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A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and Persistent Diarrhealocated on the World Wide Web at: http: // www.pe di atr i cs.org / cg i/ content /f u ll/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. Downloaded from www.pediatrics.org . Provided by Indonesia:AAP Sponsored on August 31, 2010 " id="pdf-obj-0-2" src="pdf-obj-0-2.jpg">

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.

A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and Persistent Diarrhealocated on the World Wide Web at: http: // www.pe di atr i cs.org / cg i/ content /f u ll/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. Downloaded from www.pediatrics.org . Provided by Indonesia:AAP Sponsored on August 31, 2010 " id="pdf-obj-0-31" src="pdf-obj-0-31.jpg">

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ARTICLE

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 b , Jacob V. Aranda, MD, PhD b

a Department of Pediatrics, Children’s Medical Center, Medical College of Georgia, Augusta, Georgia; b Department of Pediatrics, Wayne State University School of Medicine, and Children’s 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 financial relationships relevant to this article to disclose.

ABSTRACT

OBJECTIVE. Children in developing countries are at a high risk for zinc deficiency. Supplemental zinc has previously been shown to provide therapeutic benefits in diarrhea. The objective of this study was to examine the efficacy 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 the efficacy 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 identified 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 significantly lower for zinc compared with placebo. Presence of diarrhea between zinc and placebo at day 1 was not significantly different in acute diarrhea or persistent diarrhea trials. At day 3, presence was significantly lower for zinc in persistent diarrhea trials (n 221) but not in acute diarrhea trials. Vomiting after therapy was significantly 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.

 

www.pediatrics.org/cgi/doi/10.1542/

peds.2007-0921

doi:10.1542/peds.2007-0921

Key Words

diarrhea, zinc

Abbreviations

WHO—World Health Organization ORS— oral rehydration solution RR—relative risk WMD—weighted mean difference CI— confidence interval cAMP—3 ,5 -cyclic monophosphate K—potassium Ca— calcium

Accepted for publication Jul 24, 2007

Address correspondence to Marek Lukacik, MD, Children’s 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

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.

D IARRHEAL DISEASES POSE a significant 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 significantly 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 deficiency state may exist in children with acute diarrhea

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TABLE 1 Average Duration of Diarrhea (Days) Reference Zinc Placebo Patel et al (2005) Valery et

TABLE 1

Average Duration of Diarrhea (Days)

Reference

Zinc

Placebo

Patel et al 20 (2005) Valery et al 19 (2005) Fischer Walker et al 16 (2006)

4.34 2.28 3.26 3.31 4.93 3.90

4.41 1.98 3.30 5.21 4.49 3.17

Data are means 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 efficacy of zinc in the treatment of diarrhea is supported by several random- ized, controlled trials that showed reduction of diarrhea duration, stool output, and stool frequency. Meta-anal- yses on the therapeutic effects 8 of zinc in acute and persistent diarrhea as well as prevention 9 of diarrhea with zinc supplementation have been previously pub- lished. The published data so far have shown the efficacy 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 efficacy 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 diar- rhea, including dysentery. Acute diarrhea was defined 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 inclu- sion because inadequate allocation concealment, despite the use of randomization, allows a risk for selection bias. Intervention with oral zinc salt supplementation, allow- ing for any zinc salt type or formulation (sulfate, glu- conate, 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 randomiza- tion, received zinc supplementation and ORS or zinc supplemented with vitamin A were excluded.

Identification 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 (1982–2006); CINAHL (1982–2006); Current Con-

trolled Trials (2006); and abstracts published in Pediatric Research (1991–2006) and the First (Boston, 2000) and Second (Paris, France, 2004) World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. Both pub- lished and unpublished trials were included in an effort to control for publication bias. Citations of appropriate studies were verified by reviewing the bibliographies and reference lists of identified trials. Identified titles of ab- stracts 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 pub- lished studies relative to the definition 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, vom- iting frequency by therapy type, stool frequency re- duction, and probability of diarrhea continuation were extracted as secondary outcomes. All 3 authors independently extracted data from the same articles us- ing a data extraction sheet and subsequently compared results for agreement. The data thus obtained were checked for consistency among authors, integrity of ran- domization, and concealment of allocation. Questions regarding the interpretability of certain data values were resolved by all 3 authors. The final database entries were verified by the statistician (Dr Thomas). Few studies satisfied criteria for inclusion on every datum variable. When necessary, authors of selected studies were con- tacted 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.

Definitions

Definitions of diarrhea varied somewhat in all included studies. In acute trials, generally, the definitions 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 definitions were similar, with the exception that they persisted up to 14 days in duration. Definitions for duration of diarrhea varied as well but was defined, generally, from the time of enrollment into the study until the first formed stool. Duration was measured in either days or hours. For the purpose of this meta-analysis, hours were converted to days. After en- rollment/randomization, either the zinc treatment or the placebo was assigned within 24 hours.

TABLE 1 Average Duration of Diarrhea (Days) Reference Zinc Placebo Patel et al (2005) Valery et

TABLE 2

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

Reference

Zinc Day 1

Placebo Day 1

Zinc Day 3

Placebo Day 3

Zinc Day 5

Placebo Day 5

Valery et al 19 (2005) Fischer Walker et al 16 (2006)

98/107 (91.6%)

538/554 (97.1%)

100/108 (92.6%)

526/556 (94.6%)

55/107 (51.4%)

391/554 (70.6%)

55/108 (50.9%)

385/556 (69.2%)

22/107 (20.6%)

226/554 (40.8%)

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 identified for inclusion: 16 acute and 6 persis- tent diarrhea trials. Briefly, the analysis software pro- duces 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% confidence 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 vari- ability are termed heterogeneity. Meta-analysis should be considered only when a group of trials is sufficiently 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 conceal- ment of allocation, help to control for clinical/method- ologic 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 identification and measure- ment 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 pres- ence of statistical heterogeneity. Variability (heterogene- ity) among the obtained effects sizes was formally op- erationalized using a 2 test of significance. 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 statis- tical heterogeneity is inevitable; therefore, the test for heterogeneity is irrelevant to the choice of analysis: het- erogeneity 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 inconsis- tency is I 2 , 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

considered substantial heterogeneity, and that percent- age cutoff was adopted and examined also in our anal- yses.

Gravity

Another more recent approach 13 proposed jackknife re- sampling 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 com- monly weighted according to their sample size and/or internal variability. Gee 13 proposed that jackknife re- sampling could be used to examine study influence 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 ob- tained. The difference between the average of these k results and each study’s individual result (when omit- ted) is taken as an index of “raw gravity.” This differ- ence, 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 influential. SPSS 15.0 14 was used to calculate standardized gravity values.

Fixed- or Random-Effects Model

Choice of whether to interpret a fixed-effects or ran- dom-effects model was considered thoroughly. Fixed- effect meta-analyses ignore heterogeneity. The fixed- effect estimate and its CI address the question, “What is the best estimate of the treatment effect?” The random- effects 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 ran- dom-effects estimate may not reflect the actual effect in any population being studied. In a fixed-effects meta- analysis, a pooled-effect estimate is termed, generally, as the best estimate of the treatment effect. It is for these reasons that we chose a fixed-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 supplemen- tation 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 5 1519 were not double-blinded. Sixteen of these published studies met the definition 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 commu- nities. 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

Country

Zinc Supplement

Zinc Dosage

Zinc/Control Group, N

Age, mo

Sachdev et al 17 (1988)

India

Sulfate

20 mg

25/25

6–18

Sazawal et al 31 (1995)

India

Gluconate

20 mg

456/481

6–35

Roy et al 30 (1997)

Bangladesh

Acetate

20 mg

57/54

3–24

Faruque et al 27 (1999)

Bangladesh

Acetate

14/40 mg

343/341

6–23

Hidayat et al 28 (1998)

Indonesia

Acetate

4/5 mg/kg

739/659

3–25

Dutta et al 26 (2000)

India

Sulfate

40 mg

44/36

3–24

Strand et al 32 (2002)

Nepal

Gluconate

15/30 mg

445/449

6–35

Bahl et al 23 (2002) a

India

Gluconate

15/30 mg

404/401

6–35

Al-Sonboli et al 22 (2003)

Brazil

Sulfate

22.5/45 mg

37/37

3–60

Polat et al 29 (2003) b

Turkey

Sulfate

20 mg

92/90

2–29

Bhatnagar et al 24 (2004)

India

Sulfate

15/30 mg

143/144

3–36

Valery et al 19 (2005) c

Australia

Sulfate

20/40 mg

107/108

0–11, 12–23, 24

Patel et al 20 (2005)

India

Sulfate/copper sulfate

40 mg/5 mg

102/98

6–59

Brooks et al 25 (2005) d

Bangladesh

Acetate

20 mg

86/89

1–6

Baqui et al 15 (2002)

Bangladesh

Acetate

20 mg

3974/4096

3–59

Fischer Walker et al 16 (2006)

Pakistan, Ethiopia, India

Sulfate

10 mg

554/556

1–5

a Three study groups were examined (control, zinc syrup, and zinc/ORS). We included only those who received zinc syrup or a control. b Four 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

Country

Zinc Supplement

Zinc Dosage

Zinc/Control Group, N

Age, mo

Sachdev et al 18 (1990)

India

Bangladesh

Bangladesh

Pakistan

Peru

India

Sulfate

20 mg

20/20

6–18

Roy et al 21 (1998)

Acetate

20 mg

95/95

3–24

Khatun et al 34 (2001)

Acetate

20 mg

24/24

6–24

Bhutta et al 33 (1999)

Sulfate

3 mg/kg

43/44

6–36

Penny et al 35 (1999)

Gluconate

20 mg

139/136

6–35

Bhandari et al 36 (2002)

Gluconate

10/20 mg

1228/1236

6–30

Mortality

Mortality was originally a primary outcome in this meta- analysis; however, of both acute and persistent trials, only 3 15,20,21 reported mortality outcome, making it diffi- cult 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 trial 15 (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 re- stricted to noninjury deaths, there were 13 in the zinc- treated group and 27 in the placebo group. The investi- gators 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 di- arrhea in 1 child. Because acute and persistent diarrhea are, most likely, distinct disease entities, the outcomes

obtained are presented initially for acute diarrhea (last- ing 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 aver- age duration of acute diarrhea 1517,19,20,2232 (n 15 231), those who received zinc experienced a significantly lower average duration of diarrhea than those who re-

ceived 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 significant heterogeneity (Q 95.58, de- grees of freedom [df] Q 15, P .001, I 2 84.3%). Figure 1 depicts a Forrest plot for these results, in which every study is displayed as a point estimate with CIs. Examination of significant heterogeneity in the acute diarrhea trials revealed 5 trials 17,19,20,25,30 with insignifi- cant differences between zinc and placebo groups in average duration of diarrhea. P values ranged from .478 to nonsignificant 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 tri- als 17,19,20,30 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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329

TABLE 5

Mean Duration of Acute Diarrhea

 

Reference

N1

N2

Lower

Upper

Effect

SE

P

Sachdev et al 17 (1988)

25

25

.371

.769

.199

.284

.478

Sazawal et al 31 (1995)

456

481

.128

.386

.257

.066

.000

Roy et al 30 (1997)

37

37

.312

.616

.152

.233

.511

Hidayat et al 28 (1998)

738

659

.015

.225

.120

.054

.025

Faruque et al 27 (1999)

341

340

.045

.347

.196

.077

.011

Dutta et al 26 (2000)

44

36

1.811

2.995

2.403

.297

.000

Strand et al 32 (2002)

445

449

.052

.315

.184

.067

.006

Baqui et al 15 (2002)

3974

4096

.243

.331

.287

.022

.000

Bahl et al 23 (2002)

404

401

.016

.261

.122

.071

.083

Polat et al 29 (2003)

92

90

.425

1.030

.727

.153

.000

Al-Sonboli et al 22 (2003)

37

37

.435

1.412

.924

.245

.000

Bhatnagar et al 24 (2004)

143

144

.025

.441

.208

.118

.079

Patel et al 20 (2005)

102

98

.246

.312

.033

.141

.817

Valery et al 19 (2005)

107

108

.260

.278

.009

.136

.946

Brooks et al 25 (2005)

86

89

.298

.298

.000

.151

NS

Fischer Walker et al 16 (2006)

554

556

.006

.242

.124

.060

.039

Fixed combined (16)

7585

7646

.208

.272

.240

.016

.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, nonsignificant.

TABLE 5 Mean Duration of Acute Diarrhea Reference N1 N2 Lower Upper Effect SE P Sachdev

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 reflect a better outcome for the placebo group, and values 0.0 indicate a better out- come for the zinc group. If the point estimate and CI fell above 0.0, then the study would meet the criterion for statistical significance ( .05). If the CI overlapped 0.0, then the P value would exceed .05 and the study would not be statistically significant.

trial 25 found no difference at all between treatment groups. Participants in all 5 trials had been admitted for dehydration secondary to diarrhea, although the sever- ity of dehydration ranged. Four of the trials 17,20,25,30 ad- ministered an ORS before treatment assignment. Three trials received zinc sulfate and 2 received acetate. In contrast, all acute diarrhea trials 23,31,32 that provided zinc gluconate and not zinc sulfate had a shorter duration of diarrhea than placebo (P .08). Two trials 17,20 originated from India, 2 25,30 from Bangladesh, and 1 19 from Austra- lia. One trial 15 in which average duration was signifi- cantly lower (1.2 days lower) with zinc use also had a

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 study 15 had a great deal of impact on the strength and direction of the estimated effect size value found for average dura- tion 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 consid- ered 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 differ- ences in mean duration of diarrhea would be statistically significant.

Occurrence of Diarrhea at Day 1 Five acute diarrhea trials 16,19,20,27,32 reported the occur- rence of diarrhea at day 1 (n 3100). No statistically significant 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, significant heterogeneity did occur (Q 10.60, df Q 4, P .03, I 2 62.3%).

Occurrence of Diarrhea at Day 3

Six acute diarrhea trials 16,19,20,23,27,32 collected data for oc- currence of diarrhea at day 3. No statistically significant differences occurred between treatment groups in occur- rence of diarrhea at day 3 (RR: 0.97; 95% CI: 0.91–1.03; P .36); however, the occurrence of statistically signif- icant heterogeneity was found (Q 10.880, df Q 5, P 0.05, I 2 54.0%). Only 1 trial 30 found a significantly (P .01) lower occurrence of diarrhea at day 3 with zinc (27.4%) than placebo (35.4%; effect size: 0.774); how- ever, the occurrence of statistically significant heteroge- neity was found (Q 10.880, df Q 5, P .05, I 2

54.0%).

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TABLE 6

Acute Diarrhea: Gravity Values for Duration of Diarrhea

 

Reference

Effect Size

Raw Gravity

Standardized Gravity

Sample Size

Valery et al 19 (2005)

0.243

0.00481

0.332

215

Strand et al 32 (2002)

0.243

0.00481

0.332

894

Sazawal et al 31 (1995)

0.239

0.00081

0.056

937

Sachdev et al 17 (1988)

0.240

0.00181

0.125

50

Roy et al 30 (1997)

0.240

0.00181

0.125

74

Polat et al 29 (2003)

0.234

0.00419

0.289

182

Patel et al 20 (2005)

0.243

0.00481

0.332

200

Hidayat et al 28 (1998)

0.252

0.01381

0.953

1397

Fischer Walker et al 16 (2006)

0.249

0.01081

0.746

1110

Faruque et al 27 (1999)

0.242

0.00381

0.263

681

Dutta et al 26 (2000)

0.233

0.00519

0.358

80

Brooks et al 25 (2005)

0.243

0.00481

0.332

175

Bhatnagar et al 24 (2004)

0.240

0.00181

0.125

287

Baqui et al 15 (2002)

0.187

0.05119

3.531

8070

Bahl et al 23 (2002)

0.246

0.00781

0.539

805

Al-Sonboli et al 22 (2003)

0.237

0.00119

0.082

74

TABLE 6 Acute Diarrhea: Gravity Values for Duration of Diarrhea Reference Effect Size Raw Gravity Standardized

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 significant 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 significant hetero-

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TABLE 7

Effects of Zinc Therapy of Acute Diarrhea

 

Reference

 

Country

Stool Frequency Reduction

 

Probability of Diarrhea Continuation

Sachdev et al 17 (1988) Sazawal et al 31 (1995) Roy et al 30 (1997) Faruque et al 27 (1999) Hidayat et al 28 (1998) Dutta et al 26 (2000) Strand et al 32 (2002) Bahl et al 23 (2002) Al-Sonboli et al 22 (2003) Polat et al 29 (2003) Bhatnagar et al 24 (2004) Valery et al 19 (2005) Brooks et al 25 (2005) Brooks et al 25 (2005) Baqui et al 15 (2002) Fischer Walker et al 16 (2006)

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

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

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 defined 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 first 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 andreportingthe median. Theratio ofthe median wasthentaken. Theresulting 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 first 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

N1

N2

Lower

Upper

Effect

SE

P

Sachdev et al 18 (1990)

20

73

87

43

24

247

20

0.123

1.182

0.530

0.322

.096

Roy et al 21 (1998)

68

0.201

0.466

0.133

0.169

.430

Penny et al 35 (1999)

86

0.134

0.742

0.438

0.154

.004

Bhutta et al 33 (1999)

44

0.295

0.558

0.132

0.215

.537

Khatun et al 34 (2001)

24

0.167

1.010

0.422

0.292

.144

Fixed combined (5)

242

0.120

0.478

0.299

0.091

.001

geneity was found (Q 18.957, df Q 5, P .002, I 2

73.6%).

Vomiting

In 11 acute diarrhea trials 16,17,19,2225,2932 (n 4438), the proportion of participants who vomited after the initial dose was significantly 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 significantly higher proportion of patients who received zinc gluconate vom-

ited (160 [14.6%] of 1095) than zinc sulfate/acetate therapy 16,17,19,22,24,25,29,30 (118 [10.7%] of 1101; RR: 1.18; 95% CI: 1.05–1.31; P .006).

Shortening of Diarrhea Duration

Eight trials of acute diarrhea 1517,20,25,26,29,31 found an av- erage shortening of diarrhea duration of 15.0% for those who received zinc in comparison with placebo (Table 7).

Reduction in Stool Frequency

Seven trials of acute diarrhea 17,22,23,25,29,31,32 found an av- erage reduction in stool frequency of 22.1% with zinc therapy in comparison with placebo. One single trial 16 found a 5.0% higher stool frequency using zinc than placebo.

Stool Output

Three trials of acute diarrhea 24,26,30 found an average lowering of stool output of 30.3%.

Probability of Diarrhea Reduction

Eight acute diarrhea trials 20,2325,27,28,30,32 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 In 5 persistent diarrhea trials 18,21,3335 (n 489), those who received zinc also experienced a significantly 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 significant heterogeneity (Q 3.08,

  • 332 LUKACIK et al

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FIGURE 3 Mean difference in duration of persistent diarrhea. The effect size index in this plot

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 reflect a better outcome for the placebo group, and values 0.0 indicate a better out- come for the zinc group. If the point estimate and CI fell above 0.0, then the study would meet the criterion for statistical significance ( .05). If the CI overlapped 0.0, then the P value would exceed .05 and the study would not be statistically significant.

df Q 4, P .544, I 2 29.9%). Figure 3 depicts the Forrest plot for these results.

Occurrence of Diarrhea at Day 1 In 2 trials of persistent diarrhea 34,35 (n 221), no statis- tically significant differences occurred between treat- ment groups in occurrence of diarrhea at day 1 (RR:

1.00; 95% CI: 0.93–1.08; P .98), and no statistically significant variability occurred among the effect sizes (Q 0.01, df Q 1, P .93).

Occurrence of Diarrhea at Day 3

In 2 trials of persistent diarrhea 34,35 (n 221), a signifi- cantly 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 significant variability occurred among the effect sizes (Q 0.33, df Q 1, P .56).

Occurrence of Diarrhea at Day 5

This was not examined; fewer than 2 studies reported.

Vomiting In 4 persistent diarrhea trials 18,21,35,36 (n 2969), a sig- nificantly higher proportion vomited on zinc (41 [2.8%] of 1482) than with placebo (2 [0.001%] of 1487; RR:

3.64; 95% CI: 1.02–13.02; 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 gluconate 35,36 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% re- duction in frequency.

Stool Output

Stool output was not measured in the persistent trials.

Probability of Diarrhea Reduction

Two persistent diarrhea trials 33,36 that measured the probability of diarrhea reduction found an 18.0% reduc- tion when zinc was used over placebo.

DISCUSSION

On the basis of these findings, which now add to the large body of previously published clinical data and up- date previous meta-analyses and systematic reviews, 8,37 zinc therapy is useful for treating both acute and persis- tent diarrhea and for their prophylaxis. Still, as exten- sively 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 studies 17,19,20,25,30 found no statistically significant differ- ences between zinc and placebo on the average duration of diarrhea (at least a P .48). Similarly, 2 (40.0%) of 5 persistent diarrhea studies 21,33 also found no statistically significant differences in average duration of diarrhea between treatments (at least a P .43). Still, the average stool frequency reductions, shortening of diarrhea dura- tions, and probabilities of a shortening of diarrhea dura- tion 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 dif- ficult because there are many different diarrheal agents, with such a variety of infectious agents, including bac- teria, parasites, and viruses. Identification of specific di- arrheal agents is complicated by the lack of access to laboratory tests in many developing countries. Viral gas- troenteritis 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, fol- lowed by nonbloody diarrhea. Although not normally fatal, the diarrhea caused by the virus can be quite severe, leading to potentially life-threatening dehydra- tion. Although easily treated with intravenous fluids in developed nations, these supplies are often unavailable in the developing world, and the dehydration that is caused by rotavirus is a significant cause of mortality. In fact, conclusions from these randomized trials for

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333

TABLE 9

Effects of Zinc Therapy of Persistent Diarrhea

 

Reference

Country

Stool Frequency Reduction

Probability of Diarrhea Continuation

Sachdev et al 18 (1990)

India

Bangladesh

Bangladesh

Pakistan

Peru

Nepal

22% lower frequency

19% shorter duration

Roy et al 21 (1998)

Not reported

7% shorter duration

Khatun et al 34 (2001)

7% lower frequency

17% shorter duration

Bhutta et al 33 (1999)

9% lower frequency

14% reduction in probability

Penny et al 35 (1999)

Not reported

19% shorter duration

Bhandari et al 36 (2002)

12% lower frequency

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 defined 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 bytheriskratio ofthe mean number of stools inthe first 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 first 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 efficacy of zinc treatment on diarrhea duration in- cluded an improved absorption of water and electrolytes by the intestine and quicker regeneration of gut epithe- lium. 38 Increased levels of brush border (apical) enzymes suggesting a zinc transporter for enterocytes 39 and a stronger immune response that increased clearance of pathogens from the intestine 40 were also described. Efficacy of oral rehydration therapy in correcting de- hydration and reducing mortality led to treatment mod- ifications of ORS with zinc therapy. Success with zinc therapy has generally been attributed to a decrease in the volume of small intestinal fluid and sodium absorp- tion triggered by zinc delivery. Still, the mechanisms by which zinc improves fluid 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 se- cretion, and whether deficiency 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-depen- dent fluid secretion. Treatment with ORS would have its greatest effect on reducing fluid loss by increasing small intestine absorption. Thus, zinc therapy after pretreat- ment with ORS may not have shown a beneficial effect (reduced average duration of diarrhea) over placebo in 5 trials 17,19,20,25,30 of this meta-analysis simply because pre- treatment with ORS had already maximized the small intestine absorption rate. Zinc inhibits cAMP-induced chloride secretion by spe- cifically 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 toxin–induced but not Escherichia coli heat-stable enterotoxin-induced ion secretion in cul- tured Caco-2 cells. One study 42 showed that cAMP acted as the intracellular effector of heat-labile enterotoxin- induced fluid secretion. Guanosine 3 ,5 -cyclic mono- phosphate mediates heat-stable–induced fluid secretion. If substantiated, then the effectiveness of zinc would be

  • 334 LUKACIK et al

limited to heat-labile–induced diarrhea or to diarrhea mediated by cAMP but not either 3 ,5 -cyclic mono- phosphate or intracellular Ca. It has been reported also 43 that a zinc-sensing receptor triggers the release of intra- cellular Ca 2 and regulates ion transport. A micromolar concentration of extracellular zinc set off a massive re- lease of calcium from intracellular pools in the colono- cytic cell line. A sustained increase in intracellular Ca level may augment K efflux and a hyperpolarization of cell membrane potential, leading to an advantageous electrical gradient for chloride secretion. Although the alternative treatment of oral rehydra- tion therapy is more available, there are still significant setbacks in distributing the therapy. An antisecretory drug vaccine would be a much more cost-effective solu- tion. An antisecretory drug vaccine could induce immu- nity without the children’s needing to go through mul- tiple 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 bur- den on the health system. The model for an antisecretory drug should perform by inhibiting intestinal chloride and HCO 3 secretion 6 in contrast to focusing on decreasing gastrointestinal mo- tility and regeneration and/or restoration of gut epithe- lium. 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 sys- tems? What is the relationship of zinc to intestinal fluid balance? Definitively what are the linkages of intestinal zinc transporters to body zinc status? Is there a brush border (apical) membrane zinc trans- porter for enterocytes? Answers to these and other questions will hopefully drive the creation of a treat- ment drug that collectively induces cation absorption; inhibits anion secretion; reduces stool frequency and output; reduces diarrhea duration; and is safe, tolera- ble, and inexpensive.

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ACKNOWLEDGMENT

We thank William D. Lyman, PhD, for help and sugges- tions in writing this article.

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HIGH-STAKES FLIMFLAM

“It’s 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 high- stakes 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 magi- cally 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 Harvard’s Graduate School of Education, told me in a recent interview that it’s 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 students—as opposed to improving student learning, which is not the same thing—there are all kinds of incentives to raise those scores by any means necessary. ‘We’ve now had four or five 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. That’s 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 figuring out ways, as Dr. Koretz put it, to ‘game’ the system. Guess what’s been happening? ‘We’ve had high-stakes testing, really, since the 1970s in some states,’ said Dr. Koretz. ‘We’ve 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 inflation of test scores.’”

  • 336 LUKACIK et al

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

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