Professional Documents
Culture Documents
A Meta-Analysis of The Effects of Oral Zinc in The Treatment of Acute and Persistent Diarrhea
A Meta-Analysis of The Effects of Oral Zinc in The Treatment of Acute and Persistent Diarrhea
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
examined acute diarrhea (n ⫽ 15 231), and 6 examined persistent diarrhea (n ⫽ ORS— oral rehydration solution
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.aappublications.org/news by guest on July 4, 2019
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 ⱖ5 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 ⱖ3 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.
328 LUKACIK et al
Downloaded from www.aappublications.org/news by guest on July 4, 2019
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, ⱖ24
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 ⱖ24 months. All
330 LUKACIK et al
Downloaded from www.aappublications.org/news by guest on July 4, 2019
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.
332 LUKACIK et al
Downloaded from www.aappublications.org/news by guest on July 4, 2019
Stool Output
Stool output was not measured in the persistent trials.
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 ⱖ .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 ⱖ .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
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
The model for an antisecretory drug should perform
greatest effect on reducing fluid loss by increasing small
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.aappublications.org/news by guest on July 4, 2019
ACKNOWLEDGMENT double blind randomized trial. Indian Pediatr. 2005;42(5):
We thank William D. Lyman, PhD, for help and sugges- 433– 442
tions in writing this article. 21. Roy SK, Tomkins AM, Mahalanabis D, et al. Impact of zinc
supplementation on persistent diarrhoea in malnourished
Bangladeshi children. Acta Paediatr. 1998;87(12):1235–1239
REFERENCES 22. Al-Sonboli N, Gurgel RQ, Shenkin A, Hart CA, Cuevas LE. Zinc
1. Black RE, Morris SS, Bryce J. Where and why are 10 million supplementation in Brazilian children with acute diarrhoea.
children dying every year? Lancet. 2003;361(9376):2226 –2234 Ann Trop Paediatr. 2003;23(1):3– 8
2. Kosek M, Bern C, Guerrant RL. The global burden of diarrhoeal 23. Bahl R, Bhandari N, Saksena M, et al. Efficacy of zinc-fortified
disease, as estimated from studies published between 1992 and oral rehydration solution in 6- to 35-month-old children with
2000. Bull World Health Organ. 2003;81(3):197–204 acute diarrhea. J Pediatr. 2002;141(5):677– 682
3. Snyder JD, Merson MH. The magnitude of the global problem 24. Bhatnagar S, Bahl R, Sharma PK, Kumar GT, Saxena SK, Bhan
of acute diarrhoeal disease: a review of active surveillance data. MK. Zinc with oral rehydration therapy reduces stool output
Bull World Health Organ. 1982;60(4):605– 613 and duration of diarrhea in hospitalized children: a randomized
4. Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates controlled trial. J Pediatr Gastroenterol Nutr. 2004;38(1):34 – 40
of the causes of death in children. Lancet. 2005;365(9465): 25. Brooks WA, Santosham M, Roy SK, et al. Efficacy of zinc in
1147–1152 young infants with acute watery diarrhea. Am J Clin Nutr.
5. Claeson M, Merson MH. Global progress in the control of 2005;82(3):605– 610
diarrheal diseases. Pediatr Infect Dis J. 1990;9(5):345–355 26. Dutta P, Mitra U, Datta A, et al. Impact of zinc supplementation
6. Hoque KM, Binder HJ. Zinc in the treatment of acute diarrhea: in malnourished children with acute watery diarrhoea. J Trop
current status and assessment. Gastroenterology. 2006;130(7): Pediatr. 2000;46(5):259 –263
2201–2205 27. Faruque AS, Mahalanabis D, Haque SS, Fuchs GJ, Habte D.
7. Blanchard RK, Cousins RJ. Regulation of intestinal gene ex- Double-blind, randomized, controlled trial of zinc or vitamin A
pression by dietary zinc: induction of uroguanylin mRNA by supplementation in young children with acute diarrhoea. Acta
zinc deficiency. J Nutr. 2000;130(5S suppl):1393S–1398S Paediatr. 1999;88(2):154 –160
8. Bhutta ZA, Bird SM, Black RE, et al. Therapeutic effects of oral 28. Hidayat A, Achadi A, Sunoto, Soedarmo SP. The effect of zinc
zinc in acute and persistent diarrhea in children in developing supplementation in children under three years of age with acute
countries: pooled analysis of randomized controlled trials. Am J diarrhea in Indonesia. Med J Indonesia. 1998;7(4):237–241
Clin Nutr. 2000;72(6):1516 –1522 29. Polat TB, Uysalol M, Cetinkaya F. Efficacy of zinc supplemen-
9. Bhutta ZA, Black RE, Brown KH, et al. Prevention of diarrhea tation on the severity and duration of diarrhea in malnour-
and pneumonia by zinc supplementation in children in devel-
ished Turkish children. Pediatr Int. 2003;45(5):555–559
oping countries: pooled analysis of randomized controlled tri-
30. Roy SK, Tomkins AM, Akramuzzaman SM, et al. Randomised
als. Zinc Investigators’ Collaborative Group. J Pediatr. 1999;
controlled trial of zinc supplementation in malnourished Ban-
135(6):689 – 697
gladeshi children with acute diarrhoea. Arch Dis Child. 1997;
10. Comprehensive Meta-Analysis: A Computer Program for Research
77(3):196 –200
Synthesis [computer program]. Englewood, NJ: Biostat Inc;
31. Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S.
2003
Zinc supplementation in young children with acute diarrhea in
11. Cohen J. The earth is round (p ⬍. 05). Am Psychol. 1994;49(12):
India. N Engl J Med. 1995;333(13):839 – 844
997–1003
32. Strand TA, Chandyo RK, Bahl R, et al. Effectiveness and effi-
12. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring
cacy of zinc for the treatment of acute diarrhea in young
inconsistency in meta-analyses. BMJ. 2003;327(7414):
children. Pediatrics. 2002;109(5):898 –903
557–560
33. Bhutta ZA, Nizami SQ, Isani Z. Zinc supplementation in mal-
13. Gee T. Capturing study influence: the concept of ‘gravity’ in
meta-analysis. Counsel Psychother Health J. 2005;1:52–75 nourished children with persistent diarrhea in Pakistan. Pedi-
14. SPSS 15.0 for Windows [computer program]. Version 15.0. Chi- atrics. 1999;103(4). Available at: www.pediatrics.org/cgi/
cago, IL: SPSS Inc; 2006 content/full/103/4/e42
15. Baqui AH, Black RE, El Arifeen S, et al. Effect of zinc supple- 34. Khatun UH, Malek MA, Black RE, et al. A randomized con-
mentation started during diarrhoea on morbidity and mortality trolled clinical trial of zinc, vitamin A or both in undernour-
in Bangladeshi children: community randomised trial. BMJ. ished children with persistent diarrhea in Bangladesh. Acta
2002;325(7372):1059 Paediatr. 2001;90(4):376 –380
16. Fischer Walker CL, Bhutta ZA, Bhandari N, et al. Zinc supple- 35. Penny ME, Peerson JM, Marin RM, et al. Randomized, commu-
mentation for the treatment of diarrhea in infants in Pakistan, nity-based trial of the effect of zinc supplementation, with and
India and Ethiopia. J Pediatr Gastroenterol Nutr. 2006;43(3): without other micronutrients, on the duration of persistent child-
357–363 hood diarrhea in Lima, Peru. J Pediatr. 1999;135(2 Pt 1):208 –217
17. Sachdev HP, Mittal NK, Mittal SK, Yadav HS. A controlled trial 36. Bhandari N, Bahl R, Taneja S, et al. Substantial reduction in
on utility of oral zinc supplementation in acute dehydrating severe diarrheal morbidity by daily zinc supplementation in
diarrhea in infants. J Pediatr Gastroenterol Nutr. 1988;7(6): young north Indian children. Pediatrics. 2002;109(6). Available
877– 881 at: www.pediatrics.org/cgi/content/full/109/6/e86
18. Sachdev HP, Mittal NK, Yadav HS. Oral zinc supplementation 37. Black RE. Zinc deficiency, infectious disease and mortality in the
in persistent diarrhoea in infants. Ann Trop Paediatr. 1990; developing world. J Nutr. 2003;133(5 suppl 1):1485S–1489S
10(1):63– 69 38. Bettger WJ, O’Dell BL. A critical physiological role of zinc in
19. Valery PC, Torzillo PJ, Boyce NC, et al. Zinc and vitamin A the structure and function of biomembranes. Life Sci. 1981;
supplementation in Australian Indigenous children with acute 28(13):1425–1438
diarrhoea: a randomised controlled trial. Med J Aust. 2005; 39. Gebhard RL, Karouani R, Prigge WF, McClain CJ. The effect of
182(10):530 –535 severe zinc deficiency on activity of intestinal disaccharidases
20. Patel AB, Dhande LA, Rawat MS. Therapeutic evaluation of and 3-hydroxy-3-methylglutaryl coenzyme A reductase in the
zinc and copper supplementation in acute diarrhea in children: rat. J Nutr. 1983;113(4):855– 859
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.aappublications.org/news by guest on July 4, 2019
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
DOI: 10.1542/peds.2007-0921
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/121/2/326
References This article cites 39 articles, 6 of which you can access for free at:
http://pediatrics.aappublications.org/content/121/2/326#BIBL
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Infectious Disease
http://www.aappublications.org/cgi/collection/infectious_diseases_su
b
Epidemiology
http://www.aappublications.org/cgi/collection/epidemiology_sub
Permissions & Licensing Information about reproducing this article in parts (figures, tables) or
in its entirety can be found online at:
http://www.aappublications.org/site/misc/Permissions.xhtml
Reprints Information about ordering reprints can be found online:
http://www.aappublications.org/site/misc/reprints.xhtml
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/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:
1073-0397.