A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and
                             Persistent Diarrhea...
ARTICLE


A Meta-analysis of the Effects of Oral Zinc in the
Treatment of Acute and Persistent Diarrhea
Marek Lukacik, MDa...
TABLE 1 Average Duration of Diarrhea (Days)                                                      trolled Trials (2006); an...
Statistical Analyses                                             considered substantial heterogeneity, and that percent-
C...
TABLE 3 Characteristics of Acute Diarrhea Trials
          Reference                               Country                ...
TABLE 5 Mean Duration of Acute Diarrhea
                                  Reference                       N1             N...
TABLE 6 Acute Diarrhea: Gravity Values for Duration of Diarrhea
                                 Reference                ...
TABLE 7 Effects of Zinc Therapy of Acute Diarrhea
          Reference                                     Country         ...
Stool Output
                                                                                                Stool output ...
TABLE 9 Effects of Zinc Therapy of Persistent Diarrhea
                          Reference                     Country    ...
ACKNOWLEDGMENT                                                                 double blind randomized trial. Indian Pedia...
40. Fenwick PK, Aggett PJ, Macdonald DC, Huber C, Wakelin D.            42. Canani RB, Cirillo P, Buccigrossi V, et al. Zi...
A Meta-analysis of the Effects of Oral Zinc in the Treatment of Acute and
                              Persistent Diarrhe...
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Articulo publicado en el PEDIATRICS por Marek Lukacik, MDa, Ronald L. Thomas, PhDb, Jacob V. Aranda, MD, PhDb. sobre el uso de zinc en la diarrea aguda y persistente, donde se verifica que acorta la duracion de la enfermedad.

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A Meta-analysis of the Effects of Oral Zinc in the

  1. 1. 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. Downloaded from www.pediatrics.org by on August 1, 2009
  2. 2. 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 aDepartment of Pediatrics, Children’s Medical Center, Medical College of Georgia, Augusta, Georgia; bDepartment 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 www.pediatrics.org/cgi/doi/10.1542/ peds.2007-0921 supplemental oral zinc therapy during recovery from acute or persistent diarrhea. doi:10.1542/peds.2007-0921 METHODS. We conducted a meta-analysis of randomized, controlled trials to compare Key Words the efficacy and safety of supplementary oral zinc with placebo in children with acute diarrhea, zinc and persistent diarrhea. Results were reported using a pooled relative risk or a Abbreviations weighted mean difference. A total of 22 studies were identified for inclusion: 16 WHO—World Health Organization ORS— oral rehydration solution examined acute diarrhea (n 15 231), and 6 examined persistent diarrhea (n RR—relative risk 2968). WMD—weighted mean difference CI— confidence interval RESULTS. Mean duration of acute diarrhea and persistent diarrhea was significantly cAMP—3 ,5 -cyclic monophosphate lower for zinc compared with placebo. Presence of diarrhea between zinc and K—potassium placebo at day 1 was not significantly different in acute diarrhea or persistent Ca— calcium diarrhea trials. At day 3, presence was significantly lower for zinc in persistent Accepted for publication Jul 24, 2007 diarrhea trials (n 221) but not in acute diarrhea trials. Vomiting after therapy was Address correspondence to Marek Lukacik, MD, Children’s Medical Center Department of significantly higher for zinc in 11 acute diarrhea trials (n 4438) and 4 persistent Pediatrics, Medical College of Georgia, 1120 diarrhea trials (n 2969). Those who received zinc gluconate in comparison with 15th St, Augusta, GA 30912. E-mail: mlukacik@ zinc sulfate/acetate vomited more frequently. Overall, children who received zinc mcg.edu reported an 18.8% and 12.5% reduction in average stool frequency, 15.0% and PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2008 by the 15.5% shortening of diarrhea duration, and a 17.9% and 18.0% probability of American Academy of Pediatrics 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. 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 326 LUKACIK et al Downloaded from www.pediatrics.org by on August 1, 2009
  3. 3. TABLE 1 Average Duration of Diarrhea (Days) trolled Trials (2006); and abstracts published in Pediatric Reference Zinc Placebo Research (1991–2006) and the First (Boston, 2000) and Second (Paris, France, 2004) World Congress of Pediatric Patel et al20 (2005) 4.34 2.28 4.41 1.98 Gastroenterology, Hepatology and Nutrition. Both pub- Valery et al19 (2005) 3.26 3.31 3.30 5.21 Fischer Walker et al16 (2006) 4.93 3.90 4.49 3.17 lished and unpublished trials were included in an effort to control for publication bias. Citations of appropriate Data are means SD. Data previously obtained during the course of the study. studies were verified by reviewing the bibliographies and reference lists of identified trials. Identified titles of ab- stracts with potential relevance were downloaded, and as a result of intestinal loss. A comprehensive review on full manuscripts were then obtained for all abstracts that this subject was recently published.6 An alternative view were deemed relevant on the basis of the inclusion is that zinc may be working as a pharmacologic agent at criteria. Twenty-two trials met inclusion criteria: 16 pub- the level of gene expression.7 The efficacy of zinc in the lished studies relative to the definition of acute diarrhea treatment of diarrhea is supported by several random- and 6 relative to persistent diarrhea. ized, controlled trials that showed reduction of diarrhea duration, stool output, and stool frequency. Meta-anal- yses on the therapeutic effects8 of zinc in acute and Primary and Secondary Outcomes persistent diarrhea as well as prevention9 of diarrhea Data on 8 clinically relevant outcome measures were with zinc supplementation have been previously pub- collected. We held average duration of diarrhea and lished. The published data so far have shown the efficacy presence of diarrhea episodes at days 1, 3, and 5 as our of zinc in the treatment of acute and chronic diarrhea. primary outcomes. Data on vomiting frequency, vom- Our meta-analysis was performed to include new studies iting frequency by therapy type, stool frequency re- published since the last meta-analysis and to examine duction, and probability of diarrhea continuation the efficacy and safety of zinc therapy during recovery were extracted as secondary outcomes. All 3 authors from acute or persistent diarrhea. independently extracted data from the same articles us- ing a data extraction sheet and subsequently compared results for agreement. The data thus obtained were METHODS checked for consistency among authors, integrity of ran- Inclusion Criteria domization, and concealment of allocation. Questions Studies that were selected for inclusion tested the same regarding the interpretability of certain data values were primary hypotheses (average duration of diarrhea and resolved by all 3 authors. The final database entries were presence of diarrhea at days 1, 3, and 5) using similar verified by the statistician (Dr Thomas). Few studies patient characteristics (primarily children aged between satisfied criteria for inclusion on every datum variable. 1 and 60 months), with either acute or persistent diar- When necessary, authors of selected studies were con- rhea, including dysentery. Acute diarrhea was defined as tacted to verify extracted data values derived from lasting up to 14 days, with persistent diarrhea lasting graphs and/or to provide additional information in a 14 days. Random allocation to treatment groups and scaling form that could be combined with other studies. concealment of allocation had to be met to satisfy inclu- Where those instances occurred, they are noted in Tables sion because inadequate allocation concealment, despite 1 and 2. the use of randomization, allows a risk for selection bias. Intervention with oral zinc salt supplementation, allow- Definitions ing for any zinc salt type or formulation (sulfate, glu- Definitions of diarrhea varied somewhat in all included conate, or acetate) if applied at 5 mg/day for any studies. In acute trials, generally, the definitions stated length of duration, was examined against a control using for diarrhea were the passage of 3 loose, watery stools a placebo. All comparisons between treatment groups or 1 loose, watery stool with blood within 24 hours for had to be free of confounding by additional agents or between 3 and 7 days in duration. In persistent diarrhea co-interventions. Study groups who, after randomiza- trials, the definitions were similar, with the exception tion, received zinc supplementation and ORS or zinc that they persisted up to 14 days in duration. supplemented with vitamin A were excluded. Definitions for duration of diarrhea varied as well but was defined, generally, from the time of enrollment into Identification of Trials the study until the first formed stool. Duration was The search strategy used computerized bibliographic measured in either days or hours. For the purpose of this searches of Medline (1966 –2006); the Cochrane Central meta-analysis, hours were converted to days. After en- Register of Controlled Trials (2006); Embase (1974 –2006); rollment/randomization, either the zinc treatment or the Lilacs (1982–2006); CINAHL (1982–2006); Current Con- placebo was assigned within 24 hours. 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 al19 (2005) 98/107 (91.6%) 100/108 (92.6%) 55/107 (51.4%) 55/108 (50.9%) 22/107 (20.6%) 20/108 (18.5%) Fischer Walker et al16 (2006) 538/554 (97.1%) 526/556 (94.6%) 391/554 (70.6%) 385/556 (69.2%) 226/554 (40.8%) 204/556 (36.7%) PEDIATRICS Volume 121, Number 2, February 2008 327 Downloaded from www.pediatrics.org by on August 1, 2009
  4. 4. Statistical Analyses considered substantial heterogeneity, and that percent- Comprehensive Meta-Analysis,10 a stand-alone program, age cutoff was adopted and examined also in our anal- was used to synthesize data that were obtained from the yses. 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 Gravity meta-analysis results. The program is augmented using Another more recent approach13 proposed jackknife re- accepted computational algorithms. Where appropriate, sampling to measure a concept termed “gravity.” In any results were reported using a pooled relative risk (RR). meta-analysis, arguments have focused on the inclusion For continuous outcomes, the weighted mean difference or exclusion of some studies, with debate on which ones (WMD) was calculated. The 95% confidence intervals should be included or excluded because studies are com- (CIs) were reported around the weighted effect size. monly weighted according to their sample size and/or internal variability. Gee13 proposed that jackknife re- Heterogeneity sampling could be used to examine study influence and Given that studies that are selected for inclusion in a detect outlier studies. The technique recomputes the meta-analysis will differ, the types of variability (clinical, meta-analysis once for each of k studies, where each methodologic, and/or statistical) that may occur among study is individually excluded. K results are then ob- studies must be investigated. These various types of vari- tained. The difference between the average of these k ability are termed heterogeneity. Meta-analysis should results and each study’s individual result (when omit- be considered only when a group of trials is sufficiently ted) is taken as an index of “raw gravity.” This differ- homogeneous (as indicated in the inclusion criteria) in ence, divided by the SD of the k differences, is taken as terms of participants, interventions, and outcomes to a z score, or “standardized gravity,” which can be used to provide a meaningful summary. Strict adherence to the establish which studies might be unusually influential. inclusion criteria listed, such as blinding and conceal- SPSS 15.014 was used to calculate standardized gravity ment of allocation, help to control for clinical/method- values. ologic heterogeneity. Still, statistical heterogeneity can also occur when variability in the treatment effects being evaluated in the different trials exists. This results when Fixed- or Random-Effects Model the observed treatment effects are more different from Choice of whether to interpret a fixed-effects or ran- each other than would be expected as a result of random dom-effects model was considered thoroughly. Fixed- error (chance) alone. Following convention, statistical effect meta-analyses ignore heterogeneity. The fixed- heterogeneity in the results of this meta-analysis are effect estimate and its CI address the question, “What is referred to simply as heterogeneity. the best estimate of the treatment effect?” The random- Different approaches for identification and measure- effects estimate and its CI address the question, “What is ment of heterogeneity were therefore undertaken to the average treatment effect?” The answers to these examine the extent to which the results of the studies questions are analogous when no heterogeneity is included were consistent. CIs for the results of individual present or when the distribution of the treatment effects studies (depicted graphically using horizontal lines) were is roughly symmetrical. If they are not, then the ran- examined for poor overlap, a general indication of pres- dom-effects estimate may not reflect the actual effect in ence of statistical heterogeneity. Variability (heterogene- any population being studied. In a fixed-effects meta- ity) among the obtained effects sizes was formally op- analysis, a pooled-effect estimate is termed, generally, as erationalized using a 2 test of significance. The formula the best estimate of the treatment effect. It is for these for heterogeneity assesses the dispersion of individual reasons that we chose a fixed-effects model for our outcomes, vis-a-vis the combined effect, and denotes ` meta-analysis, along with the various stated approaches this value using a Q statistic.11 A low P value (or a large to examine heterogeneity if found. 2 statistic relative to its degree of freedom) provides evidence of heterogeneity of treatment effects (variation in effect estimates beyond chance). RESULTS Because some degree of clinical and methodologic The author, year, country, amount of zinc supplemen- diversity always occurs in a meta-analysis, some statis- tation and type, sample size, and age for each of the 22 tical heterogeneity is inevitable; therefore, the test for studies selected for inclusion in the meta-analysis are heterogeneity is irrelevant to the choice of analysis: het- listed in Tables 3 and 4. Although all 22 studies were erogeneity will always exist regardless of whether it can randomly assigned clinical trials, it seemed that 515–19 be detected using a statistical test. Still, methods have were not double-blinded. Sixteen of these published been developed for quantifying inconsistency across studies met the definition for acute diarrhea and 6 for studies that move the focus away from testing whether persistent diarrhea. heterogeneity is present to assessing its impact on the Overall, 56.3% (9 of 16) of acute diarrhea trials were meta-analysis. A useful statistic for quantifying inconsis- conducted in inpatient hospital settings, and 43.7% (7 of tency is I2, the percentage of the variability in effect size 16) were conducted in outpatient homes and commu- estimates that is attributable to heterogeneity rather nities. Of the 6 persistent diarrhea trials, 66.7% (4 of 6) than sampling error (chance).12 A value 50% may be were inpatient and 33.3% (2 of 6) were outpatient. 328 LUKACIK et al Downloaded from www.pediatrics.org by on August 1, 2009
  5. 5. TABLE 3 Characteristics of Acute Diarrhea Trials Reference Country Zinc Supplement Zinc Dosage Zinc/Control Group, N Age, mo 17 Sachdev et al (1988) India Sulfate 20 mg 25/25 6–18 Sazawal et al31 (1995) India Gluconate 20 mg 456/481 6–35 Roy et al30 (1997) Bangladesh Acetate 20 mg 57/54 3–24 Faruque et al27 (1999) Bangladesh Acetate 14/40 mg 343/341 6–23 Hidayat et al28 (1998) Indonesia Acetate 4/5 mg/kg 739/659 3–25 Dutta et al26 (2000) India Sulfate 40 mg 44/36 3–24 Strand et al32 (2002) Nepal Gluconate 15/30 mg 445/449 6–35 Bahl et al23 (2002)a India Gluconate 15/30 mg 404/401 6–35 Al-Sonboli et al22 (2003) Brazil Sulfate 22.5/45 mg 37/37 3–60 Polat et al29 (2003)b Turkey Sulfate 20 mg 92/90 2–29 Bhatnagar et al24 (2004) India Sulfate 15/30 mg 143/144 3–36 Valery et al19 (2005)c Australia Sulfate 20/40 mg 107/108 0–11, 12–23, 24 Patel et al20 (2005) India Sulfate/copper sulfate 40 mg/5 mg 102/98 6–59 Brooks et al25 (2005)d Bangladesh Acetate 20 mg 86/89 1–6 Baqui et al15 (2002) Bangladesh Acetate 20 mg 3974/4096 3–59 Fischer Walker et al16 (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 al18 (1990) India Sulfate 20 mg 20/20 6–18 Roy et al21 (1998) Bangladesh Acetate 20 mg 95/95 3–24 Khatun et al34 (2001) Bangladesh Acetate 20 mg 24/24 6–24 Bhutta et al33 (1999) Pakistan Sulfate 3 mg/kg 43/44 6–36 Penny et al35 (1999) Peru Gluconate 20 mg 139/136 6–35 Bhandari et al36 (2002) India Gluconate 10/20 mg 1228/1236 6–30 Mortality obtained are presented initially for acute diarrhea (last- Mortality was originally a primary outcome in this meta- ing up to 14 days) and followed by persistent diarrhea analysis; however, of both acute and persistent trials, (lasting 14 days). only 315,20,21 reported mortality outcome, making it diffi- cult to compare across all included trials. Two of these Results for Acute Diarrhea Trials were acute diarrhea trials,15,20 and 1 was a persistent diarrhea trial.21 In the largest acute diarrhea outpatient Duration of Acute Diarrhea trial15 (n 8070), 33 children (0.008%; 33 of 3974) died In 16 trials that examined the primary measure of aver- in the zinc-treated group and 37 (0.009%; 37 of 4096) age duration of acute diarrhea15–17,19,20,22–32 (n 15 231), died in the placebo group. Thirty deaths were attributed those who received zinc experienced a significantly to drowning, and the remaining were not injury related lower average duration of diarrhea than those who re- (ie, not attributable to zinc intervention). When re- ceived a placebo (WMD: 0.24; SE: 0.02; 95% CI: 0.21– stricted to noninjury deaths, there were 13 in the zinc- 0.27; P .001; Table 5, Fig 1) but also with the presence treated group and 27 in the placebo group. The investi- of statistically significant heterogeneity (Q 95.58, de- gators attributed the lower noninjury death rate in the grees of freedom [df]Q 15, P .001, I2 84.3%). intervention group almost entirely to fewer deaths from Figure 1 depicts a Forrest plot for these results, in which diarrhea and acute lower respiratory infection. Diarrhea every study is displayed as a point estimate with CIs. and acute lower respiratory infection together accounted Examination of significant heterogeneity in the acute for 10 deaths in the zinc intervention group and 20 diarrhea trials revealed 5 trials17,19,20,25,30 with insignifi- deaths in the placebo group. In the other acute diarrhea cant differences between zinc and placebo groups in trial,20 2 children in the placebo group died of septicemia. average duration of diarrhea. P values ranged from .478 In the persistent diarrhea trial,21 the causes of death were to nonsignificant in sample sizes that ranged from 50 to septicemia with diarrhea in 3 children, septicemia in 1 215. Although those who received zinc had a shorter child, bronchopneumonia in 1 child, and continued di- average duration of diarrhea, the difference in 4 tri- arrhea in 1 child. Because acute and persistent diarrhea als17,19,20,30 was very small, with an average difference of are, most likely, distinct disease entities, the outcomes 0.18 0.18 days ranging from 0.04 to 0.40 days. One PEDIATRICS Volume 121, Number 2, February 2008 329 Downloaded from www.pediatrics.org by on August 1, 2009
  6. 6. TABLE 5 Mean Duration of Acute Diarrhea Reference N1 N2 Lower Upper Effect SE P 17 Sachdev et al (1988) 25 25 .371 .769 .199 .284 .478 Sazawal et al31 (1995) 456 481 .128 .386 .257 .066 .000 Roy et al30 (1997) 37 37 .312 .616 .152 .233 .511 Hidayat et al28 (1998) 738 659 .015 .225 .120 .054 .025 Faruque et al27 (1999) 341 340 .045 .347 .196 .077 .011 Dutta et al26 (2000) 44 36 1.811 2.995 2.403 .297 .000 Strand et al32 (2002) 445 449 .052 .315 .184 .067 .006 Baqui et al15 (2002) 3974 4096 .243 .331 .287 .022 .000 Bahl et al23 (2002) 404 401 .016 .261 .122 .071 .083 Polat et al29 (2003) 92 90 .425 1.030 .727 .153 .000 Al-Sonboli et al22 (2003) 37 37 .435 1.412 .924 .245 .000 Bhatnagar et al24 (2004) 143 144 .025 .441 .208 .118 .079 Patel et al20 (2005) 102 98 .246 .312 .033 .141 .817 Valery et al19 (2005) 107 108 .260 .278 .009 .136 .946 Brooks et al25 (2005) 86 89 .298 .298 .000 .151 NS Fischer Walker et al16 (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. 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 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 trials16,19,20,27,32 reported the occur- rence of diarrhea at day 1 (n 3100). No statistically FIGURE 1 Mean difference in duration of acute diarrhea. The effect size index in this plot is the significant difference in the occurrence of acute diarrhea standard mean difference, so a point estimate of 0.0 indicates no effect. Values 0.0 at day 1 was found (RR: 1.01; 95% CI: 0.99 –1.03; P reflect a better outcome for the placebo group, and values 0.0 indicate a better out- 0.30). Although the variability in effect sizes ranged come for the zinc group. If the point estimate and CI fell above 0.0, then the study would from a low of 0.968 to 1.695, significant heterogeneity meet the criterion for statistical significance ( .05). If the CI overlapped 0.0, then the P did occur (Q 10.60, dfQ 4, P .03, I2 62.3%). value would exceed .05 and the study would not be statistically significant. Occurrence of Diarrhea at Day 3 trial25 found no difference at all between treatment Six acute diarrhea trials16,19,20,23,27,32 collected data for oc- groups. Participants in all 5 trials had been admitted for currence of diarrhea at day 3. No statistically significant dehydration secondary to diarrhea, although the sever- differences occurred between treatment groups in occur- ity of dehydration ranged. Four of the trials17,20,25,30 ad- rence of diarrhea at day 3 (RR: 0.97; 95% CI: 0.91–1.03; ministered an ORS before treatment assignment. Three P .36); however, the occurrence of statistically signif- trials received zinc sulfate and 2 received acetate. In icant heterogeneity was found (Q 10.880, dfQ 5, P contrast, all acute diarrhea trials23,31,32 that provided zinc 0.05, I2 54.0%). Only 1 trial30 found a significantly gluconate and not zinc sulfate had a shorter duration of (P .01) lower occurrence of diarrhea at day 3 with zinc diarrhea than placebo (P .08). Two trials17,20 originated (27.4%) than placebo (35.4%; effect size: 0.774); how- from India, 225,30 from Bangladesh, and 119 from Austra- ever, the occurrence of statistically significant heteroge- lia. One trial15 in which average duration was signifi- neity was found (Q 10.880, dfQ 5, P .05, I2 cantly lower (1.2 days lower) with zinc use also had a 54.0%). 330 LUKACIK et al Downloaded from www.pediatrics.org by on August 1, 2009
  7. 7. TABLE 6 Acute Diarrhea: Gravity Values for Duration of Diarrhea Reference Effect Size Raw Gravity Standardized Gravity Sample Size 19 Valery et al (2005) 0.243 0.00481 0.332 215 Strand et al32 (2002) 0.243 0.00481 0.332 894 Sazawal et al31 (1995) 0.239 0.00081 0.056 937 Sachdev et al17 (1988) 0.240 0.00181 0.125 50 Roy et al30 (1997) 0.240 0.00181 0.125 74 Polat et al29 (2003) 0.234 0.00419 0.289 182 Patel et al20 (2005) 0.243 0.00481 0.332 200 Hidayat et al28 (1998) 0.252 0.01381 0.953 1397 Fischer Walker et al16 (2006) 0.249 0.01081 0.746 1110 Faruque et al27 (1999) 0.242 0.00381 0.263 681 Dutta et al26 (2000) 0.233 0.00519 0.358 80 Brooks et al25 (2005) 0.243 0.00481 0.332 175 Bhatnagar et al24 (2004) 0.240 0.00181 0.125 287 Baqui et al15 (2002) 0.187 0.05119 3.531 8070 Bahl et al23 (2002) 0.246 0.00781 0.539 805 Al-Sonboli et al22 (2003) 0.237 0.00119 0.082 74 FIGURE 2 Standardized gravity results. Occurrence of Diarrhea at Day 5 treatment groups in occurrence of diarrhea at day 5 (RR: Similarly, in the same 6 acute diarrhea trials,16,19,20,23,27,32 0.94; 95% CI: 0.84 –1.05; P .26). Similar to day 3 no statistically significant differences occurred between results, the occurrence of statistically significant hetero- PEDIATRICS Volume 121, Number 2, February 2008 331 Downloaded from www.pediatrics.org by on August 1, 2009
  8. 8. TABLE 7 Effects of Zinc Therapy of Acute Diarrhea Reference Country Stool Frequency Reduction Probability of Diarrhea Continuation 17 Sachdev et al (1988) India 18% lower frequency 9% shorter duration Sazawal et al31 (1995) India 39% lower frequency 19% shorter duration Roy et al30 (1997) Bangladesh 28% lower stool output 14% reduction in probability Faruque et al27 (1999) Bangladesh Not reported 20% reduction in probability Hidayat et al28 (1998) Indonesia Not reported 11% reduction in probability Dutta et al26 (2000) India 38% lower stool output 32% shorter duration Strand et al32 (2002) Nepal 8% lower frequency 26% reduction in probability Bahl et al23 (2002) India 17% lower frequency 11% reduction in probability Al-Sonboli et al22 (2003) Brazil 59% lower frequency Not reported Polat et al29 (2003) Turkey 14% lower frequency 20% shorter duration Bhatnagar et al24 (2004) India 25% lower stool output 30% reduction in probability Valery et al19 (2005) Australia Not reported Not reported Brooks et al25 (2005) India Not reported 19% reduction in probability, 7% shorter duration Brooks et al25 (2005) Bangladesh 0% lower frequency 12% reduction in probability, 0% shorter duration Baqui et al15 (2002) Bangladesh Not reported 24% shorter duration Fischer Walker et al16 (2006) Pakistan, Ethiopia, India 5% higher frequency 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 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. TABLE 8 Mean Duration of Persistent Diarrhea Reference N1 N2 Lower Upper Effect SE P Sachdev et al18 (1990) 20 20 0.123 1.182 0.530 0.322 .096 Roy et al21 (1998) 73 68 0.201 0.466 0.133 0.169 .430 Penny et al35 (1999) 87 86 0.134 0.742 0.438 0.154 .004 Bhutta et al33 (1999) 43 44 0.295 0.558 0.132 0.215 .537 Khatun et al34 (2001) 24 24 0.167 1.010 0.422 0.292 .144 Fixed combined (5) 247 242 0.120 0.478 0.299 0.091 .001 geneity was found (Q 18.957, dfQ 5, P .002, I2 Reduction in Stool Frequency 73.6%). Seven trials of acute diarrhea17,22,23,25,29,31,32 found an av- erage reduction in stool frequency of 22.1% with zinc therapy in comparison with placebo. One single trial16 Vomiting found a 5.0% higher stool frequency using zinc than In 11 acute diarrhea trials16,17,19,22–25,29–32 (n 4438), the placebo. proportion of participants who vomited after the initial dose was significantly higher with zinc (278 [12.7%] of Stool Output 2196) use than with placebo (171 [7.6%] of 2242; RR: Three trials of acute diarrhea24,26,30 found an average 1.55; 95% CI: 1.30 –1.84; P 0.001%; Q 25.54, P lowering of stool output of 30.3%. .004). Probability of Diarrhea Reduction Vomiting After Administration of Zinc Sulfate or Gluconate Eight acute diarrhea trials20,23–25,27,28,30,32 measured the In 3 acute diarrhea trials,23,31,32 a significantly higher probability of diarrhea reduction and found a 17.9% proportion of patients who received zinc gluconate vom- reduction using zinc compared with placebo. ited (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; Results for Persistent Diarrhea Trials 95% CI: 1.05–1.31; P .006). Duration of Persistent Diarrhea In 5 persistent diarrhea trials18,21,33–35 (n 489), those Shortening of Diarrhea Duration who received zinc also experienced a significantly lower Eight trials of acute diarrhea15–17,20,25,26,29,31 found an av- average duration of diarrhea than the placebo group erage shortening of diarrhea duration of 15.0% for those (WMD: 0.30; SE: 0.09; 95% CI: 0.12– 0.48; P .001; who received zinc in comparison with placebo (Table 7). Table 8) but without significant heterogeneity (Q 3.08, 332 LUKACIK et al Downloaded from www.pediatrics.org by on August 1, 2009
  9. 9. 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% reduc- tion when zinc was used over placebo. FIGURE 3 Mean difference in duration of persistent diarrhea. The effect size index in this plot is the DISCUSSION standard mean difference, so a point estimate of 0.0 indicates no effect. Values 0.0 On the basis of these findings, which now add to the reflect a better outcome for the placebo group, and values 0.0 indicate a better out- large body of previously published clinical data and up- 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 date previous meta-analyses and systematic reviews,8,37 value would exceed .05 and the study would not be statistically significant. 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 dfQ 4, P .544, I2 29.9%). Figure 3 depicts the which zinc physiologically exerts its antidiarrheal effect. Forrest plot for these results. In this meta-analysis, 5 (31.3%) of 16 acute diarrhea studies17,19,20,25,30 found no statistically significant differ- Occurrence of Diarrhea at Day 1 ences between zinc and placebo on the average duration In 2 trials of persistent diarrhea34,35 (n 221), no statis- of diarrhea (at least a P .48). Similarly, 2 (40.0%) of 5 tically significant differences occurred between treat- persistent diarrhea studies21,33 also found no statistically ment groups in occurrence of diarrhea at day 1 (RR: significant differences in average duration of diarrhea 1.00; 95% CI: 0.93–1.08; P .98), and no statistically between treatments (at least a P .43). Still, the average significant variability occurred among the effect sizes stool frequency reductions, shortening of diarrhea dura- (Q 0.01, dfQ 1, P .93). tions, and probabilities of a shortening of diarrhea dura- tion reported were higher in studies with zinc therapy in Occurrence of Diarrhea at Day 3 comparison with placebo. In 2 trials of persistent diarrhea34,35 (n 221), a signifi- To the majority of individuals, diarrhea means an cantly lower occurrence of diarrhea at day 3 occurred in increased frequency or decreased consistency of bowel those who were treated with zinc in comparison with movements. In many developed countries, the average placebo (RR: 0.70; 95% CI: 0.51– 0.94; P .02). No number of bowel movements is 3 per day; however, statistically significant variability occurred among the diarrhea is associated with an increase in stool weight, effect sizes (Q 0.33, dfQ 1, P .56). mainly as a result of excess water, which normally makes up a large percentage of fecal matter. Given this, Occurrence of Diarrhea at Day 5 diarrhea is distinguished from diseases that cause only This was not examined; fewer than 2 studies reported. an increase in the number of bowel movements or fecal incontinence. Vomiting Determining the exact causes of diarrhea can be dif- In 4 persistent diarrhea trials18,21,35,36 (n 2969), a sig- ficult because there are many different diarrheal agents, nificantly higher proportion vomited on zinc (41 [2.8%] with such a variety of infectious agents, including bac- of 1482) than with placebo (2 [0.001%] of 1487; RR: teria, parasites, and viruses. Identification of specific di- 3.64; 95% CI: 1.02–13.02; P .047; Q 5.91, P .116). arrheal agents is complicated by the lack of access to laboratory tests in many developing countries. Viral gas- Vomiting After Zinc Sulfate or Gluconate troenteritis caused by rotavirus is the primary cause of In 4 persistent diarrhea trials,18,21,35,36 those who received diarrhea among infants worldwide. Other causes include zinc gluconate35,36 vomited more frequently (41 [3%] of bacterial pathogens such as Vibrio cholerae, Shigella, and 1367) than did those who received zinc sulfate/acetate Salmonella. Protozoa such as Cryptosporidium parvum and (0 [0%] of 115; RR: 1.09; 95% CI: 0.94 –1.09; P .07). Giardia lamblia are 2 of the most common protozoan diarrheal agents. The primary symptoms of rotavirus Shortening of Diarrhea Duration infection are fever and vomiting for several days, fol- In 4 persistent diarrhea trials,18,21,34,35 those who received lowed by nonbloody diarrhea. Although not normally zinc experienced a 15.5% average shortening of diarrhea fatal, the diarrhea caused by the virus can be quite duration than those who got a placebo (Table 9). severe, leading to potentially life-threatening dehydra- tion. Although easily treated with intravenous fluids in Reduction in Stool Frequency developed nations, these supplies are often unavailable Four trials of persistent diarrhea found that those who in the developing world, and the dehydration that is received zinc also experienced an average of 9.8% re- caused by rotavirus is a significant cause of mortality. duction in frequency. In fact, conclusions from these randomized trials for PEDIATRICS Volume 121, Number 2, February 2008 333 Downloaded from www.pediatrics.org by on August 1, 2009
  10. 10. TABLE 9 Effects of Zinc Therapy of Persistent Diarrhea Reference Country Stool Frequency Reduction Probability of Diarrhea Continuation 18 Sachdev et al (1990) India 22% lower frequency 19% shorter duration Roy et al21 (1998) Bangladesh Not reported 7% shorter duration Khatun et al34 (2001) Bangladesh 7% lower frequency 17% shorter duration Bhutta et al33 (1999) Pakistan 9% lower frequency 14% reduction in probability Penny et al35 (1999) Peru Not reported 19% shorter duration Bhandari et al36 (2002) Nepal 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 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 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- limited to heat-labile–induced diarrhea or to diarrhea cluded an improved absorption of water and electrolytes mediated by cAMP but not either 3 ,5 -cyclic mono- by the intestine and quicker regeneration of gut epithe- phosphate or intracellular Ca. It has been reported also43 lium.38 Increased levels of brush border (apical) enzymes that a zinc-sensing receptor triggers the release of intra- suggesting a zinc transporter for enterocytes39 and a cellular Ca2 and regulates ion transport. A micromolar stronger immune response that increased clearance of concentration of extracellular zinc set off a massive re- pathogens from the intestine40 were also described. lease of calcium from intracellular pools in the colono- Efficacy of oral rehydration therapy in correcting de- cytic cell line. A sustained increase in intracellular Ca hydration and reducing mortality led to treatment mod- level may augment K efflux and a hyperpolarization of ifications of ORS with zinc therapy. Success with zinc cell membrane potential, leading to an advantageous therapy has generally been attributed to a decrease in electrical gradient for chloride secretion. the volume of small intestinal fluid and sodium absorp- Although the alternative treatment of oral rehydra- tion triggered by zinc delivery. Still, the mechanisms by tion therapy is more available, there are still significant which zinc improves fluid and electrolyte transportation setbacks in distributing the therapy. An antisecretory have not been elucidated fully. This includes the effect of drug vaccine would be a much more cost-effective solu- zinc on intestinal ion transport, whether zinc initiates or tion. An antisecretory drug vaccine could induce immu- increases cation absorption and/or suppresses anion se- nity without the children’s needing to go through mul- cretion, and whether deficiency enhances the likelihood tiple infections and the risks associated with infections. of secretory diarrhea. By preventing children from acquiring infection, a drug Most likely, the location of the effect of zinc is in the vaccine could greatly reduce the number of deaths as a small intestine, given its inhibition of adenosine 3 ,5 - result of diarrheal diseases and greatly reduce the bur- cyclic monophosphate (cAMP)-induced chloride-depen- den on the health system. dent fluid secretion. Treatment with ORS would have its greatest effect on reducing fluid loss by increasing small The model for an antisecretory drug should perform intestine absorption. Thus, zinc therapy after pretreat- by inhibiting intestinal chloride and HCO3 secretion6 in ment with ORS may not have shown a beneficial effect contrast to focusing on decreasing gastrointestinal mo- (reduced average duration of diarrhea) over placebo in 5 tility and regeneration and/or restoration of gut epithe- trials17,19,20,25,30 of this meta-analysis simply because pre- lium. Accelerated research directed to achieving a treatment with ORS had already maximized the small clearer understanding of the biology, chemistry, and intestine absorption rate. pathobiology of zinc in the gastrointestinal system is Zinc inhibits cAMP-induced chloride secretion by spe- necessary. Does zinc maintain intestinal defense sys- cifically inhibiting basolateral potassium (K) channels tems? What is the relationship of zinc to intestinal with no blockage effect on calcium (Ca)-mediated K fluid balance? Definitively what are the linkages of channels in in vitro studies with the rat ileum.41 Zinc also intestinal zinc transporters to body zinc status? Is inhibits cholera toxin–induced but not Escherichia coli there a brush border (apical) membrane zinc trans- heat-stable enterotoxin-induced ion secretion in cul- porter for enterocytes? Answers to these and other tured Caco-2 cells. One study42 showed that cAMP acted questions will hopefully drive the creation of a treat- as the intracellular effector of heat-labile enterotoxin- ment drug that collectively induces cation absorption; induced fluid secretion. Guanosine 3 ,5 -cyclic mono- inhibits anion secretion; reduces stool frequency and phosphate mediates heat-stable–induced fluid secretion. output; reduces diarrhea duration; and is safe, tolera- If substantiated, then the effectiveness of zinc would be ble, and inexpensive. 334 LUKACIK et al Downloaded from www.pediatrics.org by on August 1, 2009
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  12. 12. 40. Fenwick PK, Aggett PJ, Macdonald DC, Huber C, Wakelin D. 42. Canani RB, Cirillo P, Buccigrossi V, et al. Zinc inhibits cholera Zinc deprivation and zinc repletion: effect on the response of toxin-induced, but not Escherichia coli heat-stable entero- rats to infection with Strongyloides ratti. Am J Clin Nutr. 1990; toxin-induced, ion secretion in human enterocytes. J Infect Dis. 52(1):173–177 2005;191(7):1072–1077 41. Hoque KM, Rajendran VM, Binder HJ. Zinc inhibits cAMP- 43. Hershfinkel M, Moran A, Grossman N, Sekler I. A zinc- stimulated Cl secretion via basolateral K-channel blockade in sensing receptor triggers the release of intracellular Ca2 rat ileum. Am J Physiol Gastrointest Liver Physiol. 2005;288(5): and regulates ion transport. Proc Natl Acad Sci USA. 2001; G956 –G963 98(20):11749 –11754 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.’” Herbert B. New York Times. October 9, 2007 Noted by JFL, MD 336 LUKACIK et al Downloaded from www.pediatrics.org by on August 1, 2009
  13. 13. 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 including high-resolution figures, can be found at: & Services http://www.pediatrics.org/cgi/content/full/121/2/326 References This article cites 39 articles, 8 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/121/2/326#BIBL Citations This article has been cited by 1 HighWire-hosted articles: http://www.pediatrics.org/cgi/content/full/121/2/326#otherarticle s Subspecialty Collections 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 Permissions & Licensing 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 Reprints Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml Downloaded from www.pediatrics.org by on August 1, 2009

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