clinical and methodologic diversity always occurs in a meta-analysis, some statistical heterogeneity is inevitable; therefore, the test for heterogeneity is irrelevant to the choice of analysis: heterogeneity will always exist regardless of whether it can be detected using a statistical test. Still, methods have been developed for quantifying inconsistency across studies that move the focus away from testing whether heterogeneity is present to assessing its impact on the meta-analysis. A useful statistic for quantifying inconsistency is I2, the percentage of the variability in effect size estimates that is attributable to heterogeneity rather than sampling error (chance).12 A value 50% may be
328 LUKACIK et al

considered substantial heterogeneity, and that percentage cutoff was adopted and examined also in our analyses. Gravity Another more recent approach13 proposed jackknife resampling to measure a concept termed gravity. In any meta-analysis, arguments have focused on the inclusion or exclusion of some studies, with debate on which ones should be included or excluded because studies are commonly weighted according to their sample size and/or internal variability. Gee13 proposed that jackknife resampling could be used to examine study inuence and detect outlier studies. The technique recomputes the meta-analysis once for each of k studies, where each study is individually excluded. K results are then obtained. The difference between the average of these k results and each studys individual result (when omitted) is taken as an index of raw gravity. This difference, divided by the SD of the k differences, is taken as a z score, or standardized gravity, which can be used to establish which studies might be unusually inuential. SPSS 15.014 was used to calculate standardized gravity values. Fixed- or Random-Effects Model Choice of whether to interpret a xed-effects or random-effects model was considered thoroughly. Fixedeffect meta-analyses ignore heterogeneity. The xedeffect estimate and its CI address the question, What is the best estimate of the treatment effect? The randomeffects estimate and its CI address the question, What is the average treatment effect? The answers to these questions are analogous when no heterogeneity is present or when the distribution of the treatment effects is roughly symmetrical. If they are not, then the random-effects estimate may not reect the actual effect in any population being studied. In a xed-effects metaanalysis, a pooled-effect estimate is termed, generally, as the best estimate of the treatment effect. It is for these reasons that we chose a xed-effects model for our meta-analysis, along with the various stated approaches to examine heterogeneity if found. RESULTS The author, year, country, amount of zinc supplementation and type, sample size, and age for each of the 22 studies selected for inclusion in the meta-analysis are listed in Tables 3 and 4. Although all 22 studies were randomly assigned clinical trials, it seemed that 51519 were not double-blinded. Sixteen of these published studies met the denition for acute diarrhea and 6 for persistent diarrhea. Overall, 56.3% (9 of 16) of acute diarrhea trials were conducted in inpatient hospital settings, and 43.7% (7 of 16) were conducted in outpatient homes and communities. Of the 6 persistent diarrhea trials, 66.7% (4 of 6) were inpatient and 33.3% (2 of 6) were outpatient.

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TABLE 3 Characteristics of Acute Diarrhea Trials

Reference Sachdev et al (1988) Sazawal et al31 (1995) Roy et al30 (1997) Faruque et al27 (1999) Hidayat et al28 (1998) Dutta et al26 (2000) Strand et al32 (2002) Bahl et al23 (2002)a Al-Sonboli et al22 (2003) Polat et al29 (2003)b Bhatnagar et al24 (2004) Valery et al19 (2005)c Patel et al20 (2005) Brooks et al25 (2005)d Baqui et al15 (2002) Fischer Walker et al16 (2006)
a Three b Four

Country India India Bangladesh Bangladesh Indonesia India Nepal India Brazil Turkey India Australia India Bangladesh Bangladesh Pakistan, Ethiopia, India

Zinc Supplement Sulfate Gluconate Acetate Acetate Acetate Sulfate Gluconate Gluconate Sulfate Sulfate Sulfate Sulfate Sulfate/copper sulfate Acetate Acetate Sulfate

Zinc Dosage 20 mg 20 mg 20 mg 14/40 mg 4/5 mg/kg 40 mg 15/30 mg 15/30 mg 22.5/45 mg 20 mg 15/30 mg 20/40 mg 40 mg/5 mg 20 mg 20 mg 10 mg

Zinc/Control Group, N 25/25 456/481 57/54 343/341 739/659 44/36 445/449 404/401 37/37 92/90 143/144 107/108 102/98 86/89 3974/4096 554/556

Age, mo 618 635 324 623 325 324 635 635 360 229 336 011, 1223, 659 16 359 15

17

24

study groups were examined (control, zinc syrup, and zinc/ORS). We included only those who received zinc syrup or a control. study groups were examined: low/normal zinc in 2 intervention groups and low/normal zinc in 2 control groups. We combined the groups into either intervention or control, without excluding those with low zinc levels. c Children up to 11 years of age were included; however, 45.1% (97 of 215) were 0 to 11 months of age; 38.1% (82 of 215) were 12 to 23 months; and only 16.8% (36 of 215) were 24 months. All study participants were included in our analyses. d Three groups were used (control, 5 mg of zinc acetate, and 20 mg of zinc acetate). We examined only those who used 20 mg of zinc versus control subjects. Brooks et al enrolled only male children.

TABLE 4 Characteristics of Persistent Diarrhea Trials

Reference Sachdev et al18 (1990) Roy et al21 (1998) Khatun et al34 (2001) Bhutta et al33 (1999) Penny et al35 (1999) Bhandari et al36 (2002) Country India Bangladesh Bangladesh Pakistan Peru India Zinc Supplement Sulfate Acetate Acetate Sulfate Gluconate Gluconate Zinc Dosage 20 mg 20 mg 20 mg 3 mg/kg 20 mg 10/20 mg Zinc/Control Group, N 20/20 95/95 24/24 43/44 139/136 1228/1236 Age, mo 618 324 624 636 635 630

Mortality Mortality was originally a primary outcome in this metaanalysis; however, of both acute and persistent trials, only 315,20,21 reported mortality outcome, making it difcult to compare across all included trials. Two of these were acute diarrhea trials,15,20 and 1 was a persistent diarrhea trial.21 In the largest acute diarrhea outpatient trial15 (n 8070), 33 children (0.008%; 33 of 3974) died in the zinc-treated group and 37 (0.009%; 37 of 4096) died in the placebo group. Thirty deaths were attributed to drowning, and the remaining were not injury related (ie, not attributable to zinc intervention). When restricted to noninjury deaths, there were 13 in the zinctreated group and 27 in the placebo group. The investigators attributed the lower noninjury death rate in the intervention group almost entirely to fewer deaths from diarrhea and acute lower respiratory infection. Diarrhea and acute lower respiratory infection together accounted for 10 deaths in the zinc intervention group and 20 deaths in the placebo group. In the other acute diarrhea trial,20 2 children in the placebo group died of septicemia. In the persistent diarrhea trial,21 the causes of death were septicemia with diarrhea in 3 children, septicemia in 1 child, bronchopneumonia in 1 child, and continued diarrhea in 1 child. Because acute and persistent diarrhea are, most likely, distinct disease entities, the outcomes

obtained are presented initially for acute diarrhea (lasting up to 14 days) and followed by persistent diarrhea (lasting 14 days). Results for Acute Diarrhea Trials Duration of Acute Diarrhea In 16 trials that examined the primary measure of average duration of acute diarrhea1517,19,20,2232 (n 15 231), those who received zinc experienced a signicantly lower average duration of diarrhea than those who received a placebo (WMD: 0.24; SE: 0.02; 95% CI: 0.21 0.27; P .001; Table 5, Fig 1) but also with the presence of statistically signicant heterogeneity (Q 95.58, de15, P .001, I2 84.3%). grees of freedom [df]Q Figure 1 depicts a Forrest plot for these results, in which every study is displayed as a point estimate with CIs. Examination of signicant heterogeneity in the acute diarrhea trials revealed 5 trials17,19,20,25,30 with insignicant differences between zinc and placebo groups in average duration of diarrhea. P values ranged from .478 to nonsignicant in sample sizes that ranged from 50 to 215. Although those who received zinc had a shorter average duration of diarrhea, the difference in 4 trials17,19,20,30 was very small, with an average difference of 0.18 0.18 days ranging from 0.04 to 0.40 days. One
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TABLE 5 Mean Duration of Acute Diarrhea

Reference Sachdev et al (1988) Sazawal et al31 (1995) Roy et al30 (1997) Hidayat et al28 (1998) Faruque et al27 (1999) Dutta et al26 (2000) Strand et al32 (2002) Baqui et al15 (2002) Bahl et al23 (2002) Polat et al29 (2003) Al-Sonboli et al22 (2003) Bhatnagar et al24 (2004) Patel et al20 (2005) Valery et al19 (2005) Brooks et al25 (2005) Fischer Walker et al16 (2006) Fixed combined (16)
17

N1 25 456 37 738 341 44 445 3974 404 92 37 143 102 107 86 554 7585

N2 25 481 37 659 340 36 449 4096 401 90 37 144 98 108 89 556 7646

Lower .371 .128 .312 .015 .045 1.811 .052 .243 .016 .425 .435 .025 .246 .260 .298 .006 .208

Upper .769 .386 .616 .225 .347 2.995 .315 .331 .261 1.030 1.412 .441 .312 .278 .298 .242 .272

Effect .199 .257 .152 .120 .196 2.403 .184 .287 .122 .727 .924 .208 .033 .009 .000 .124 .240

SE .284 .066 .233 .054 .077 .297 .067 .022 .071 .153 .245 .118 .141 .136 .151 .060 .016

P .478 .000 .511 .025 .011 .000 .006 .000 .083 .000 .000 .079 .817 .946 NS .039 .000

N1 indicates sample size for zinc group; N2, sample size for the placebo group; Lower, lower limit of the 95% CI for the standard difference; Upper, upper limit of the 95% CI for the standard difference; Effect, standard difference; NS, nonsignicant.

tremendously higher sample size (n 8070) than all of the others. Table 6 shows the effect sizes, calculated raw gravity values, standardized gravity values, and sample sizes for each study when removed. It is clear that 1 study15 had a great deal of impact on the strength and direction of the estimated effect size value found for average duration of acute diarrhea among all studies. When removed, the reaveraged effect size obtained (0.187) and plotted standardized gravity value (3.531; Fig 2) were considered outlying values in comparisons with all others. This is largely attributed to the enormous sample size (n 8070) used in the trial, because even very small differences in mean duration of diarrhea would be statistically signicant. Occurrence of Diarrhea at Day 1 Five acute diarrhea trials16,19,20,27,32 reported the occurrence of diarrhea at day 1 (n 3100). No statistically signicant difference in the occurrence of acute diarrhea at day 1 was found (RR: 1.01; 95% CI: 0.99 1.03; P 0.30). Although the variability in effect sizes ranged from a low of 0.968 to 1.695, signicant heterogeneity did occur (Q 10.60, dfQ 4, P .03, I2 62.3%). Occurrence of Diarrhea at Day 3 Six acute diarrhea trials16,19,20,23,27,32 collected data for occurrence of diarrhea at day 3. No statistically signicant differences occurred between treatment groups in occurrence of diarrhea at day 3 (RR: 0.97; 95% CI: 0.911.03; P .36); however, the occurrence of statistically significant heterogeneity was found (Q 10.880, dfQ 5, P 0.05, I2 54.0%). Only 1 trial30 found a signicantly (P .01) lower occurrence of diarrhea at day 3 with zinc (27.4%) than placebo (35.4%; effect size: 0.774); however, the occurrence of statistically signicant heteroge5, P .05, I2 neity was found (Q 10.880, dfQ 54.0%).

FIGURE 1 Mean difference in duration of acute diarrhea. The effect size index in this plot is the standard mean difference, so a point estimate of 0.0 indicates no effect. Values 0.0 reect a better outcome for the placebo group, and values 0.0 indicate a better outcome for the zinc group. If the point estimate and CI fell above 0.0, then the study would meet the criterion for statistical signicance ( .05). If the CI overlapped 0.0, then the P value would exceed .05 and the study would not be statistically signicant.

trial25 found no difference at all between treatment groups. Participants in all 5 trials had been admitted for dehydration secondary to diarrhea, although the severity of dehydration ranged. Four of the trials17,20,25,30 administered an ORS before treatment assignment. Three trials received zinc sulfate and 2 received acetate. In contrast, all acute diarrhea trials23,31,32 that provided zinc gluconate and not zinc sulfate had a shorter duration of diarrhea than placebo (P .08). Two trials17,20 originated from India, 225,30 from Bangladesh, and 119 from Australia. One trial15 in which average duration was signicantly lower (1.2 days lower) with zinc use also had a
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TABLE 6 Acute Diarrhea: Gravity Values for Duration of Diarrhea

Reference Valery et al (2005) Strand et al32 (2002) Sazawal et al31 (1995) Sachdev et al17 (1988) Roy et al30 (1997) Polat et al29 (2003) Patel et al20 (2005) Hidayat et al28 (1998) Fischer Walker et al16 (2006) Faruque et al27 (1999) Dutta et al26 (2000) Brooks et al25 (2005) Bhatnagar et al24 (2004) Baqui et al15 (2002) Bahl et al23 (2002) Al-Sonboli et al22 (2003)
19

Effect Size 0.243 0.243 0.239 0.240 0.240 0.234 0.243 0.252 0.249 0.242 0.233 0.243 0.240 0.187 0.246 0.237

Raw Gravity 0.00481 0.00481 0.00081 0.00181 0.00181 0.00419 0.00481 0.01381 0.01081 0.00381 0.00519 0.00481 0.00181 0.05119 0.00781 0.00119

Standardized Gravity 0.332 0.332 0.056 0.125 0.125 0.289 0.332 0.953 0.746 0.263 0.358 0.332 0.125 3.531 0.539 0.082

Sample Size 215 894 937 50 74 182 200 1397 1110 681 80 175 287 8070 805 74

FIGURE 2 Standardized gravity results.

Occurrence of Diarrhea at Day 5 Similarly, in the same 6 acute diarrhea trials,16,19,20,23,27,32 no statistically signicant differences occurred between

treatment groups in occurrence of diarrhea at day 5 (RR: 0.94; 95% CI: 0.84 1.05; P .26). Similar to day 3 results, the occurrence of statistically signicant heteroPEDIATRICS Volume 121, Number 2, February 2008 331

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TABLE 7 Effects of Zinc Therapy of Acute Diarrhea

Reference Sachdev et al (1988) Sazawal et al31 (1995) Roy et al30 (1997) Faruque et al27 (1999) Hidayat et al28 (1998) Dutta et al26 (2000) Strand et al32 (2002) Bahl et al23 (2002) Al-Sonboli et al22 (2003) Polat et al29 (2003) Bhatnagar et al24 (2004) Valery et al19 (2005) Brooks et al25 (2005) Brooks et al25 (2005) Baqui et al15 (2002) Fischer Walker et al16 (2006)
17

Country India India Bangladesh Bangladesh Indonesia India Nepal India Brazil Turkey India Australia India Bangladesh Bangladesh Pakistan, Ethiopia, India

Stool Frequency Reduction 18% lower frequency 39% lower frequency 28% lower stool output Not reported Not reported 38% lower stool output 8% lower frequency 17% lower frequency 59% lower frequency 14% lower frequency 25% lower stool output Not reported Not reported 0% lower frequency Not reported 5% higher frequency

Probability of Diarrhea Continuation 9% shorter duration 19% shorter duration 14% reduction in probability 20% reduction in probability 11% reduction in probability 32% shorter duration 26% reduction in probability 11% reduction in probability Not reported 20% shorter duration 30% reduction in probability Not reported 19% reduction in probability, 7% shorter duration 12% reduction in probability, 0% shorter duration 24% shorter duration 9% shorter duration

Average stool frequency reduction 18.8%; average lowering of stool output 30.3%; average shortening of duration 15.0%; average probability of diarrhea reduction 17.9%. Variances in data reporting of outcome measures: For this meta-analysis, shortening of diarrhea duration was dened as the percentage ratio of the mean number of days of diarrhea in each study group. It was then reported as a shorter percentage of time with diarrhea for one group or the other. Probability of diarrhea duration was calculated by authors using various statistical approaches, such as the odds ratio, risk ratio, or hazards ratio. This difference in statistic negated a comparison in the meta-analysis. Stool frequency reduction was calculated by taking a ratio of the average diarrhea frequency in some studies per 24 hours or by the risk ratio of the mean number of stools in the rst 4 days of another study. Lower stool output was calculated, in 2 studies, by taking a ratio of the total stool weight per kilogram of body weight and reporting the median. The ratio of the median was then taken. The resulting percentage was interpreted as a lowering of stool output in one group or the other. In another study, it was reported as the total stool output until the last rst formed stool, measured in grams per kilogram for each group. The geometric mean was then taken and a ratio between groups obtained. The group with the lower percentage was interpreted as a lowering of stool output in one group or another.

TABLE 8 Mean Duration of Persistent Diarrhea

Reference Sachdev et al18 (1990) Roy et al21 (1998) Penny et al35 (1999) Bhutta et al33 (1999) Khatun et al34 (2001) Fixed combined (5) N1 20 73 87 43 24 247 N2 20 68 86 44 24 242 Lower 0.123 0.201 0.134 0.295 0.167 0.120 Upper 1.182 0.466 0.742 0.558 1.010 0.478 Effect 0.530 0.133 0.438 0.132 0.422 0.299 SE 0.322 0.169 0.154 0.215 0.292 0.091 P .096 .430 .004 .537 .144 .001

geneity was found (Q 73.6%).

18.957, dfQ

5, P

.002, I2

Vomiting 4438), the In 11 acute diarrhea trials16,17,19,2225,2932 (n proportion of participants who vomited after the initial dose was signicantly higher with zinc (278 [12.7%] of 2196) use than with placebo (171 [7.6%] of 2242; RR: 1.55; 95% CI: 1.30 1.84; P 0.001%; Q 25.54, P .004). Vomiting After Administration of Zinc Sulfate or Gluconate In 3 acute diarrhea trials,23,31,32 a signicantly higher proportion of patients who received zinc gluconate vomited (160 [14.6%] of 1095) than zinc sulfate/acetate therapy16,17,19,22,24,25,29,30 (118 [10.7%] of 1101; RR: 1.18; 95% CI: 1.051.31; P .006). Shortening of Diarrhea Duration Eight trials of acute diarrhea1517,20,25,26,29,31 found an average shortening of diarrhea duration of 15.0% for those who received zinc in comparison with placebo (Table 7).
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Reduction in Stool Frequency Seven trials of acute diarrhea17,22,23,25,29,31,32 found an average reduction in stool frequency of 22.1% with zinc therapy in comparison with placebo. One single trial16 found a 5.0% higher stool frequency using zinc than placebo. Stool Output Three trials of acute diarrhea24,26,30 found an average lowering of stool output of 30.3%. Probability of Diarrhea Reduction Eight acute diarrhea trials20,2325,27,28,30,32 measured the probability of diarrhea reduction and found a 17.9% reduction using zinc compared with placebo. Results for Persistent Diarrhea Trials Duration of Persistent Diarrhea 489), those In 5 persistent diarrhea trials18,21,3335 (n who received zinc also experienced a signicantly lower average duration of diarrhea than the placebo group (WMD: 0.30; SE: 0.09; 95% CI: 0.12 0.48; P .001; Table 8) but without signicant heterogeneity (Q 3.08,

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Stool Output Stool output was not measured in the persistent trials. Probability of Diarrhea Reduction Two persistent diarrhea trials33,36 that measured the probability of diarrhea reduction found an 18.0% reduction when zinc was used over placebo.
FIGURE 3 Mean difference in duration of persistent diarrhea. The effect size index in this plot is the standard mean difference, so a point estimate of 0.0 indicates no effect. Values 0.0 reect a better outcome for the placebo group, and values 0.0 indicate a better outcome for the zinc group. If the point estimate and CI fell above 0.0, then the study would meet the criterion for statistical signicance ( .05). If the CI overlapped 0.0, then the P value would exceed .05 and the study would not be statistically signicant.

dfQ 4, P .544, I2 29.9%). Figure 3 depicts the Forrest plot for these results. Occurrence of Diarrhea at Day 1 In 2 trials of persistent diarrhea34,35 (n 221), no statistically signicant differences occurred between treatment groups in occurrence of diarrhea at day 1 (RR: 1.00; 95% CI: 0.931.08; P .98), and no statistically signicant variability occurred among the effect sizes (Q 0.01, dfQ 1, P .93). Occurrence of Diarrhea at Day 3 In 2 trials of persistent diarrhea34,35 (n 221), a signicantly lower occurrence of diarrhea at day 3 occurred in those who were treated with zinc in comparison with placebo (RR: 0.70; 95% CI: 0.51 0.94; P .02). No statistically signicant variability occurred among the effect sizes (Q 0.33, dfQ 1, P .56). Occurrence of Diarrhea at Day 5 This was not examined; fewer than 2 studies reported. Vomiting 2969), a sigIn 4 persistent diarrhea trials18,21,35,36 (n nicantly higher proportion vomited on zinc (41 [2.8%] of 1482) than with placebo (2 [0.001%] of 1487; RR: 3.64; 95% CI: 1.0213.02; P .047; Q 5.91, P .116). Vomiting After Zinc Sulfate or Gluconate In 4 persistent diarrhea trials,18,21,35,36 those who received zinc gluconate35,36 vomited more frequently (41 [3%] of 1367) than did those who received zinc sulfate/acetate (0 [0%] of 115; RR: 1.09; 95% CI: 0.94 1.09; P .07). Shortening of Diarrhea Duration In 4 persistent diarrhea trials,18,21,34,35 those who received zinc experienced a 15.5% average shortening of diarrhea duration than those who got a placebo (Table 9). Reduction in Stool Frequency Four trials of persistent diarrhea found that those who received zinc also experienced an average of 9.8% reduction in frequency.

DISCUSSION On the basis of these ndings, which now add to the large body of previously published clinical data and update previous meta-analyses and systematic reviews,8,37 zinc therapy is useful for treating both acute and persistent diarrhea and for their prophylaxis. Still, as extensively addressed in a recent systematic review,6 much information is lacking relative to the mechanisms by which zinc physiologically exerts its antidiarrheal effect. In this meta-analysis, 5 (31.3%) of 16 acute diarrhea studies17,19,20,25,30 found no statistically signicant differences between zinc and placebo on the average duration of diarrhea (at least a P .48). Similarly, 2 (40.0%) of 5 persistent diarrhea studies21,33 also found no statistically signicant differences in average duration of diarrhea between treatments (at least a P .43). Still, the average stool frequency reductions, shortening of diarrhea durations, and probabilities of a shortening of diarrhea duration reported were higher in studies with zinc therapy in comparison with placebo. To the majority of individuals, diarrhea means an increased frequency or decreased consistency of bowel movements. In many developed countries, the average number of bowel movements is 3 per day; however, diarrhea is associated with an increase in stool weight, mainly as a result of excess water, which normally makes up a large percentage of fecal matter. Given this, diarrhea is distinguished from diseases that cause only an increase in the number of bowel movements or fecal incontinence. Determining the exact causes of diarrhea can be difcult because there are many different diarrheal agents, with such a variety of infectious agents, including bacteria, parasites, and viruses. Identication of specic diarrheal agents is complicated by the lack of access to laboratory tests in many developing countries. Viral gastroenteritis caused by rotavirus is the primary cause of diarrhea among infants worldwide. Other causes include bacterial pathogens such as Vibrio cholerae, Shigella, and Salmonella. Protozoa such as Cryptosporidium parvum and Giardia lamblia are 2 of the most common protozoan diarrheal agents. The primary symptoms of rotavirus infection are fever and vomiting for several days, followed by nonbloody diarrhea. Although not normally fatal, the diarrhea caused by the virus can be quite severe, leading to potentially life-threatening dehydration. Although easily treated with intravenous uids in developed nations, these supplies are often unavailable in the developing world, and the dehydration that is caused by rotavirus is a signicant cause of mortality. In fact, conclusions from these randomized trials for
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TABLE 9 Effects of Zinc Therapy of Persistent Diarrhea

Reference Sachdev et al (1990) Roy et al21 (1998) Khatun et al34 (2001) Bhutta et al33 (1999) Penny et al35 (1999) Bhandari et al36 (2002)
18

Country India Bangladesh Bangladesh Pakistan Peru Nepal

Stool Frequency Reduction 22% lower frequency Not reported 7% lower frequency 9% lower frequency Not reported 12% lower frequency

Probability of Diarrhea Continuation 19% shorter duration 7% shorter duration 17% shorter duration 14% reduction in probability 19% shorter duration 22% reduction in probability

Average stool frequency reduction 12.5%; average shortening of duration 15.5%; average probability of diarrhea reduction 18.0%. Variances in data reporting of outcome measures: For this meta-analysis, shortening of diarrhea duration was dened as the percentage ratio of the mean number of days of diarrhea in each study group. It was then reported as a shorter percentage of time with diarrhea for one group or the other. Probability of diarrhea duration was calculated by authors using various statistical approaches, such as the odds ratio, risk ratio, or hazards ratio. This difference in statistic negated a comparison in the meta-analysis. Stool frequency reduction was calculated by taking a ratio of the average diarrhea frequency in some studies per 24 hours or by the risk ratio of the mean number of stools in the rst 4 days of another study. Lower stool output was calculated, in 2 studies, by taking a ratio of the total stool weight per kilogram of body weight and reporting the median. The ratio of the median was then taken. The resulting percentage was interpreted as a lowering of stool output in one group or the other. In another study, it was reported as the total stool output until the last rst formed stool, measured in grams per kilogram for each group. The geometric mean was then taken and a ratio between groups obtained. The group with the lower percentage was interpreted as a lowering of stool output in one group or another.

the efcacy of zinc treatment on diarrhea duration included an improved absorption of water and electrolytes by the intestine and quicker regeneration of gut epithelium.38 Increased levels of brush border (apical) enzymes suggesting a zinc transporter for enterocytes39 and a stronger immune response that increased clearance of pathogens from the intestine40 were also described. Efcacy of oral rehydration therapy in correcting dehydration and reducing mortality led to treatment modications of ORS with zinc therapy. Success with zinc therapy has generally been attributed to a decrease in the volume of small intestinal uid and sodium absorption triggered by zinc delivery. Still, the mechanisms by which zinc improves uid and electrolyte transportation have not been elucidated fully. This includes the effect of zinc on intestinal ion transport, whether zinc initiates or increases cation absorption and/or suppresses anion secretion, and whether deciency enhances the likelihood of secretory diarrhea. Most likely, the location of the effect of zinc is in the small intestine, given its inhibition of adenosine 3 ,5 cyclic monophosphate (cAMP)-induced chloride-dependent uid secretion. Treatment with ORS would have its greatest effect on reducing uid loss by increasing small intestine absorption. Thus, zinc therapy after pretreatment with ORS may not have shown a benecial effect (reduced average duration of diarrhea) over placebo in 5 trials17,19,20,25,30 of this meta-analysis simply because pretreatment with ORS had already maximized the small intestine absorption rate. Zinc inhibits cAMP-induced chloride secretion by specically inhibiting basolateral potassium (K) channels with no blockage effect on calcium (Ca)-mediated K channels in in vitro studies with the rat ileum.41 Zinc also inhibits cholera toxininduced but not Escherichia coli heat-stable enterotoxin-induced ion secretion in cultured Caco-2 cells. One study42 showed that cAMP acted as the intracellular effector of heat-labile enterotoxininduced uid secretion. Guanosine 3 ,5 -cyclic monophosphate mediates heat-stableinduced uid secretion. If substantiated, then the effectiveness of zinc would be
334 LUKACIK et al

limited to heat-labileinduced diarrhea or to diarrhea mediated by cAMP but not either 3 ,5 -cyclic monophosphate or intracellular Ca. It has been reported also43 that a zinc-sensing receptor triggers the release of intracellular Ca2 and regulates ion transport. A micromolar concentration of extracellular zinc set off a massive release of calcium from intracellular pools in the colonocytic cell line. A sustained increase in intracellular Ca level may augment K efux and a hyperpolarization of cell membrane potential, leading to an advantageous electrical gradient for chloride secretion. Although the alternative treatment of oral rehydration therapy is more available, there are still signicant setbacks in distributing the therapy. An antisecretory drug vaccine would be a much more cost-effective solution. An antisecretory drug vaccine could induce immunity without the childrens needing to go through multiple infections and the risks associated with infections. By preventing children from acquiring infection, a drug vaccine could greatly reduce the number of deaths as a result of diarrheal diseases and greatly reduce the burden on the health system. The model for an antisecretory drug should perform by inhibiting intestinal chloride and HCO3 secretion6 in contrast to focusing on decreasing gastrointestinal motility and regeneration and/or restoration of gut epithelium. Accelerated research directed to achieving a clearer understanding of the biology, chemistry, and pathobiology of zinc in the gastrointestinal system is necessary. Does zinc maintain intestinal defense systems? What is the relationship of zinc to intestinal uid balance? Denitively what are the linkages of intestinal zinc transporters to body zinc status? Is there a brush border (apical) membrane zinc transporter for enterocytes? Answers to these and other questions will hopefully drive the creation of a treatment drug that collectively induces cation absorption; inhibits anion secretion; reduces stool frequency and output; reduces diarrhea duration; and is safe, tolerable, and inexpensive.

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ACKNOWLEDGMENT We thank William D. Lyman, PhD, for help and suggestions in writing this article. REFERENCES
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HIGH-STAKES FLIMFLAM Its time to rein in the test zealots who have gotten such a stranglehold on the public schools in the US. Politicians and others have promoted highstakes testing as a panacea that would bring accountability to teaching and substantially boost the classroom performance of students. Measuring, said President Bush, in a discussion of his No Child Left Behind law, is the gateway to success. Not only has high-stakes testing largely failed to magically swing open the gates to successful learning, it is questionable in many cases whether the tests themselves are anything more than a shell game. Daniel Koretz, a professor at Harvards Graduate School of Education, told me in a recent interview that its important to ask whether you can trust improvements in test scores when you are holding people accountable for the tests. The short answer, he said, is no. If teachers, administrators, politicians and others have a stake in raising the test scores of studentsas opposed to improving student learning, which is not the same thingthere are all kinds of incentives to raise those scores by any means necessary. Weve now had four or ve different waves of educational reform, said Dr. Koretz, that were based on the idea that if we can just get a good test in place and beat people up to raise scores, kids will learn more. Thats really what No Child Left Behind is. The problem is that you can raise scores the hard way by teaching more effectively and getting the students to work harder, or you can take shortcuts and start guring out ways, as Dr. Koretz put it, to game the system. Guess whats been happening? Weve had high-stakes testing, really, since the 1970s in some states, said Dr. Koretz. Weve had maybe six good studies that ask: If the scores go up, can we believe them? Or are people taking shortcuts? And all of those studies found really substantial ination of test scores.
Herbert B. New York Times. October 9, 2007 Noted by JFL, MD

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A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and Persistent Diarrhea Marek Lukacik, Ronald L. Thomas and Jacob V. Aranda Pediatrics 2008;121;326-336 DOI: 10.1542/peds.2007-0921
Updated Information & Services References including high-resolution figures, can be found at: http://www.pediatrics.org/cgi/content/full/121/2/326 This article cites 39 articles, 9 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/121/2/326#BIBL This article has been cited by 4 HighWire-hosted articles: http://www.pediatrics.org/cgi/content/full/121/2/326#otherarticle s This article, along with others on similar topics, appears in the following collection(s): Infectious Disease & Immunity http://www.pediatrics.org/cgi/collection/infectious_disease Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml

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