Oral zinc for treating diarrhoea in children

  • Review
  • Intervention

Authors

  • Marzia Lazzerini,

    Corresponding author
    1. Institute for Maternal and Child Health IRCCS Burlo Garofolo, WHO Collaborating Centre for Maternal and Child Health, Trieste, Italy
    • Marzia Lazzerini, WHO Collaborating Centre for Maternal and Child Health, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell'Istria 65/1, 34137, Trieste, Italy. marzia.lazzerini@burlo.trieste.it.

  • Humphrey Wanzira

    1. Institute for Maternal and Child Health IRCCS Burlo Garofolo, WHO Collaborating Centre for Maternal and Child Health, Trieste, Italy

Abstract

Background

In developing countries, diarrhoea causes around 500,000 child deaths annually. Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF).

Objectives

To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea.

Search methods

We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library 2016, Issue 5), MEDLINE, Embase, LILACS, CINAHL, mRCT, and reference lists up to 30 September 2016. We also contacted researchers.

Selection criteria

Randomized controlled trials (RCTs) that compared oral zinc supplementation with placebo in children aged one month to five years with acute or persistent diarrhoea, including dysentery.

Data collection and analysis

Both review authors assessed trial eligibility and risk of bias, extracted and analysed data, and drafted the review. The primary outcomes were diarrhoea duration and severity. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD) with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses (using either a fixed-effect or random-effects model) and assessed heterogeneity.

We assessed the certainty of the evidence using the GRADE approach.

Main results

Thirty-three trials that included 10,841 children met our inclusion criteria. Most included trials were conducted in Asian countries that were at high risk of zinc deficiency.

Acute diarrhoea

There is currently not enough evidence from well-conducted RCTs to be able to say whether zinc supplementation during acute diarrhoea reduces death or number of children hospitalized (very low certainty evidence).

In children older than six months of age, zinc supplementation may shorten the average duration of diarrhoea by around half a day (MD −11.46 hours, 95% CI −19.72 to −3.19; 2581 children, 9 trials, low certainty evidence), and probably reduces the number of children whose diarrhoea persists until day seven (RR 0.73, 95% CI 0.61 to 0.88; 3865 children, 6 trials, moderate certainty evidence). In children with signs of malnutrition the effect appears greater, reducing the duration of diarrhoea by around a day (MD −26.39 hours, 95% CI −36.54 to −16.23; 419 children, 5 trials, high certainty evidence).

Conversely, in children younger than six months of age, the available evidence suggests zinc supplementation may have no effect on the mean duration of diarrhoea (MD 5.23 hours, 95% CI −4.00 to 14.45; 1334 children, 2 trials, low certainty evidence), or the number of children who still have diarrhoea on day seven (RR 1.24, 95% CI 0.99 to 1.54; 1074 children, 1 trial, low certainty evidence).

None of the included trials reported serious adverse events. However, zinc supplementation increased the risk of vomiting in both age groups (children greater than six months of age: RR 1.57, 95% CI 1.32 to 1.86; 2605 children, 6 trials, moderate certainty evidence; children less than six months of age: RR 1.54, 95% CI 1.05 to 2.24; 1334 children, 2 trials, moderate certainty evidence).

Persistent diarrhoea

In children with persistent diarrhoea, zinc supplementation probably shortens the average duration of diarrhoea by around 16 hours (MD −15.84 hours, 95% CI −25.43 to −6.24; 529 children, 5 trials, moderate certainty evidence).

Authors' conclusions

In areas where the prevalence of zinc deficiency or the prevalence of malnutrition is high, zinc may be of benefit in children aged six months or more. The current evidence does not support the use of zinc supplementation in children less six months of age, in well-nourished children, and in settings where children are at low risk of zinc deficiency.

Résumé scientifique

Le zinc par voie orale pour le traitement de la diarrhée chez les enfants

Contexte

Dans les pays en voie de développement, la diarrhée cause environ 500 000 décès chez les enfants par an. La supplémentation en zinc lors de diarrhée aiguë est actuellement recommandée par l'Organisation mondiale de la Santé (OMS) et le Fonds des Nations unies pour l'enfance (UNICEF).

Objectifs

Évaluer la supplémentation orale en zinc dans le traitement des enfants atteints de diarrhée aiguë ou persistante.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur les maladies infectieuses, CENTRAL (la bibliothèque Cochrane 2016, numéro 5), MEDLINE, Embase, LILACS, CINAHL, mRCT, et les références bibliographiques jusqu'au 30 septembre 2016. Nous avons également contacté des chercheurs.

Critères de sélection

Les essais contrôlés randomisés (ECR) qui comparaient la supplémentation orale en zinc à un placebo chez des enfants âgés de un mois à cinq ans souffrant de diarrhée aiguë ou persistante, dysenterie comprise.

Recueil et analyse des données

Les deux auteurs de la revue ont évalué l'éligibilité et le risque de biais, extrait et analysé les données et ont rédigé la revue. Les critères de jugement principaux étaient la durée et la gravité de la diarrhée. Nous avons résumé les résultats dichotomiques en utilisant les risques relatifs (RR) et les résultats continus en utilisant les différences moyennes (DM) avec des intervalles de confiance à 95 % (IC). Lorsque cela était approprié, nous avons combiné les données dans des méta-analyses (en utilisant un modèle à effets fixes ou à effets aléatoires) et évalué l'hétérogénéité.

Nous avons évalué le niveau de certitude des preuves en utilisant l'approche GRADE.

Résultats principaux

Trente-trois essais qui incluaient 10 841 enfants remplissaient nos critères d'inclusion. La plupart des essais inclus ont été réalisés dans des pays asiatiques où le risque de carence en zinc est élevé.

Diarrhée aiguë

Il n'existe actuellement pas suffisamment de preuves issues d'ECR bien menés pour permettre de déterminer si la supplémentation en zinc lors de diarrhée aiguë réduit la mortalité ou le nombre d'enfants hospitalisés (preuves de très faible certitude).

Chez les enfants âgés de plus de six mois, la supplémentation en zinc peut réduire la durée moyenne de la diarrhée d'environ la moitié d'un jour (DM -11,46 heures, IC à 95 % de -19,72 à -3,19 ; 2581 enfants, 9 essais, preuves de faible certitude) et réduit probablement le nombre d'enfants dont la diarrhée persiste jusqu'à sept jours (RR 0,73, IC à 95 % 0,61 à 0,88 ; 3865 enfants, 6 essais, preuves de certitude modérée). Chez les enfants présentant des signes de malnutrition l'effet semble plus grand, la durée de la diarrhée est réduite d'environ un jour (DM -26,39 heures, IC à 95 % de -36,54 à -16,23 ; 419 enfants, 5 essais, preuves de haute certitude).

À l'inverse, chez les enfants âgés de moins de six mois, les preuves disponibles suggèrent que la supplémentation en zinc pourrait n'avoir aucun effet sur la durée moyenne de la diarrhée (DM 5,23 heures, IC à 95 % de -4,00 à 14,45 ; 1334 enfants, 2 essais, preuves de certitude modérée), ou le nombre d'enfants qui continuent de présenter des diarrhées après sept jours (RR 1,24, IC à 95 % 0,99 à 1,54 ; 1074 enfants, 1 essai, preuves de certitude modérée).

Aucun des essais inclus n'a rapporté des événements indésirables graves. Cependant, la supplémentation en zinc a augmenté le risque de vomissements dans les deux groupes d'âge (enfants âgés de plus de six mois : RR 1,57, IC à 95 % 1,32 à 1,86 ; 2605 enfants, 6 essais, preuves de certitude modérée ; les enfants de moins de six mois : RR 1,54, IC à 95 % 1,05 à 2,24 ; 1334 enfants, 2 essais, preuves de certitude modérée).

Diarrhée persistante

Chez les enfants souffrant de diarrhée persistante, la supplémentation en zinc réduit probablement la durée moyenne de la diarrhée d'environ 16 heures (DM -15,84 heures, IC à 95 % de -25,43 à -6,24 ; 529 enfants, 5 essais, preuves de certitude modérée).

Conclusions des auteurs

Dans les régions où la prévalence de la carence en zinc ou de la malnutrition est élevée, le zinc pourrait être bénéfique chez les enfants âgés de six mois ou plus. Les preuves actuelles ne permettent pas de recommander l'utilisation de la supplémentation en zinc chez les enfants de moins de six mois, chez les enfants bien nourris et dans des contextes où les enfants présentent un faible risque de carence en zinc.

บทคัดย่อ

การให้กินธาตุสังกะสีสำหรับรักษาโรคอุจจาระร่วงในเด็ก

บทนำ

ในประเทศกำลังพัฒนา โรคอุจจาระร่วงเป็นสาเหตุของการเสียชีวิตในเด็กประมาณ 500,000 คนต่อปี ในขณะนี้การเสริมสังกะสีในช่วงที่เป็นโรคอุจจาระร่วงเฉียบพลันได้รับการแนะนำโดยองค์การอนามัยโลก (WHO) และกองทุนเพื่อเด็กแห่งสหประชาชาติ (UNICEF)

วัตถุประสงค์

เพื่อประเมินการเสริมธาตุสังกะสีสำหรับรักษาเด็กที่มีอาการอุจจาระร่วงเฉียบพลันหรือมีอาการนาน (persistent diarrhoea)

วิธีการสืบค้น

ผู้ทบทวนค้นหา the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library 2016, Issue 5), MEDLINE, Embase, LILACS, CINAHL, และการศึกษาแบบสุ่มมีกลุ่มควบคุม ( RCT) และรายการอ้างอิงถึง 30 กันยายน 2016 นอกจากนี้ผู้ทบทวนยังติดต่อนักวิจัยด้วย

เกณฑ์การคัดเลือก

การศึกษาแบบสุ่มที่มีกลุ่มควบคุม (RCT) โดยเทียบระหว่างการเสริมธาตุสังกะสีกับยาหลอกในเด็กอายุ 1 เดือนถึง 5 ปีที่มีอาการอุจจาระร่วงเฉียบพลันหรือมีอาการนานรวมทั้งโรคบิด

การรวบรวมและวิเคราะห์ข้อมูล

ผู้ทบทวน 2 คนประเมินการศึกษาในแง่ของเกณฑ์ที่จะนำมาทบทวน ความเสี่ยงของการมีอคติ เก็บและวิเคราะห์ข้อมูล และรายงานการทบทวนนี้ ผลลัพธ์หลักที่สนใจคือระยะเวลาของอาการและความรุนแรงของอุจจาระร่วง และสรุปผลลัพธ์ชนิดที่มีเพียง 2 ทาง (dichotomous outcomes) เป็น risk ratios (RR) ส่วนข้อมูลต่อเนื่องสรุปเป็นความแตกต่างของค่าเฉลี่ย (mean differences) กับช่วงความเชื่อมั่น 95%, 95% confidence intervals (CI) ในกรณีที่เหมาะสม ผู้ทบทวนรวมข้อมูลจากหลายการศึกษาโดยการวิเคราะห์แบบ meta-analyses (ใช้ fixed-effect หรือ random-effects model) และประเมิน heterogeneity

ประเมินคุณภาพของหลักฐานที่ได้โดยวิธี GRADE

ผลการวิจัย

มีการศึกษา 33 เรื่องที่เข้าเกณฑ์การทบทวนนี้ รวมทั้งหมดมีเด็ก 10,841 คน การศึกษาส่วนใหญ่ทำในทวีปเอเชียที่มีความเสี่ยงสูงของการขาดธาตุสังกะสี

โรคอุจจาระร่วงเฉียบพลัน

ขณะนี้มีหลักฐานไม่เพียงพอจาก RCTs ที่ดำเนินการศึกษาอย่างดีที่จะบอกได้ว่าการเสริมสังกะสีขณะที่เป็นโรคอุจจาระร่วงเฉียบพลันจะช่วยลดการเสียชีวิตหรือลดจำนวนเด็กที่ต้องอยู่รักษาในโรงพยาบาล ( หลักฐานความเชื่อมั่นต่ำมาก )

ในเด็กอายุมากกว่า 6 เดือนการเสริมธาตุสังกะสีอาจย่นระยะเวลาเฉลี่ยของโรคอุจจาระร่วงประมาณครึ่งวัน ((MD −11.46 ชั่วโมง, 95% CI −19.72 ถึง −3.19; จำนวนเด็ก 2581 คน, 9 การศึกษา ( หลักฐานความเชื่อมั่นต่ำ และอาจลดจำนวนเด็กที่ยังมีอาการอุจจาระร่วงจนถึงวันที่ 7 (RR 0.73, 95% CI 0.61 ถึง 0.88; เด็กจำนวน 3865 คน, 6 การศึกษา หลักฐานความเชื่อมั่นระดับปานกลาง ) ในเด็กที่มีอาการของการขาดสารอาหาร เห็นผลดีชัดเจนกว่าคือลดระยะเวลาของโรคอุจจาระร่วงได้ประมาณ 1 วัน ( (MD −26.39 ชั่วโมง, 95% CI −36.54 ถึง −16.23; เด็ก 419 คน ใน 5 การศึกษา หลักฐานความเชื่อมั่นสูง )

ในทางตรงกันข้าม ในเด็กอายุน้อยกว่า 6 เดือนมีหลักฐานที่แสดงให้เห็นว่าการเสริมสังกะสีอาจไม่มีผลต่อระยะเวลาเฉลี่ยของอาการอุจจาระร่วง (MD 5.23 ชั่วโมง, 95% CI −4.00 ถึง 14.45; เด็ก 1334 คนใน 2 การศึกษา หลักฐานความเชื่อมั่นระดับต่ำ) หรือจำนวนของเด็กที่ยังคงมีอาการอุจจาระร่วงในวันที่ 7 (RR 1.24, 95% CI 0.99 ถึง 1.54; เด็ก 1074 คนใน 1 การศึกษาหลักฐานความเชื่อมั่นระดับต่ำ)

ไม่มีการศึกษาใดรายงานเหตุการณ์ไม่พึงประสงค์ที่ร้ายแรง อย่างไรก็ตามการเสริมสังกะสีเพิ่มความเสี่ยงของการอาเจียนในทั้ง 2 กลุ่มอายุ (เด็กอายุมากกว่า 6 เดือน: RR 1.57, 95% CI 1.32 ถึง 1.86; เด็ก 2605 คน ใน 6 การศึกษา หลักฐานความเชื่อมั่นระดับปานกลาง ; เด็กอายุน้อยกว่า 6 เดือน RR 1.54, 95% CI 1.05 ถึง 2.24; เด็ก 1334 คนใน 2 การศึกษา หลักฐานความเชื่อมั่นระดับปานกลาง )

โรคอุจจาระร่วงที่เป็นนาน (Persistent diarrhoea)

ในเด็กที่มีอาการอุจจาระร่วงนาน (persistent diarrhea) การเสริมสังกะสีอาจลดระยะเวลาของโรคอุจจาระร่วงโดยเฉลี่ยประมาณ 16 ชั่วโมง (MD −15.84 ชั่วโมง, 95% CI −25.43 ถึง −6.24; เด็ก 529 คนใน 5 การศึกษา ความเชื่อมั่นระดับปานกลาง )

ข้อสรุปของผู้วิจัย

ในพื้นที่ที่มีความชุกของการขาดธาตุสังกะสีหรือความชุกของการขาดสารอาหารมาก การเสริมสังกะสีอาจจะมีประโยชน์ในเด็กอายุ 6 เดือนขึ้นไป หลักฐานในปัจจุบัน ยังไม่สนับสนุนการเสริมธาตุสังกะสีในเด็กอายุน้อยกว่า 6 เดือน เด็กที่มีภาวะโภชนาการดี และในพื้นที่ที่เด็กมีความเสี่ยงของการขาดสังกะสีต่ำ

摘要

口服锌治疗小儿腹泻

研究背景

在发展中国家,每年儿童腹泻死亡的数量达到500000。目前锌补充剂在急性腹泻的作用建议由世界卫生组织(WHO)和联合国儿童基金会(UNICEF)进行补充。

研究目的

本篇综述旨在评价口服锌治疗小儿急性或者慢性腹泻的作用。

检索策略

我们检索了Cochrane传染病组专业注册库( Cochrane Infectious Diseases Group Specialized Register),CENRAL(Cochrane图书馆,至2016年第5期)、MEDLINE、EMBASE、LILACS、CINAHL,截止到2016年9月30日。我们还联系了研究人员。

标准/纳入排除标准

纳入比较口服锌补充剂和安慰剂对一个月至五岁儿童患急性腹泻和持续腹泻的影响的随机对照临床试验(RCT)。

数据收集与分析

两位综述作者评价了文献是否符合纳入标准及其偏倚风险,提取并分析了数据资料,并起草了该综述。主要结局是腹泻持续时间和严重程度。我们的结局数据用95%可信区间(CI)风险比(RR)表达的二分类结果,用95%可信区间(CI)平均差值(MD)表达连续性结果。在适当的情况下,我们将meta分析中的数据结合起来(使用固定效应或随机效应模型)并评价异质性。

我们用GRADE评价证据的质量。

主要结果

纳入了10841名儿童在内的三十三项试验符合我们的纳入标准。大多数纳入的试验都是在锌高度缺乏的亚洲国家进行的。

急性腹泻

目前还没有足够的证据证明,在急性腹泻中补锌会减少住院病人的死亡或住院人数(极低质量证据)。

年龄超过六个月的儿童,补充锌可以平均缩短大约一天的腹泻持续时间(平均值为−11.46小时,95%CI=−19.72 - −3.19;2581名儿童,9个试验,低质量证据),并可能减少儿童腹泻持续七天的人数(RR=0.73,95%CI=0.61-0.88;3865名儿童,6个试验,中等质量证据)。在营养不良的儿童有较大疗效的迹象,减少约一天的持续腹泻时间(MD=−26.39小时,95%CI=−36.54 - −16.23;419名患者,5个试验,高质量证据)。

相反,在不超过六个月的年龄更小的儿童中,现有的证据表明,锌补充剂可能对腹泻平均持续时间没有影响(MD=5.23小时,95%CI=−4 - 14.45;1334名儿童,2个试验, 质量证据),以及对患病七天以上的儿童也没有影响(RR=1.24,95%CI=0.99 - 1.54;1074名儿童,1个试验, 质量证据)。

所有的试验都没有报告严重的不良事件。然而,锌补充剂增加了两个年龄组(六个月以上的儿童)呕吐的风险:RR=1.57,95%CI=1.32-1.86;2605名儿童,6个试验,质量证据;小于六个月的儿童:RR=1.54,95%CI=1.05-2.24;1334名儿童,2个试验,中等质量证据)。

持续性腹泻

在持续性腹泻的儿童中,锌补充剂可能缩短平均约16小时的腹泻持续时间(MD=−15.84小时,95%CI=−25.43 - −6.24;529名儿童,5个试验,中等质量证据)。

作者结论

在缺锌或营养不良盛行率高的地区,锌补充剂对六个月以上的儿童有益。目前的证据不支持在六个月以下的儿童、营养良好的儿童以及儿童低锌缺乏的环境中使用锌补充剂。

Plain language summary

Oral zinc supplementation for treating diarrhoea in children

In low- and middle-income countries, millions of children suffer from severe diarrhoea every year and many die from dehydration. Giving fluids by mouth (using an oral rehydration solution (ORS)) has been shown to save children's lives, but it has no effect on the length of time the children suffer with diarrhoea. Zinc supplementation could help reduce the duration and the severity of diarrhoea, and therefore have an additional benefit over ORS in reducing children mortality.

What is oral zinc and how may it shorten the duration and severity of diarrhoea

Zinc is usually given as zinc sulphate, zinc acetate, or zinc gluconate, which are all water-soluble compounds. The World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) recommend 10 mg to 20 mg of zinc per day for children with diarrhoea. There are several mechanism of action of zinc on acute diarrhoea, some of which are specific to the gastrointestinal system: zinc restores mucosal barrier integrity and enterocyte brush-border enzyme activity, it promotes the production of antibodies and circulating lymphocytes against intestinal pathogens, and has a direct effect on ion channels, acting as a potassium channel blocker of adenosine 3-5-cyclic monophosphate-mediated chlorine secretion. Cochrane researchers examined the evidence available up to 30 September 2016.

What the evidence in the review suggests

Thirty-three trials that included 10,841 children met the inclusion criteria of this review.

Among children with acute diarrhoea, we don't know if treating children with zinc has an effect on death or number of children hospitalized (very low certainty evidence). In children older than six months, zinc supplementation may shorten the average duration of diarrhoea by around half a day (low certainty evidence), and probably reduces the number of children whose diarrhoea persists until day seven (moderate certainty evidence). In children with signs of malnutrition the effect appears greater, reducing the duration of diarrhoea by around a day (high certainty evidence). Conversely, in children younger than six months, the available evidence suggests zinc supplementation may have no effect on the mean duration of diarrhoea (low certainty evidence), or the number of children who still have diarrhoea on day seven (low certainty evidence). Zinc supplementation increased the risk of vomiting in both age groups (moderate certainty evidence). No other adverse effects were reported.

Among children with persistent diarrhoea, zinc supplementation probably shortens the average duration of diarrhoea by around 16 hours (moderate certainty) but it probably increases the risk of vomiting (moderate certainty evidence).

In areas where the prevalence of zinc deficiency or the prevalence of malnutrition is high, zinc may be of benefit in children aged six months or more. The current evidence does not support the use of zinc supplementation in children less six months of age, in well-nourished children, and in settings where children are at low risk of zinc deficiency.

Résumé simplifié

La supplémentation orale en zinc pour le traitement de la diarrhée chez les enfants

Dans les pays à revenu faible et intermédiaire, des millions d'enfants souffrent chaque année de diarrhée grave et nombreux sont ceux qui meurent d'une déshydratation. Il a été prouvé que l'administration de liquides par voie orale (à l'aide d'une solution de réhydratation orale (SRO)) permet de sauver la vie de nombreux enfants, mais la SRO n'a pas d'effet sur la durée de la diarrhée dont ces enfants souffrent. La supplémentation en zinc pourrait aider à réduire la durée et la gravité de la diarrhée, et donc avoir un bénéfice supplémentaire par rapport à une SRO pour réduire la mortalité chez les enfants.

Qu'est-ce que le zinc par voie orale et comment pourrait-il raccourcir la durée et la gravité de la diarrhée ?

Le zinc est généralement administré sous forme de sulfate de zinc, d'acétate de zinc, ou de gluconate de zinc ; tous des composés étant solubles dans l'eau. L'Organisation Mondiale de la Santé (OMS) et le Fonds des Nations unies pour l'enfance (UNICEF) recommandent 10 mg à 20 mg de zinc par jour pour les enfants atteints de diarrhée. Il existe plusieurs mécanismes d'action du zinc sur la diarrhée aiguë, dont certains sont spécifiques au système gastro-intestinal : le zinc permet de rétablir l'intégrité de la barrière muqueuse et l'activité enzymatique des bordures en brosse des entérocytes. Il favorise la production d'anticorps et la circulation des lymphocytes agissant contre les agents pathogènes intestinaux, et il a un effet direct sur les canaux ioniques, agissant comme un inhibiteur des canaux potassium permettant la sécrétion de chlorure par l'adénosine 3′,5′-monophosphate cyclique. Les chercheurs de Cochrane ont examiné les preuves disponibles jusqu'au 30 septembre 2016.

Ce que les preuves de la revue suggèrent :

Trente-trois essais incluant 10 841 enfants remplissaient les critères d'inclusion de cette revue.

Chez les enfants atteints de diarrhée aiguë, nous ne savons pas si le traitement au zinc a un effet sur les décès ou le nombre d'enfants hospitalisés (preuves de très faible certitude). Chez les enfants âgés de plus de six mois, la supplémentation en zinc peut réduire la durée moyenne de la diarrhée d'environ la moitié d'un jour (preuves de faible certitude) et réduit probablement le nombre d'enfants dont la diarrhée persiste jusqu'à sept jours (preuves de certitude modérée). Chez les enfants présentant des signes de malnutrition l'effet semble plus important, la durée de la diarrhée était réduite d'environ un jour (haute certitude de preuves). À l'inverse, chez les enfants âgés de moins de six mois, les preuves disponibles suggèrent que la supplémentation en zinc pourrait n'avoir aucun effet sur la durée moyenne de la diarrhée (preuves de certitude modérée), ou le nombre d'enfants qui continuent de présenter des diarrhées après sept jours (certitude modérée de preuves). La supplémentation en zinc a augmenté le risque de vomissements dans les deux groupes d'âge (preuves de certitude modérée). Aucun autre effet indésirable n'a été signalé.

Chez les enfants souffrant de diarrhée persistante, la supplémentation en zinc réduit probablement la durée moyenne de la diarrhée d'environ 16 heures (certitude de qualité modérée), mais elle augmente probablement aussi le risque de vomissements (preuves de certitude modérée).

Dans les régions où la prévalence de la carence en zinc ou de la malnutrition est élevée, le zinc pourrait être bénéfique chez les enfants âgés de six mois ou plus. Les preuves actuelles ne permettent pas de recommander l'utilisation de la supplémentation en zinc chez les enfants de moins de six mois, chez les enfants bien nourris et dans des contextes où les enfants présentent un faible risque de carence en zinc.

Notes de traduction

Traduction réalisée par Martin Vuillème et révisée par Cochrane France

எளியமொழிச் சுருக்கம்

குழந்தைகளில் வயிற்றுப்போக்கு சிகிச்சைக்கு மிகை நிரப்பு மருந்தாக வாய்வழி துத்தநாகம் உட்கொள்ளல்

குறைந்த மற்றும் மத்திய வருவாய் உள்ள நாடுகளில், இலட்சக்கணக்கான குழந்தைகள் ஒவ்வொரு ஆண்டும் கடுமையான வயிற்றுப்போக்கால் பாதிக்கப்படுகின்றனர். பலர் நீர் சத்து குறைவால் இறக்கின்றனர். (வாய் வழி நீரேற்றக் கரைசலை பயன்படுத்தி), வாய் மூலம் திரவங்கள் கொடுப்பது குழந்தைகள் உயிர்களை காப்பாற்றும் என்று நிரூபிக்கப்பட்டுள்ளது, ஆனால் அது குழந்தைகள் வயிற்றுப்போக்கு பாதிக்கப்படுகின்ற கால அளவை பாதிப்பதாக தெரியவில்லை. வயிற்றுப் போக்கின் காலம் மற்றும் தீவிரத்தன்மையை துத்தநாகம் ஊட்டச்சத்து குறைக்க உதவும்.எனவே அவை ORS-டன் ஒப்பிடுகையில் கூடுதல் பயனாக குழந்தைகள் இறப்பை குறைக்கும்.

வாய்வழி துத்தநாகம் என்றால் என்ன? அது எவ்வாறு வயிற்றுப் போக்கின் கால மற்றும் தீவிரத்தன்மையை குறைக்கும்.

துத்தநாகம் வழக்கமாக ,துத்தநாக சல்பேட், துத்தநாக அசிடேட், அல்லது துத்தநாக குளுக்கோனேட், போன்ற நீரில் கரையக்கூடிய கலவைகளாக அளிக்கப்படுகிறது. குழந்தைகளின் வயிற்றுப் போக்குக்கு, உலக சுகாதார அமைப்பு (WHO) மற்றும் ஐக்கிய நாடுகளின் குழந்தைகள் நிதியம் (யூனிசெஃப்) ஒரு நாளைக்கு 10 mg முதல் 20 mg துத்தநாகம் அளிக்க பரிந்துரைக்கிறது. கடுமையான வயிற்றுப் போக்குக்கு துத்தநாகம் எவ்வாறு வேலை செய்யும் என்பதற்கு பல வினைவழிஉள்ளது.அதில் சில இரைப்பை-குடல் மண்டலம் சம்பந்தமானது: துத்தநாகம் மியூகோசல் தடை சிரத்தன்மை மற்றும் எண்டிரோசைட் ப்ரஷ்-எல்லை என்சைம் நடவடிக்கையை மீட்கும்.நிணநீர்க்கலங்கள் மற்றும் குடல் நோய்க்கிருமிகளுக்கு எதிராக பிறபொருளெதிரி உருவாகுவதை அதிகரிக்கும். மற்றும் அயனி சேனல்களில் நேரடி விளைவுஉள்ளது . பொட்டாசியம் சேனல் தடுப்பானாக செயல்பட்டு அடேநோசினே 3-5 சிக்ளிக் மோனோபோஸ்பேட் வழியாக செயலூக்கப்பட்ட குளோரின் சுரப்பை கட்டுப்படுத்துகிறது . 30 செப்டம்பர் 2016 வரைஉள்ள ஆதரங்களை காக்ரேன் ஆராய்ச்சியாளர்கள் ஆராய்ந்தார்கள்.

இந்த திறனாய்வில் உள்ள ஆதாரம் நமக்கு என்ன சொல்கிறது?

இந்த திறனாய்வில், தேர்வு அடிப்படைக் கூறுகளை பூர்த்திசெய்த, 10,841 குழந்தைகள் கொண்ட 33 ஆய்வுகள் சேர்க்கப்பட்டுள்ளன.

துத்தநாகம் கொண்டு சிகிச்சை அளிப்பது, கடுமையான வயிற்றுப் போக்கால் பாதிக்கப்பட்ட குழந்தைகளின் இறப்பு மற்றும் மருத்துவமனையில் சேர்ப்பதில் தாக்கம் எதுவும் இருக்குமா என்று எங்களுக்கு தெரியவில்லை (மிக குறைவான உறுதிப்பாடுஉள்ள ஆதாரம்). துத்தநாகம் ஊட்டச்சத்து வயிற்றுப் போக்கு உள்ள 6 மாதங்களுக்கு மேல் வயதான குழந்தைகளுக்கு வயிற்றுப் போக்கினால் கால அளவை சராசரியாகப் பாதி நாள் வரை குறைக்கும் (மிதமான உறுதிப்பாடு) மேலும் 7 நாட்கள் வரை நீடிக்கும் வயிற்றுப் போக்குகினால் பாதிக்கும் குழந்தைகளின் எண்ணிக்கையைக் குறைக்கலாம் (மிதமான உறுதிப்பாடுஉள்ள ஆதாரம்) வயிற்றுப் போக்கின் காலத்தை ஊட்டச் சத்துக் குறைபாடு உள்ள குழந்தைகளுக்கு இதன் திறன் அதிகமாக உள்ளதாக தோன்றுகிறது. இது வயிற்றுப் போக்கின் காலத்தைசுமார் ஒருநாள் குறைக்கிறது (அதிக உறுதிப்பாடுஉள்ள ஆதாரம்). ஆனால் இதற்கு மாறாக 6 மாதங்களுக்கு குறையான வயதுடைய குழந்தைகளுக்கு வயிற்றுப் போக்கின் சராசரி கால அளவில் துத்தநாகம் ஊட்டச்சத்து எந்த தாக்கத்தையும் ஏற்படுத்துவதாக தெரியவில்லை (குறைந்த உறுதிப்பாடுஉள்ள ஆதாரம்) மற்றும் ஏழாம் நாள் வரை வயிற்றுப் போக்கு உள்ள குழந்தைகளின் எண்ணிக்கையிலும் எம்மாற்றமும் ஏற்படுத்தவில்லை (குறைவான ( உறுதிப்பாடுஉள்ள ஆதாரம்). துத்தநாகம் ஊட்டச்சத்து வாந்தி வருவதற்கான வாய்ப்பை இரண்டு வயது குழுக்களிலும் அதிகரிக்கும். (மிதமான உறுதிப்பாடுஉள்ள ஆதரம்). வேறு எந்த பாதகமான நிகழ்வுகளும் அறிவிக்கப்படவில்லை.

துத்தநாகம் ஊட்டச்சத்து விடாப்பிடியான வயிற்றுப் போக்கு உள்ள குழந்தைகளுக்கு வயிற்றுப் போக்கு கால அளவை 16 மணி நேரம் வரை குறைக்கும் (மிதமான உறுதிப்பாடு) ஆனால் வாந்தி வருதலின் ஆபத்தை அதிகரிக்கலாம் (மிதமான உறுதிப்பாடுஉள்ள ஆதரம்)

துத்தநாகம் குறைபாடு பாதிப்பு விகிதம் உள்ள பகுதிகள் அல்லது ஊட்டச் சத்துக் குறைபாடு பாதிப்பு விகிதம் அதிகமாக உள்ள இடங்களில், 6 மாதங்கள் அல்லது அதற்கு மேல் வயது வந்த குழந்தைகளுக்கு துத்தநாகம் பயன்உள்ளதாக இருக்கலாம். துத்தநாகம் குறைபாடு குறைவான ஆபத்துக்கூறு உள்ள இடங்களில் வாழும் குழந்தைகள், ஆறு மாதத்திற்கு குறைவான வயதுள்ள குழந்தைகள், மற்றும் நன்கு ஊட்டச்சத்து உள்ள குழந்தைகளுக்கு, துத்தநாக ஊட்டச்சத்து பயன்பாட்டை தற்போதைய ஆதாரம் ஆதரிக்கவில்லை.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பு: சி.இ.பி.என்.அர் குழு

ข้้อสรุปภาษาธรรมดา

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ในประเทศที่มีรายได้ต่ำและรายได้ปานกลาง มีเด็กหลายล้านคนต้องเจ็บป่วยจากโรคอุจจาระร่วงอย่างรุนแรงทุกปีและหลายคนเสียชีวิคจากการขาดน้ำ การให้ของเหลวทางปาก (โดยใช้เครื่องดื่มเกลือแร่ (ORS)) สามารถช่วยชีวิตเด็กได้ แต่ไม่มีผลต่อระยะเวลาที่เด็กมีอาการท้องเสีย การเสริมสังกะสีจะช่วยลดระยะเวลาและความรุนแรงของโรคอุจจาระร่วง ดังนั้นจึงมีประโยชน์เพิ่มเติมจาก ORS ในการลดอัตราการตายของเด็ก

การให้กินธาตุสังกะสีคืออะไรและธาตุสังกะสีช่วยลดระยะเวลาและความรุนแรงของโรคอุจจาระร่วงได้อย่างไร

สังกะสีชนิดกินมักจะเป็น zinc sulphate, zinc acetate หรือ zinc gluconate ซึ่งทั้งหมดนี้เป็นสารที่ละลายน้ำได้ องค์การอนามัยโลก (WHO) และกองทุนเพื่อเด็กแห่งสหประชาชาติ (UNICEF) แนะนำให้ธาตุสังกะสี 10 มิลลิกรัมถึง 20 มิลลิกรัมต่อวันสำหรับเด็กที่มีอาการอุจจาระร่วง การออกฤทธิ์ของสังกะสีในโรคอุจจาระร่วงเฉียบพลันมีหลายกลไก โดยบางกลไกมีผลเฉพาะต่อระบบทางเดินอาหาร: สังกะสีฟื้นฟูความสมบูรณ์ของเยื่อบุทางเดินอาหาร และการทำหน้าที่ของเอนไซม์ที่สร้างโดย enterocyte ที่ brush border ของลำไส้ ช่วยเพิ่มการสร้างแอนติบอดีและ circulating lymphocytes เพื่อต่อต้านเชื้อโรคในลำไส้และมีผลโดยตรงต่อ ion channels ที่ทำหน้าที่เป็น potassium channel blocker ของ adenosine 3-5-cyclic monophosphate-mediated chlorine secretion. ผู้ทบทวนสืบค้นหลักฐานที่มีอยู่ถึง 30 กันยายน 2016

มีหลักฐานอะไรบ้างเกี่ยวกับเรื่องนี้

มีการศึกษา 33 เรื่องที่เข้าเกณฑ์การทบทวนนี้ รวมทั้งหมดมีเด็ก 10841 คน

ในเด็กที่มีอาการอุจจาระร่วงเฉียบพลัน ไม่ทราบว่าการรักษาด้วยธาตุสังกะสีมีผลต่อการเสียชีวิตหรือจำนวนของเด็กที่ต้องอยู่รักษาในโรงพยาบาลหรือไม่ ( หลักฐานความเชื่อมั่นต่ำมาก ) ในเด็กอายุมากกว่า 6 เดือนการเสริมธาตุสังกะสีอาจย่นระยะเวลาเฉลี่ยของโรคอุจจาระร่วงประมาณครึ่งวัน ( หลักฐานความเชื่อมั่นต่ำ ) และอาจจะช่วยลดจำนวนของเด็กที่ยังมีอาการอุจจาระร่วงจนถึงวันที่ 7 ( หลักฐานความเชื่อมั่นระดับปานกลาง ) ในเด็กที่มีอาการของการขาดสารอาหาร เห็นผลดีชัดเจนกว่าว่าลดระยะเวลาของโรคอุจจาระร่วงได้ประมาณ 1 วัน ( หลักฐานความเชื่อมั่นสูง ) ในทางตรงกันข้าม ในเด็กอายุน้อยกว่า 6 เดือนมีหลักฐานที่แสดงให้เห็นว่าการเสริมสังกะสีอาจไม่มีผลต่อระยะเวลาเฉลี่ยของโรคอุจจาระร่วง (หลักฐานความเชื่อมั่นระดับต่ำ ) หรือจำนวนของเด็กที่ยังคงมีอาการอุจจาระร่วงในวันที่7 (หลักฐานความเชื่อมั่นระดับต่ำ) การเสริมสังกะสีเพิ่มความเสี่ยงของการอาเจียนในทั้งสองกลุ่มอายุ ( หลักฐานความเชื่อมั่นระดับปานกลาง ) ไม่มีการรายงานภาวะแทรกซ้อนอื่นๆ

ในเด็กที่มีอาการอุจจารร่วงนาน (persistent diarrhea) การเสริมสังกะสีอาจลดระยะเวลาของโรคอุจจาระร่วงโดยเฉลี่ยประมาณ 16 ชั่วโมง ( ความเชื่อมั่นระดับปานกลาง ) แต่อาจเพิ่มความเสี่ยงของการอาเจียน ( หลักฐานความเชื่อมั่นระดับปานกลาง )

ในพื้นที่ที่มีความชุกของการขาดธาตุสังกะสีหรือความชุกของการขาดสารอาหารมาก การเสริมสังกะสีอาจจะมีประโยชน์ในเด็กอายุ 6 เดือนขึ้นไป หลักฐานในปัจจุบัน ยังไม่สนับสนุนการเสริมธาตุสังกะสีในเด็กอายุน้อยกว่า 6 เดือน เด็กที่มีภาวะโภชนาการดี และในพื้นที่ที่เด็กมีความเสี่ยงของการขาดสังกะสีต่ำ

หมายเหตุการแปล

ผู้แปล ศ.พญ ผกากรอง ลุมพิกานนท์ ภาควิชากุมารเวชศาสตร์ คณะแพทยศาสตร์ มหาวิทยาลัยขอนแก่น 22 ธันวาคม 2016 และ อัพเดทการแปล โดย นางสาวน้ำเพชร จำปาทอง ในวันที่ 26 พฤษภาคม 2017

Резюме на простом языке

Дополнительное пероральное введение цинка для лечения диареи у детей

В странах с низким и средним уровнем дохода миллионы детей ежегодно страдают от тяжелой диареи и многие умирают от дегидратации (обезвоживания). Было показано, что приём жидкости через рот (с использованием раствора для пероральной регидратации) спасает жизни детей, но не оказывает влияния на продолжительность страдания детей от диареи. Дополнительное введение цинка может помочь уменьшить продолжительность и тяжесть диареи, и, следовательно, приносит дополнительную пользу по отношению к пероральным регидратационным растворам в снижении детской смертности.

Что такое пероральный цинк и как он может сократить продолжительность и тяжесть диареи

Цинк обычно применяют в виде сульфата цинка, ацетата цинка или глюконата цинка, все они являются водорастворимыми соединениями. Всемирная организация здравоохранения (ВОЗ) и Детский Фонд Организации Объединенных Наций (ЮНИСЕФ) рекомендует детям с диареей от 10 мг до 20 мг цинка в сутки. Существует несколько механизмов действия цинка при острой диарее, некоторые из которых являются специфичными для желудочно-кишечного тракта: цинк восстанавливает целостность барьера слизистых оболочек и активность ферментов щеточной каёмки энтероцитов, он способствует выработке антител и циркулирующих лимфоцитов против кишечных патогенов и непосредственно влияет на ионные каналы, действуя как блокатор калиевого канала секреции хлора, опосредованной 3-5-циклическим аденозинмонофосфатом. Исследователи Кокрейн изучили доказательства, доступные на 30 сентября 2016 года.

Какие доказательства представлены в этом обзоре

Тридцать три клинических испытания, которые включали 10841 ребёнка, соответствовали критериям включения этого обзора.

Мы не знаем, влияет ли лечение цинком на смертность или число госпитализированных детей среди детей с острой диареей ( очень низкая уверенность в доказательствах). У детей старше 6 месяцев дополнительное введение цинка может сокращать среднюю продолжительность диареи примерно на половину суток (низкая уверенность в доказательствах) и, вероятно, уменьшает число детей, у которых диарея сохраняется на седьмые сутки ( умеренная уверенность в доказательствах). У детей с симптомами недостаточности питания эффект был более выраженным, продолжительность диареи сокращалась примерно на сутки (высокая уверенность в доказательствах). И наоборот, у детей младше шести месяцев, имеющиеся данные свидетельствуют о том, что добавки цинка могут не влиять на среднюю продолжительность диареи (низкая уверенность в доказательствах), или на число детей, у которых сохраняется диарея на седьмой день (низкая уверенность в доказательствах). Дополнительное введение цинка увеличивает риск развития рвоты в обеих возрастных группах (умеренная уверенность в доказательствах). О других неблагоприятных эффектах не сообщали.

Среди детей с сохраняющейся диареей дополнительное введение цинка, вероятно, сокращает среднюю продолжительность диареи примерно на 16 часов (умеренная уверенность в доказательствах) но, вероятно, увеличивает риск развития рвоты ( умеренная уверенность в доказательствах).

В районах с высокой распространенностью дефицита цинка или недостаточности питания цинк может быть полезным у детей в возрасте шести месяцев или старше. Имеющиеся в настоящее время доказательства не поддерживают использование дополнительного введения цинка у детей младше 6 месяцев, хорошо питающихся детей и в условиях, где дети имеют низкий риск дефицита цинка.

Заметки по переводу

Перевод: Камалова Аэлита Асхатовна. Редактирование: Юдина Екатерина Викторовна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com

Ringkasan bahasa mudah

Suplemen zink oral untuk merawat cirit-birit dalam kalangan kanak-kanak

Di negara-negara berpendapatan rendah dan sederhana, berjuta-juta kanak-kanak mengalami cirit-birit yang teruk setiap tahun dan ramai yang mati akibat dehidrasi. Pemberian cecair melalui mulut (menggunakan cecair rehidrasi oral (ORS)) terbukti dapat menyelamatkan nyawa kanak-kanak, tetapi ia tiada kesan kepada tempoh cirit-birit dalam kalangan kanak-kanak. Supplemen zink dapat membantu mengurangkan tempoh dan keterukan cirit-birit, dan oleh itu mempunyai manfaat tambahan berbanding ORS dalam mengurangkan kematian kanak-kanak.

Apa itu zink oral dan bagaimana ia boleh memendekkan tempoh dan keterukan cirit-birit

Zink biasanya diberi sebagai zink sulfat, zink acetat atau zink glukonat; yang mana semuanya adalah sebatian larut air. Pertubuhan Kesihatan Sedunia (WHO) dan Tabung Darurat Kanak-kanak Antarabangsa Bangsa-Bangsa Bersatu (UNICEF) mengesyorkan zink oral 10 mg hingga 20 mg setiap hari untuk kanak-kanak yang mengalami cirit-birit. Terdapat beberapa mekanisma tindakan zink oral terhadap cirit-birit akut, ada yang khusus kepada sistem gastrousus: zink oral mengembalikan integriti mukosa dan aktiviti enzim enterosit sel pinggir berus. ia menggalakkan penghasilan antibodi dan pengedaran limfosit terhadap patogen usus, dan mempunyai kesan langsung ke atas saluran ion, bertindak sebagai penghalang saluran kalium untuk rembesan klorin yang berantarakan adenosin 3-5 siklik monofosfat. Para penyelidik Cochrane menilai bukti sedia ada sehingga 30 September 2016.

Apakah bukti yang dicadangkan dalam ulasan

Tiga-puluh tiga kajian yang melibatkan 10,841 kanak-kanak memenuhi kriteria kemasukan dalam ulasan ini.

Dalam kalangan kanak-kanak dengan cirit-birit akut, kami tidak tahu jika merawat kanak-kanak dengan zink oral memberikan kesan ke atas kematian atau bilangan kanak-kanak yang dimasukkan ke hospital (bukti yang sangat rendah kepastiannya). Dalam kalangan kanak-kanak berumur lebih dari enam bulan, supplemen zink oral boleh memendekkan tempoh purata cirit-birit sebanyak setengah hari (bukti kepastian rendah), dan mungkin mengurangkan bilangan kanak-kanak yang mengalami cirit-birit berterusan sehingga hari ketujuh (bukti kepastian sederhana). Dalam kalangan kanak-kanak dengan tanda-tanda malnutrisi kesannya kelihatan lebih baik, mengurangkan tempoh cirit-birit lebih kurang sehari (bukti kepastian tinggi). Sebaliknya, dalam kalangan kanak-kanak kurang daripada enam bulan, bukti sedia ada mencadangkan supplemen zink oral mungkin tiada kesan ke atas tempoh purata cirit-birit ( bukti kepastian rendah), atau bilangan kanak-kanak yang masih mengalami cirit-birit pada hari ketujuh (bukti kepastian rendah). Supplemen zink oral meningkatkan risiko muntah dalam kedua-dua kumpulan umur (bukti kepastian sederhana). Tiada kesan buruk lain dilaporkan.

Dalam kalangan kanak-kanak dengan cirit-birit yang berterusan, supplemen zink mungkin memendekkan tempoh purata cirit-birit lebih kurang 16 jam (kepastian sederhana) tetapi ia mungkin meningkatkan risiko muntah ( bukti kepastian sederhana).

Di kawasan-kawasan di mana prevalen kekurangan zinc atau malnutrisi yang tinggi, zink boleh memberi manfaat pada kanak-kanak berumur enam bulan atau lebih. Bukti semasa tidak menyokong penggunaan supplemen zink oral bagi kanak-kanak yang berumur kurang daripada enam bulan, kanak-kanak yang cukup khasiat dan dalam persekitaran kanak-kanak yang berisiko rendah untuk kekurangan zink.

Catatan terjemahan

Diterjemahkan oleh Khaw Loke Tim (International Medical University). Disunting oleh Noorliza Mastura Ismail (Kolej Perubatan Melaka-Manipal). Untuk sebarang pertanyaan sila hubungi LokeTimKhaw@imu.edu.my.

Streszczenie prostym językiem

Doustna suplementacja cynku w leczeniu biegunki u dzieci

W krajach o niskim i średnim dochodzie co roku miliony dzieci cierpi z powodu ostrej biegunki, a wiele z nich umiera z powodu odwodnienia. Wykazano, że podawanie dzieciom płynów doustnych (doustne płyny nawadniające) ratuje im życie, jednak nie ma żadnego wpływu na czas trwania choroby. Suplementacja cynku może pomóc ograniczyć czas trwania i nasilenie biegunki, a zatem ma dodatkową przewagę nad doustnymi płynami nawadniającymi w zmniejszaniu śmiertelności wśród dzieci.

Co to jest cynk doustny i jak może skrócić czas trwania oraz nasilenie biegunki

Cynk jest przeważnie podawany w formie siarczanu cynku, octanu cynku lub glukonianu cynku, które są rozpuszczalne w wodzie. Światowa Organizacja Zdrowia (ang. WHO) i Fundusz Narodów Zjednoczonych na Rzecz Dzieci (ang. UNICEF) zalecają podawanie dzieciom z biegunką od 10 mg do 20 mg cynku na dzień. Istnieje kilka mechanizmów działania cynku w ostrej biegunce. Niektóre z nich dotyczą układu pokarmowego: cynk przywraca integralność bariery śluzówkowej i aktywność enzymów enterocytów rąbka szczoteczkowego (komórki jelita cienkiego budujące powierzchniową warstwę błony śluzowej; przyp.tłum.), wspiera produkcję przeciwciał i krwinek białych skierowanych przeciw patogenom jelitowym oraz ma bezpośredni wpływ na kanały jonowe, zachowując się jak bloker kanałów potasowych w procesie wydzielania chlorków sterowanego przez związek o nazwie cykliczny adenozyno-3-5-monofosforan. Naukowcy Cochrane zbadali dane naukowe dostępne do 30 września 2016r.

Co sugerują dane uzyskane w przeglądzie

Kryteria włączenia do przeglądu spełniły 33 badania, w których wzięło udział 10 841 dzieci.

Nie wiemy, czy wśród dzieci z ostrą biegunką leczenie cynkiem ma wpływ na śmiertelność lub liczbę hospitalizowanych dzieci (dane bardzo niskiej jakości ). W przypadku dzieci powyżej 6 miesiąca życia suplementacja cynku może skrócić średni czas trwania biegunki o około pół dnia (dane niskiej jakości ) i prawdopodobnie zmniejszyć liczbę dzieci, u których biegunka utrzyma się do siódmego dnia (dane umiarkowanej jakości ). W przypadku dzieci z oznakami niedożywienia wpływ podawania cynku wydaje się większy, gdyż czas trwania biegunki zmniejsza się o około jeden dzień (dane wysokiej jakości ). Z drugiej strony dostępne dane sugerują, że w przypadku dzieci poniżej 6 miesiąca życia podawanie cynku może nie mieć żadnego wpływu na średni czas trwania biegunki (dane niskiej jakości) ani na liczbę dzieci z biegunką trwająca conajmniej 7 dni (dane niskiej jakości ). Podawanie cynku zwiększa ryzyko wymiotów w obu grupach wiekowych (dane umiarkowanej jakości ). Nie odnotowano innych skutków ubocznych.

Wśród dzieci z utrzymującą się biegunką podawanie cynku prawdopodobnie skraca średni czas trwania biegunki o około 16 godzin (umiarkowana jakość danych), ale może zwiększać ryzyko wymiotów (dane umiarkowanej jakości).

W rejonach, w których powszechny jest niedobór cynku lub niedożywienie, cynk może być korzystny u dzieci z biegunką od szóstego miesiąca życia. Aktualne dane nie popierają podawania cynku dzieciom poniżej szóstego miesiąca życia, prawidłowo odżywionym oraz takim, u których ryzyko niedoboru cynku jest małe.

Uwagi do tłumaczenia

Tłumaczenie: Karolina Perz. Redakcja: Piotr Szymczak, Wiktoria Leśniak

概要

口服锌补充剂治疗小儿腹泻

在中低收入的国家,每年都会有部分儿童患有腹泻,甚至致死。通过口服补液(使用口腔体液补充剂)已证明可以挽救儿童的生命,但对儿童腹泻的时间长短没有影响。补充锌可有助于减少腹泻的持续时间和严重程度,因此在降低儿童死亡率方面有明显的益处。

什么是口服锌以及怎样缩短腹泻的持续时间和严重程度?

锌通常为硫酸锌、醋酸锌或葡萄糖酸锌, 这些都是水溶性化合物。世界卫生组织(WHO)和联合国儿童基金会(UNICEF)建议每天为腹泻儿童提供10毫克至20毫克的锌。锌对急性腹泻有多种作用机制,其中一些作用于胃肠系统:锌可恢复黏膜屏障的完整性和上皮细胞酶活性,它可以促进抗体的产生和循环淋巴细胞对抗肠道病原体,并具有直接作业的离子通道,可以作为钾通道阻断剂腺苷3-5循环单磷酸介导的氯分泌物。Cochrane研究人员回顾了截至2016年9月30日的证据。

研究中的证据表明了什么?

纳入了10841名儿童在内的三十三项试验符合我们的纳入标准。

在患有急性腹泻的儿童中,我们不知道用锌治疗是否对死亡或住院儿童的数量有影响(极低质量证据)。儿童年龄超过六个月的,补充锌可以平均缩短大约一天的腹泻持续时间(低质量证据),并可能减少儿童腹泻持续七天的人数(中等质量证据)。在营养不良的儿童中有较大疗效的迹象,大约可减少一天的腹泻持续时间(高质量证据)。相反,在不超过六个月的年龄更小的儿童中,现有的证据表明,锌补充剂可能对腹泻的平均持续时间没有影响( 质量证据),以及对患病七天以上的儿童影响不大( 质量证据)。锌补充剂会增加两个年龄组(六个月以上的儿童)呕吐的风险(中等质量证据)。所有的试验都没有报告严重的不良反应。

在持续性腹泻的儿童中,补充锌可能缩短腹泻持续时间,平均约16小时(中等质量证据),但是可能会增加呕吐的风险(中等质量证据)。

在缺锌或营养不良盛行率高的地区,锌对六个月以上的儿童可能有益。目前的证据不支持在六个月以下的儿童、营养良好的儿童以及儿童低锌缺乏的环境中使用锌补充剂。

翻译注解

译者:李欣霖,审校:鲁春丽。北京中医药大学循证医学中心。2018年3月17日

Summary of findings(Explanation)

Summary of findings for the main comparison. 'Summary of findings' table 1
  1. 1Downgraded by 1 for indirectness: all trials were conducted in Asia.
    2Downgraded by 1 for serious imprecision: wide CI.
    3Downgraded by 1 for serious indirectness: these trials were all conducted in Asia in countries at high risk of zinc deficiency.
    4Downgraded by 1 for serious indirectness: only one small community trial reported on number of children hospitalized.
    5Downgraded by 2 for very serious imprecision: no hospitalizations occurred in this trial.
    6Downgraded by 1 for serious indirectness: the included trials were mostly conducted in hospitals and are therefore likely to underestimate death at the community level.
    7Downgraded by 2 for very serious imprecision: only three deaths occurred in these two trials, consequently the trials are significantly underpowered to detect or exclude an effect.
    8Downgraded by 1 for serious risk of bias: two trials reported no details on sequence generation, allocation concealment, blinding, and incomplete outcome data, while one did not give any details regarding allocation concealment.

Zinc compared to placebo for children more than 6 months of age with acute diarrhoea
Patient or population: children with acute diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(trials)
Certainty of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Zinc

Duration of diarrhoea

 

All trials MD11.46
(−19.72 to −3.19)
2581
(9 trials)
⊕⊕⊝⊝
low 1,2
No comment
The mean duration of diarrhoea among placebo ranged from 31.2 to 169.5 hoursThe mean duration of diarrhoea among zinc ranged from 28.8 to 147.6 hours
Trials limited to children with signs of malnutrition MD26.39
(−36.54 to −16.23)
419
(5 trials)

⊕⊕⊕⊕

high

No comment
The mean duration of diarrhoea among placebo ranged from 103.4 to 146.4 hoursThe mean duration of diarrhoea among zinc ranged from 70.4 to 120.0 hours
Diarrhoea on day 7 128 per 1000 93 per 1000
(78 to 113)

RR 0.73

(0.61 to 0.88)

3865
(6 trials)

⊕⊕⊕⊝

moderate 3

No comment

Number of children hospitalized

(community trials only)

276
(1 trial)
⊕⊝⊝⊝
very low 4,5
No events
Death 5 per 1000 1 per 1000
(0 to 11)

RR 0.29

(0.04 to 2.20)

1134
(4 trials)
⊕⊝⊝⊝
very low 6,7
Few events
Adverse events (vomiting) 119 per 1000 188 per 1000
(173 to 242)

RR 1.57

(1.32 to 1.86)

2605
(6 trials)

⊕⊕⊕⊝

moderate 8

No comment
*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; MD: mean difference; RR: risk ratio.
GRADE Working Group grades of evidence
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

Summary of findings 2 'Summary of findings' table 2

Summary of findings 2. 'Summary of findings' table 2
  1. 1Downgraded by 1 for inconsistency: only two trials were done and both had inconsistent results.
    2Downgraded by 1 for imprecision: large CI.
    3Downgraded by 1 for inconsistency: different results in the subgroups.
    4Downgraded by 1 for indirectness: only one trial (although multi-country) as it is not possible to generalize these results.
    5Downgraded by 2 for imprecision: only one hospitalization was recorded in 1074 participants. Much larger trials would be necessary to prove or exclude an effect.
    6Downgraded by 1 for imprecision: the result is not statistically significant.
    7Downgraded by 1 for indirectness: most of this data is from Asia and may not be applicable elsewhere.
    8Downgraded by 2 for imprecision: in these two trials deaths were very rare, and consequently these trials are significantly underpowered to detect or exclude an effect on mortality.
    9Downgraded by 1 under consistency because only two trials were done.

Zinc compared to placebo for children aged less than 6 months with acute diarrhoea
Patient or population: children aged less than 6 months with acute diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(trials)
Certainty of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Zinc
Duration of diarrhoeaThe mean duration of diarrhoea among placebo ranged from 97.9 to 133.2 hoursThe mean duration of diarrhoea among zinc ranged from 105.6 to 133.2 hours MD 5.23
(−4.00 to 14.45)
1334
(2 trials)
⊕⊕⊝⊝
low 1,2
No comment
Diarrhoea on day 7 203 per 1000 252 per 1000
(201 to 313)
RR 1.24
(0.99 to 1.54)
1074
(1 trial)

⊕⊕⊝⊝

low 3,4

No comment
Number of children hospitalized (community trials only)1074
(1 trial)
⊕⊝⊝⊝
very low 5,6
No events
Death 2 per 1000

2 per 1000

(0 to 32)

RR 1.00

(0.06 to 15.89)

1334
(2 trials)
⊕⊝⊝⊝
very low 7,8
Only 1 event in each treatment group
Adverse events (vomiting) 64 per 1000 104 per 1000
(67 to 143)
RR 1.54
(1.05 to 2.24)
1334
(2 trials)

⊕⊕⊕⊝

moderate 9

No comment
*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; MD: mean difference; RR: risk ratio.
GRADE Working Group grades of evidence
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

Summary of findings 3 'Summary of findings' table 3

Summary of findings 3. 'Summary of findings' table 3
  1. 1Downgraded by 1 for indirectness: most of this data is from Asia and may not be applicable elsewhere.
    2Downgraded by 1 for imprecision: the result does not reach statistically significance, and the number of recorded events is low.
    3Downgraded by 2 for imprecision: no hospitalizations were recorded. Much larger trials would be necessary to prove or exclude an effect.
    4Downgraded by 2 for imprecision: in these three trials deaths were very rare, and consequently these trials are significantly underpowered to detect or exclude an effect on mortality.
    5Downgraded by 2 for imprecision: vomiting was very uncommon in these trials.

Zinc compared to placebo for children with persistent diarrhoea
Patient or population: children with persistent diarrhoea
Settings: all countries
Intervention: zinc
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(trials)
Certainty of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Zinc

Duration of diarrhoea

 

The mean duration of diarrhoea among placebo ranged from 84 to 132The mean duration of diarrhoea among zinc ranged from 69.4 to 122.4 hours MD −15.84
(−25.43 to −6.24)
529
(5 trials)
⊕⊕⊕⊝
moderate 1
No comment
Diarrhoea on day 7 191 per 1000 99 per 1000
(52 to 195)
RR 0.52
(0.27 to 1.02)
221
(2 trials)
⊕⊕⊝⊝
low 1,2
No comment
Hospitalization275
(1 trial)
⊕⊝⊝⊝
very low 1,3
No events
Death402
(3 trials)
⊕⊝⊝⊝
very low 1,4
No events
Adverse events (vomiting) 8 per 1000 16 per 1000
(3 to 85)
RR 1.97
(0.37 to 10.59)
505
(4 trials)
⊕⊝⊝⊝
very low 1,5
No comment
*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
Abbreviations: CI: confidence interval; MD: mean difference; RR: risk ratio.
GRADE Working Group grades of evidence
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

Background

Description of the condition

Despite improving trends in mortality rates, diarrhoea still causes nearly 10% of all deaths in children under five years of age and accounts for about 500,000 child deaths in developing countries every year (Liu 2015a; Liu 2015b). The incidence of diarrhoea decreased from 3.4 episodes per child-year in 1990 to 2.9 episodes per child-year in 2010. However, it still remains one of the most common reasons of hospital admission, with an estimated 1731 million episodes of childhood diarrhoea reported in 2011 of which 2% progressed to severe disease (Das 2014). Diarrhoea is also an important cause of malnutrition, particularly when it is prolonged (Brown 2003).

Zinc deficiency is mainly due to inadequate dietary intake and is estimated to be common in many countries, especially in children (IZiNCG 2004; Wagstaff 2004; Hess 2009). According to recent estimates, 17.3% of the world’s population is currently at risk of inadequate zinc intake (Wessells 2012). The regional estimated prevalence of inadequate zinc intake ranges from 7.5% in high-income regions to 30% in South Asia (Wessells 2012). Foods more rich in zinc are 'expensive foods', such as meat and fish (IZiNCG 2004). Zinc is also present in nuts, seeds, legumes, and wholegrain cereal, but the high phytate content of these foods interferes with its absorption (IZiNCG 2004). Zinc cannot be stored in the body, and nearly 50% of zinc excretion takes place through the gastrointestinal tract and is increased during episodes of diarrhoea (IZiNCG 2004). Zinc requirement varies with age and is highest in children due to their rapid rates of growth. As a consequence, young children who are regularly exposed to gastrointestinal pathogens and have diets low in animal products and high in phytate-rich foods are most at risk of zinc deficiency (IZiNCG 2004).

Description of the intervention

Treatment of diarrhoea with oral rehydration solution (ORS) reduces mortality due to dehydration (Liu 2015a; Liu 2015b). In addition to ORS, the World Health Organization (WHO) and United Nations Children's Fund (UNICEF) recommend for children under five years of age with diarrhoea a supplementation with 10 to 20 mg of zinc per day, at least twice the recommended daily allowance (WHO/UNICEF 2004). Zinc is usually given as zinc sulphate, zinc acetate, or zinc gluconate, which are all water-soluble compounds (IZiNCG 2004).

How the intervention might work

There are several different mechanism of action of zinc on acute diarrhoea (Berni Canani 2010; Krebs 2014). Zinc influences the activity of over 300 enzymes, some of which are responsible for DNA replication and transcription (IZiNCG 2004). Zinc promotes immunity, skin and mucosal resistance to infection, growth, and development of the nervous system (MacDonald 2000; Prasad 2008; Hess 2009). It is also an important antioxidant and preserves cellular membrane integrity (O'Dell 2000; Powell 2000; Prasad 2014). At the level of gastrointestinal system, zinc restores mucosal barrier integrity and enterocyte brush-border enzyme activity (Roy 1992; Shankar 1998), it promotes the production of antibodies and circulating lymphocytes against intestinal pathogens (Sazawal 1997b; Albert 2003; Raqib 2004), and has a direct effect on ion channels, acting as a potassium channel blocker of adenosine 3-5-cyclic monophosphate-mediated chlorine secretion (Hoque 2005; Hoque 2009).

Zinc supplementation may have different effects according to the level of zinc deficiency in the country and in the individual. It is important to verify whether zinc supplementation is effective in countries with high, or even medium or low risk of zinc deficiency (IZiNCG 2004). Despite an accurate estimation of the prevalence of zinc deficiency in populations is hampered by the lack of reliable indicators or biomarkers (Wieringa 2015), indirect indicators such as the prevalence of stunting or anaemia, and the absorbable zinc content of the national food supply are currently used at to estimate the prevalence of zinc deficiency in populations (IZiNCG 2004). Zinc requirements are higher in malnourished children because nutritional zinc deficiency is considered more severe in these children (IZiNCG 2004). However, infants have lower requirements (IZiNCG 2004), as healthy normal birthweight infants have adequate zinc levels at birth from maternal sources even if maternal stores are suboptimal (Iqbal 2001). Infants may also be able to mobilize hepatic stores accumulated during gestation (Zlotkin 1988), and are less likely to have had a zinc-depleting illness. Breastfeeding will provide zinc supplementation and protective immune factors against infections (Krebs 1999).

Zinc can cause vomiting because of its metallic taste (Fontaine 2001). In high doses, zinc can also cause epigastric pain, lethargy, and fatigue (IZiNCG 2004). One small study suggested a possible increase in mortality in malnourished children supplemented with 6 mg/kg/day of zinc compared to those supplemented with 1.5 mg/kg/day (Doherty 1998). Copper deficiency with zinc supplementation can occur although usually only when zinc is consumed in very high doses (100 to 300 mg/day for adults) over a long period of time (IZiNCG 2004), and malnourished children are at particularly high risk of this due to lower basal copper levels.

Iron and zinc deficiencies often co-exist. These two compounds may compete for the same absorptive pathways, and iron may interfere with zinc utilization (Gunshin 1997; Kordas 2004). A review of combined supplementation showed that giving zinc with iron resulted in a lower increase in iron levels compared to giving iron alone; iron supplementation alone had no effect on zinc status (Fischer Walker 2005). A trial that assessed combined supplementation on diarrhoea and malaria morbidity showed that zinc combined with iron reduced zinc's protective effect against diarrhoea (Richard 2006). Several trials have also reported a negative interaction of the combined supplementation on physical growth and development (Rosado 1997; Dijkhuizen 2001; Zlotkin 2003; Lind 2004; Bhandari 2007). Some protocols suggest supplementing malnourished children also with copper because these children are also prone to copper deficiency (Beshgetoor 1998).

Why it is important to do this review

Previous meta-analysis and systematic reviews have indicated that zinc supplementation in diarrhoea is effective (Bhutta 2000b; Lukacik 2008; Patro 2008; Haider 2009; Liberato 2015; Zou 2015; Lazzerini 2016). This Cochrane Review will have an up-to-date extensive search for trials, will explore more outcome measures of interest, and will report on more possible sources of heterogeneity. This Cochrane Review updates the last published version of this review (Lazzerini 2013).

Objectives

To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs).

Types of participants

Children between one month and five years of age with acute or persistent diarrhoea, including dysentery.

We excluded trials of infants below one month of age and studies that exclusively enrolled children with particular conditions, such preterm or low birthweight infants and children with HIV.

Acute diarrhoea is usually defined as three or more loose stools in a 24-hour period. Persistent diarrhoea is defined as diarrhoea lasting more than 14 days. Dysentery is a diarrhoeal illness in which blood is observed in the stool. The final day of diarrhoea is usually defined as the last day meeting the above definition followed by 48 hours without diarrhoea.

Types of interventions

Intervention

Oral zinc supplementation of any zinc salt at doses of 5 mg/day or more for any duration.

Control

Placebo.

Concurrent supplementation of other minerals and vitamins are eligible only if administered to both the intervention and control groups.

We excluded ORS plus zinc and food fortification interventions (such as milk fortification) as the amount of ORS/food consumed, and hence the zinc intake, would be less certain.

Types of outcome measures

Primary outcomes
Measures of diarrhoea duration
  • Diarrhoea duration.

  • Diarrhoea at 3, 5, and 7 days after starting the intervention.

Measures of diarrhoea severity
  • Stool frequency.

  • Stool output.

Secondary outcomes
  • Hospitalization (number of children hospitalized).

  • Death (from any cause and diarrhoea specific).

Adverse events
  • Serious adverse events (life-threatening or requiring hospitalization).

  • Any adverse event that results in the discontinuation of treatment.

  • Other adverse events, such as vomiting and reduced copper levels.

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).

Electronic searches

We searched the following databases using the search terms and strategy described in Table 1: the Cochrane Infectious Diseases Group Specialized Register (30 September 2016); Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2016, Issue 9); MEDLINE (1966 to 30 September 2016); Embase (1974 to 30 September 2016); LILACS (1982 to 30 September 2016); CINAHL (1982 to 30 September 2016), the metaRegister of Current Controlled Trials (mRCT; 30 September 2016), ClinicalTrials.gov (30 September 2016), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (30 September 2016).

Table 1. Detailed search strategies
  1. 1Cochrane Infectious Diseases Group Specialized Register.
    2Search terms used in combination with the search strategy for retrieving trials developed by Cochrane (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.

Search setCIDG SR1CENTRALMEDLINE2EMBASE2LILACS2CINAHLCCT
1zinczinczinczinczinczinczinc
2diarrhoeadiarrhoeaZINCZINCdiarrhoeadiarrhoeadiarrhoea
3vomitingmorbidity1 or 21 or 2morbiditymorbidityvomiting
4adverse effects2 or 3diarrhoeadiarrhoea2 or 32 or 3adverse effects
51 and 4diarrhoeamorbidity1 and 41 and 4
6vomitingmorbidity4 or 5vomitingvomiting
7adverse effectsMORBIDITY3 and 6adverse effectsadverse effects
86 or 74 or 5 or 6 or 7Limit 7 to human6 or 76 or 7
91 and 2 and 83 and 8vomiting1 and 2 and 81 and 8
10Limit 9 to humanadverse effects
11vomiting9 or 10
12adverse effects3 and 4 and 11
1311 or 12
143 and (4 or 5) and 13

Searching other resources

Researchers and organizations

For unpublished and ongoing trials, we contacted individual researchers working in the field, including researchers at the WHO.

Reference lists

We checked the reference lists of all studies identified by the above methods.

Data collection and analysis

Selection of studies

Both review authors screened all trials identified by the search strategy by title/abstract, and we retrieved the full-text articles of all potentially relevant trials. Both review authors independently applied the inclusion criteria to the full-text reports using a pilot-tested data extraction form, and scrutinized publications to ensure we included each trial only once. We contacted the trial authors for clarification if necessary, and resolved any disagreements through discussion and consensus after referring to the protocol; we recorded and reported their solutions. We listed studies excluded after full-text assessment and their reasons for exclusion in a 'Characteristics of excluded studies' table. We constructed a PRISMA flow diagram to illustrate the study selection process.

Data extraction and management

Both review authors independently extracted data using a pilot-tested data extraction form and entered the data into Review Manager 5 (RevMan 5) (Review Manager 5). When data were missing or unclear, we contacted the trial authors for clarification. For dichotomous outcomes, we recorded the number of participants that experienced the event and the number of participants assessed in each group. For continuous outcomes, we extracted the arithmetic mean values, standard deviation (SD) values, and the number of participants assessed in each group. If a trial reported continuous data using geometric means, we extracted the SD values on the log scale; we extracted median and range values and reported these in a table.

Assessment of risk of bias in included studies

Both review authors independently assessed the risk of bias for each trial using the Cochrane 'Risk of bias' assessment tool (Higgins 2011). We categorized our judgments as either at low, high, or unclear risk of bias, and we used this information to guide our interpretation of the results. Where the judgement for efficacy trials was 'unclear' we attempted to contact the trial authors for clarification and we resolved any differences of opinion through discussion. If data were missing or unclear, we contacted the trial authors for further information.

Measures of treatment effect

For dichotomous data, we reported outcome measures using the risk ratio (RR). For continuous data summarized by arithmetic means and SDs, we used the mean difference (MD) values to combine the results in a meta-analysis. We presented continuous data summarized using other summary statistics that we could not combine in a meta-analysis in a table. We calculated the geometric mean ratios and transformed them in the log scale for analysis, and presented them on the natural scale

Unit of analysis issues

There were no cluster RCTs.

Dealing with missing data

We planned to conduct an analysis so that we included all individuals with a recorded outcome in the analysis. If there was missing information or we needed more details on reported measures, we sought further clarification from the trial authors. To take into account the participants for whom there was no outcome data available, we also conducted an intention-to-treat (ITT) analysis for worst-case/best-case scenarios.

Assessment of heterogeneity

We assessed heterogeneity between trials by visually inspecting the forest plot, using the Chi² test for heterogeneity with a 5% level of statistical significance, and the I² statistic with a value of 50% representing a moderate level of heterogeneity. If we detected significant heterogeneity but considered it was appropriate to pool data, we used the random-effects model.

Assessment of reporting biases

We constructed funnel plots to look for evidence of publication bias for the outcome duration of diarrhoea and diarrhoea at day 7.

Data synthesis

We analysed the data using RevMan 5 (Review Manager 5). We presented all results with 95% confidence intervals (CIs).

Quality of the evidence

We assessed the certainty of the evidence using the GRADE approach (GRADEpro GDT 2014). We used GRADEpro Guideline Development Tool (GDT) software to construct the 'Summary of findings' tables (GRADEpro GDT 2014). The GRADE system considers ‘certainty’ to be a judgment of the extent to which we can be confident that the estimates of effect are correct. The level of ‘certainty’ is judged on a four-point scale. Evidence from RCTs is initially graded as high and downgraded by either 1, 2, or 3 levels after full consideration of: any limitations in the design of the studies, the directness (or applicability) of the evidence, the consistency and precision of the results, and the possibility of publication bias.

We have displayed the estimates of effect, and the GRADE assessments of our confidence in these estimates in 'Summary of findings tables' for the main comparisons. Where we have downgraded the evidence our reasons for doing so are displayed in footnotes.

When making conclusions about the relative effects of the interventions we used language that reflected the GRADE assessments and our confidence in the estimates, that is if the evidence was of high certainty we said "zinc reduces"; if it was of moderate certainty we stated "zinc probably reduces"; it was of low certainty we used "zinc may reduce"; and where the evidence was of very low certainty we did not draw conclusions.

Subgroup analysis and investigation of heterogeneity

We stratified the analyses for acute diarrhoea or persistent diarrhoea as these are different conditions. We also stratified the results by age (children aged less than and greater than six months) because we observed a clear difference in zinc effect according to the age of children enrolled and significant heterogeneity if we pooled all the trials together. We explored the following potential sources of heterogeneity using subgroup analyses: nutritional status (malnourished children versus well-nourished plus moderate malnourished); geographical region (by continent and by high versus medium estimated risk of zinc deficiency as defined by the International Zinc Nutrition Consultative Group (IZiNCG) (IZiNCG 2004)); zinc dose (less than versus greater than 20 mg/day); zinc salt (zinc sulphate versus zinc acetate versus zinc gluconate versus other type); concomitant copper or iron supplementation; and trial setting (hospital versus community trials). We also explored the effect of sex, although we did not specify this in the original Cochrane Protocol (Lazzerini 2005).

Sensitivity analysis

We conducted a sensitivity analysis in which we limited the analyses to those trials with adequate allocation concealment, blinding (excluded those trials classified as unclear), and those that included an adequate number of randomized participants in the analysis (excluded those trials classified as inadequate or unclear). To take into account the participants for whom no outcome data were available, we also conducted an ITT analysis for worst-case/best-case scenarios.

Results

Description of studies

Results of the search

In the previous version of this review, Lazzerini 2013, 24 trials met the inclusion criteria. We updated the literature search to 30 September 2016 and identified 68 records after removal of duplicates. After screening the articles by title and abstract, we excluded 48 articles and assessed 20 articles for eligibility. Nine new trials met the inclusion criteria of the review and thus we included 33 trials (10,841 children) in this review update. We have presented a PRISMA study flow diagram in Figure 1 and we have reported the trial selection process in Table 2.

Figure 1.

Study flow diagram.

Table 2. Results of the study selection
  1. 1See the 'Characteristics of excluded studies' section.
    Abbreviations: HIV: human immunodeficiency virus; RCT: randomized controlled trial.

Total number of studies identified through the search (up to 30 September 2016)306 trials
Total number of studies excluded as clearly did not concern the topic of interest126 trials

Studies further evaluated and excluded1

  • Not RCTs: 25 trials

  • Not placebo-controlled RCTs: 8 trials

  • RCTs on prevention of diarrhoea, not on treatment: 51 trials

  • Not concerning the population of interest (for example, studies on low birthweight, HIV): 13 trials

  • Not concerning the interventions of interest (for example, studies on zinc in oral rehydration solution (ORS), multiple micronutrients, probiotics, food fortification): 19 trials

  • Concerning different outcomes (for example, studies on serology, appetite, mental or motor development, malnutrition): 16 trials

  • Could not be compared with other studies because of methodological problems (enrolling the same children more than once) and types of outcomes (episodes of diarrhoea and not children with diarrhoea): 1 trial

  • Secondary analysis of other studies: 8

141 trials

Duplicates of included studies

6 trials
Independent trials included in the review33 trials (10,841 participants)

Included studies

Thirty-three trials in total met the inclusion criteria of this review. We have listed the details of the included trials in the 'Characteristics of included studies' table. Three included trials presented results divided in two or more subgroups, and specifically: one trial presented two intervention groups of zinc 20 mg and zinc 5 mg, and one control group (Brooks 2005a); one trial presented data for three different study sites (Fischer Walker 2006); one trial presented the results as children with low and normal zinc serum levels (Polat 2003). For these three trials there was no way to combine mean values and standard deviation (SD) values, and thus we entered the data separately as Brooks 2005a (20 mg), Brooks 2005a (5 mg), Fischer Walker 2006 ETH, Fischer Walker 2006 IND, Fischer Walker 2006 PAK, Polat 2003 (low Zn), and Polat 2003 (normal Zn).

Type of diarrhoea

Most trials included children with acute diarrhoea only. Of these, 13 used the definition for acute diarrhoea that we used in this Cochrane Review (Faruque 1999; Dutta 2000; Strand 2002; Al-Sonboli 2003; Polat 2003; Bhatnagar 2004a; Brooks 2005a; Fischer Walker 2006; Boran 2006; Dutta 2011; Crisinel 2015; Passariello 2015; Tran 2015), two trials defined diarrhoea as the presence of either four (Sazawal 1995), or five (Bahl 2002), unformed stools in 24 hours, one trial defined diarrhoea as acute onset of change in stool frequency and consistency (Karamyyar 2013), one shigellosis trial included participants with bloody mucoid diarrhoea (dysentery) or febrile diarrhoea less than five days' duration (Roy 2008a).

Three trials enrolled only children with rotavirus infection (Dalgic 2011; Jin 2013; Jiang 2016).

Eight trials did not report the definition of acute diarrhoea (Sachdev 1988; Roy 1997; Larson 2005;Fajolu 2008; Shimelis 2008; Patel 2009; Patro 2010; Jiang 2016).

Five trials were on children with persistent diarrhoea (Sachdev 1990; Roy 1998; Bhutta 1999; Penny 1999; Khatun 2001).

Age

Two trials only enrolled children under six months of age (Brooks 2005a; Fischer Walker 2006). Seventeen trials only enrolled children over six months of age (Sachdev 1988; Sachdev 1990; Sazawal 1995; Bhutta 1999; Faruque 1999; Penny 1999; Khatun 2001; Bahl 2002; Strand 2002; Boran 2006; Roy 2008a; Fajolu 2008; Patel 2009; Dutta 2011; Karamyyar 2013; Passariello 2015; Tran 2015). Fourteen trials included children of different ages greater than one month (Roy 1997; Roy 1998; Dutta 2000; Al-Sonboli 2003; Polat 2003; Bhatnagar 2004a; Larson 2005; Shimelis 2008; Patro 2010; Dalgic 2011; Jin 2013; Crisinel 2015; Patel 2015; Jiang 2016).

Nutritional status

Eight trials only enrolled malnourished children (Roy 1997; Roy 1998; Bhutta 1999; Dutta 2000; Khatun 2001; Polat 2003; Roy 2008a; Passariello 2015). Two trials included well-nourished children (Boran 2006; Patro 2010), and one trial enrolled children regardless of their nutritional status (Larson 2005), while the remaining 20 trials enrolled children who were well nourished or with mild or moderate malnutrition. No trials included only severe malnourished children. Two trials did not mention the nutritional status of children (Jin 2013; Jiang 2016). There was some variability between trials regarding the definition of malnutrition (most used 'weight/age'; only some used 'weight/height'); therefore we were unable to follow the definition of malnutrition proposed in our protocol (Lazzerini 2005).

Sex

Four trials only included males (Dutta 2000; Bhatnagar 2004a; Brooks 2005a; Dutta 2011), while the remaining 29 trials enrolled children of both sexes.

Geographical region

Most included trials were conducted in Asia. Only three trials were conducted in Europe (Patro 2010; Crisinel 2015; Passariello 2015), two in South America (Al-Sonboli 2003; Penny 1999), two in Africa (Fajolu 2008; Shimelis 2008), one multicentre trial in Asia and Africa (Fischer Walker 2006), and one trial in Australia (Tran 2015). Thus, participants were from Bangladesh (Roy 1997; Roy 1998; Faruque 1999; Khatun 2001; Brooks 2005a; Larson 2005; Roy 2008a), India (Sachdev 1988; Sachdev 1990; Sazawal 1995; Dutta 2000; Bahl 2002; Bhatnagar 2004a; Fischer Walker 2006 IND; Patel 2009; Patel 2015), Pakistan (Bhutta 1999; Fischer Walker 2006 PAK), Nepal (Strand 2002), China (Jin 2013; Jiang 2016), Turkey (Polat 2003; Boran 2006; Dalgic 2011), Brazil (Al-Sonboli 2003), Peru (Penny 1999), Ethiopia (Fischer Walker 2006 ETH; Shimelis 2008), Nigeria (Fajolu 2008), Poland (Patro 2010), Italy (Passariello 2015), Switzerland (Crisinel 2015), and Australia (Tran 2015).

Risk of zinc deficiency

Most trials were conducted in countries ranked as at high risk of zinc deficiency (IZiNCG 2004). Nine trials were conducted in countries at medium risk: Nepal (Strand 2002); Turkey (Polat 2003; Boran 2006, Dalgic 2011); Brazil (Al-Sonboli 2003), China (Jin 2013), Iran (Karamyyar 2013), Nigeria (Fajolu 2008), and Ethiopia (Shimelis 2008). Four trials were conducted in countries where zinc deficiency is considered rare: Poland (Patro 2010), Italy (Passariello 2015), Switzerland (Crisinel 2015), and Australia (Tran 2015).

Zinc dose

The most frequent zinc dose was 20 mg/day. Only three trials administered higher zinc doses: 40 mg/day (Dutta 2000); 22 or 45 mg/day (Al-Sonboli 2003); 20 and 40 mg respectively in children under and above six months of age (Passariello 2015). Two trials, of which one was of children aged less than six months only, gave 10 mg/day zinc (Fischer Walker 2006; Roy 2008a).

Seven trials used different dosages based on the age of children (under and above six months of age): 5 mg and 10 mg (Boran 2006), 10 mg and 20 mg (Fajolu 2008; Patro 2010; Crisinel 2015; Jiang 2016 ), 20 and 40 mg (Passariello 2015;); one trial used zinc at two different dosages (5 mg and 20 mg) in children aged less than six months (Brooks 2005a),

Seven trials used different doses depending on age (zinc < 20 mg in infants and ≥ 20 mg in older children), but they did not report results separately for each treatment group (Faruque 1999; Bahl 2002; Strand 2002; Bhatnagar 2004a; Boran 2006; Crisinel 2015; Passariello 2015). We classified these trials as 'not assignable' and could not include them in the sensitivity analysis for zinc dose.

Three trials reported a per kilo dose: 1 mg/kg/day (Karamyyar 2013); 2 mg/kg/day (Bhutta 1999); 3 mg/kg/day (Patel 2009). We were unable to include these trials in the subgroup analyses.

Type of zinc salt

Eight trials used zinc acetate (Roy 1997; Roy 1998; Faruque 1999; Khatun 2001; Strand 2002; Brooks 2005a; Roy 2008a; Dalgic 2011), five used zinc gluconate (Sazawal 1995; Penny 1999; Bahl 2002; Jin 2013; Jiang 2016), and three did not specify (Shimelis 2008; Dutta 2011; Passariello 2015), while all the remaining trials used zinc sulphate.

Concomitant copper or iron supplementation

One trial compared zinc alone versus zinc and copper versus placebo (Patel 2009).

Study setting

Most trials were conducted in hospitals, with the exception of six community-based trials (Penny 1999; Bahl 2002; Strand 2002; Fischer Walker 2006; Boran 2006; Passariello 2015), and one trial was held in both hospital and community settings (Larson 2005).

Treatment regimen
Treatment duration

About half of trials administered zinc for two weeks. Of the remaining trials, one gave zinc for a total of four days (Tran 2015), three gave zinc for seven days after recovery (Bahl 2002; Strand 2002; Polat 2003), four gave zinc until recovery (Al-Sonboli 2003; Brooks 2005a; Karamyyar 2013; Passariello 2015), one trial gave zinc for seven days (Khatun 2001), and three trials gave zinc for 10 days (Patro 2010; Crisinel 2015; Jiang 2016). Five trials were unclear in respect of duration of zinc supplementation (Sachdev 1988; Sachdev 1990; Sazawal 1995; Dutta 2000; Dalgic 2011). One trial on adverse events administered only one dose of zinc (Larson 2005).

Formulation

Most included trials administered zinc as syrup. Seven used dispersible tablets (Al-Sonboli 2003; Larson 2005; Fischer Walker 2006; Shimelis 2008; Jin 2013; Crisinel 2015: Jiang 2016), four used powder (Sachdev 1988; Sachdev 1990; Penny 1999; Dalgic 2011), two mixed it with ORS (Passariello 2015; Tran 2015), and one did not specify (Fajolu 2008; Patel 2015).

Dose frequency

Zinc was administered once a day in most of the included trials. It was administered twice a day in five trials (Sachdev 1988; Sachdev 1990; Khatun 2001; Roy 2008a; Patro 2010), three times a day in six trials (Roy 1997; Roy 1998; Dutta 2000; Polat 2003; Bhatnagar 2004a), and together with ORS depending on stool frequency in two trials (Passariello 2015; Tran 2015). One trial administered zinc twice a day to infants, and a single dose to children over six months (Dalgic 2011). Three trials did not specify the dose frequency (Fajolu 2008; Patel 2009, Patel 2015).

Additional treatment

Most trials administered zinc alone. Seven trials used zinc and multivitamin, which did not contain iron (Sazawal 1995; Roy 1997; Roy 1998; Bhutta 1999; Khatun 2001; Bhatnagar 2004a; Roy 2008a). One trial used zinc and vitamin A (Faruque 1999). One trial used concomitant copper (Patel 2009).

Excluded studies

For this review update we excluded 11 studies after full-text assessment. We have provided the total results of the study selection (that is, for the previous versions of this review plus this update) in Table 2, and listed the reasons for exclusion of studies after full-text assessment in the 'Characteristics of excluded studies' table.

Risk of bias in included studies

See Figure 2 and Figure 3 for the risk of bias in the included trials.

Figure 2.

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included trials.

Figure 3.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.

Allocation

Twenty-six trials used adequate methods to generate the allocation sequence. The methods used in the other trials was either at unclear (Sachdev 1988; Sachdev 1990; Khatun 2001; Fajolu 2008; Jin 2013; Jiang 2016), or at high risk of bias (Shimelis 2008).

Nineteen trials reported methods that assured adequate allocation concealment. Of the remaining trials, thirteen were at unclear risk of bias (Sachdev 1988; Sachdev 1990; Roy 1998; Khatun 2001; Al-Sonboli 2003; Brooks 2005a; Boran 2006; Fajolu 2008; Dalgic 2011; Jin 2013; Patel 2015; Tran 2015; Jiang 2016), and one was at high risk of bias (Shimelis 2008).

Blinding

Twenty-two trials were double blinded. Eight trials were at unclear risk of bias regarding the use of blinding (Sachdev 1988; Sachdev 1990; Khatun 2001; Fajolu 2008; Dalgic 2011; Jin 2013; Passariello 2015; Jiang 2016), and three trials were at high risk of bias (Boran 2006; Shimelis 2008; Patel 2015).

Incomplete outcome data

Twenty-one trials included more than 90% of the randomized participants in the analysis. Seven trials included less than 90% of the randomized participants, which we assessed as at high risk of bias (Roy 1997; Bhutta 1999; Roy 2008a; Patro 2010; Karamyyar 2013; Crisinel 2015; Tran 2015), and the five remaining trials were at unclear risk of bias (Sachdev 1988; Sachdev 1990; Roy 1998; Dutta 2000; Fajolu 2008).

Selective reporting

Only three included trials were at low risk of bias regarding selective reporting (Roy 2008a; Patel 2009; Karamyyar 2013). The risk of bias was unclear for all other included trials, and the most frequent reason for this was the fact that the trial was not registered.

Other potential sources of bias

No information was available to evaluate other sources of bias. Therefore we judged each of the included trials as at unclear risk of bias regarding other potential sources of bias.

Effects of interventions

See: Summary of findings for the main comparison 'Summary of findings' table 1; Summary of findings 2 'Summary of findings' table 2; Summary of findings 3 'Summary of findings' table 3

Comparison 1: Zinc versus placebo for children with acute diarrhoea

Diarrhoea duration

On average, the mean duration of diarrhoea in children given zinc was around 13 hours shorter than those given placebo (mean difference (MD) −13.42 hours, 95% confidence interval (CI) −20.52 to −6.31; 5096 children, 20 trials, 24 comparisons; Analysis 1.1; Figure 4), but there was substantial statistical heterogeneity between trials (I2 statistic = 84%).

Figure 4.

Zinc versus placebo for acute diarrhoea: diarrhoea duration (h)

In the primary analysis stratified by age, the benefit was only apparent in trials that recruited children over six months of age (MD −11.46 hours, 95% CI −19.72 to −3.19 hours; 2581 children, 9 trials; Summary of findings for the main comparison; Analysis 1.1; Figure 4), and trials that recruited all age groups (MD −22.18 hours, 95% CI −32.57 to −11.78 hours; 1181 children, 9 trials, 10 comparisons). In trials that only recruited children less than six months of age, no effect was demonstrated (1334 children, 2 trials, 5 comparisons; Summary of findings 2).

This age stratification did not adequately explain the statistical heterogeneity so we conducted a series of further subgroup analyses excluding the trials which only recruited children less than six months of age (Analysis 1.2 to Analysis 1.9). None of these subgroupings adequately explained the heterogeneity, but several observations are worth noting.

  • When subgrouped by the nutritional status of participants, the smallest average effect was seen in trials that only recruited well-nourished children, and the largest average effect in trials that only recruited children with signs of malnutrition (Analysis 1.2).

  • There was only one included trial from the African continent, and this trial failed to show a benefit (Analysis 1.4).

  • When subgrouped by the national risk of zinc deficiency, the smallest average effect was in countries at low risk of zinc deficiency (Analysis 1.5).

Diarrhoea on days 3, 5, and 7

On average, treatment with zinc resulted in fewer children continuing to have diarrhoea at day three (risk ratio (RR) 0.77, 95% CI 0.69 to 0.86; 2063 children, 8 trials, 9 comparisons, Analysis 1.10), at day five (RR 0.76, 95% CI 0.64 to 0.91; 2307 children, eight trials, Analysis 1.11), and at day seven (RR 0.82, 95% CI 0.72 to 0.94; 5528 children, 10 trials, 13 comparisons; Analysis 1.12; Figure 5; Summary of findings for the main comparison; Summary of findings 2). For all the three outcomes there was significant statistical heterogeneity between trials.

Figure 5.

Zinc versus placebo for acute diarrhoea: diarrhoea on day 7

For diarrhoea at day seven we conducted a series of subgroup analyses to explore the heterogeneity (Analysis 1.13 to Analysis 1.20), which found similar patterns as seen with duration of diarrhoea.

  • No subgrouping completely explained the statistical heterogeneity.

  • There was no evidence of benefit in the single trial that recruited only children less than six months of age (1074 children, 1 trial, 3 comparisons; Analysis 1.12). This was also the only trial conducted in the African continent.

  • The average effect was largest in trials that only recruited children with signs of undernutrition (Analysis 1.13).

Stool frequency

There was no significant benefit of zinc on reducing stool frequency (RR −0.10, 95% CI −0.25 to 0.04; 2643 children, 7 trials, 10 comparisons; Analysis 1.21). Heterogeneity was markedly reduced if results were stratified by age, and while no benefit of zinc was detected in children under six months of age (1334 children, 2 trials, 5 comparisons), zinc had a significant benefit in children older than six months (RR −0.32, 95% CI −0.58 to −0.06; 1235 children, 4 trials) and in the trial that recruited both age groups (RR −5.90, 95% CI −9.44 to −2.36; 74 children, 1 trial; Analysis 1.21).

Stool output

The included trials measured stool output using different units at different time points, thus we were unable to pool results (Table 3). We expressed results are expressed as arithmetic mean difference (AMD) or geometric mean ratio (GMR) values.

Table 3. Stool output: acute diarrhoea
  1. 1Arithmetic mean difference (95% CI) for means.
    2Geometric mean ratio (95% CI) for geometric means, adjusted for confounders. (Stool output using zinc is 0.69 and 0.76 times that of participants using placebo, which means a 31% and 24% less stool output under zinc treatment.)

    Abbreviations: CI: confidence interval; NA: not applicable.

Trial IDOutcomeUnitsZincPlaceboMean differenceStatistical test
NValuesNValues
Age < 6 months
Brooks 2005a (5 mg)Total (mL)Mean (95% CI)85

229

(180 to 256)

45

202

(180 to 246)

27

(−23.3 to 77.3)1

Not significant
Brooks 2005a (20 mg)Total (mL)Mean (95% CI)86

240

(200 to 266)

44

202

(180 to 246)

38

(−8.6 to 84.6)1

Not significant
Age > 6 months
Patel 2009a (zinc)Total (g)Mean (95% CI)248

972

(858 to 1087)

247

877

(728 to 1026)

−95

(−283 to 92)

Not significant
Dutta 2011Total (L)Mean (95% CI)41

1.2

(0.6 to 1.8)

43

2.0

(1.3 to 2.7)

- 0.8

(-1.1 to 1.5)

P < 0.0001
Dutta 2011Per day (ml/kg/day)Mean (95% CI)41

51.22

(27.39 to 79.05)

43

66.83

(42.41 to 71.25)

- 15.61

(-22.9 to -8.2)

P = 0.0001
Ages < and > 6 months
Bhatnagar 2004aTotal (g/kg)Geometric mean (95% CI)132

111

(86 to 147)

134

148

(116 to 190)

0.69

(0.48 to 0.99)2

P < 0.05
Per day (g/kg/day)Geometric mean (95% CI)132

62

(51 to 78)

134

78

(68 to 91)

0.76

(0.59 to 0.98)2

P < 0.05
Dutta 2000Total (kg)Mean (95% CI)44

1.5

(1.3 to 1.7)

36

2.4

(2.2 to 2.6)

−0.9

(−1.2 to −0.6)1

P = 0.0001
Roy 1997Per day (g/kg/day)Median (range)37

238

(35 to 2416)

37

329

(32 to 1464)

−91

(NA)

P = 0.06

One trial reported on children less than six months of age with no evidence of a difference (Brooks 2005a). Two trials reported on children more than six months of age with inconsistent results (Patel 2009; Dutta 2011). Three trials reported on children aged less than and greater than six months: two of these trials showed a reduction in stool output with zinc (Dutta 2000; Bhatnagar 2004a), while one trial showed no evidence of an effect (Roy 1997).

Hospitalization

Two community trials reported no hospitalizations in the zinc group and only one in the placebo group (Fischer Walker 2006, 1074 participants under six months of age; Penny 1999, 276 children over six months of age).

Death

The trials reported a low number of deaths without significant difference between the zinc group and placebo group (Analysis 1.22).

Adverse events

Vomiting was more common in those given zinc across all age groups (RR 1.54, 95% CI 1.28 to 1.85; 5942 children, 15 comparisons, 13 trials; Figure 6). There was moderate heterogeneity among trials (P = 0.005; I² statistic = 56%), and differences in control event rates (from 0.4% to 13.5%). In one large trial with adequate allocation concealment that was designed to look at safety reports, vomiting was limited to one episode in most children and mainly occurred within 10 minutes of administration (Larson 2005). Two trials found no difference in time to resolution of vomiting between zinc and placebo, although we could not pool the results (mean duration 13.63 ± 10.33 hours versus 16.35 ± 11.34 hours, P = 0.1; Dalgic 2011; median duration 2 days (interquartile range (IQR) 1 to 3) versus 2.5 days (IQR 1 to 5), P > 0.5; Crisinel 2015).

Figure 6.

Zinc versus placebo for acute diarrhoea: adverse events (vomiting)

One small trial reported a non-statistically significant difference between the two treatment groups for difficulties in treatment administration (19/45 (45%) in the zinc group versus 20/44 (44%) in the placebo group (Crisinel 2015).

Three trials reported on copper levels, with no significant differences between the zinc and placebo groups. Two trials reported the mean change in serum copper on the last day of supplementation (seven and 14 days after recovery): −1.1 ± 5.5 µmol/dL in the zinc group versus −1.5 ± 4.2 µmol/dL in the placebo group in Strand 2002, and −41.2 ± 418.8 µg/dL in the zinc group versus −79.4 ± 429.2 µg/dL in the placebo group in Patel 2009. Mean serum copper after 14 days was 121 mg/L in zinc group versus 127 mg/L in the control in Bhatnagar 2004a.

No other side effects were reported.

Publication bias

We constructed funnel plots for trials that reported diarrhoea duration (Figure 7) and diarrhoea at day 7 (Figure 8). The funnel plots are both asymmetric due to the absence of smaller trials at the base and, for diarrhoea at day 7, also at the right of the pooled estimate. Asymmetry in the funnel plot could result from possible selection bias where smaller studies reporting greater treatment benefit for the experimental group were published (publication bias). The gap in the bottom corner of the graph suggests that smaller studies without statistically significant effects remain unpublished. However, asymmetry in the funnel plot may also be due to other reasons, such as poor methodological quality in smaller studies leading to spuriously inflated effects in the treatment effect, true heterogeneity, sampling variation or chance (Higgins 2011).

Figure 7.

Funnel plot of comparison: 1 Zinc versus placebo for children with acute diarrhoea, outcome: 1.1 Diarrhoea duration (hours).

Figure 8.

Funnel plot of comparison: 1 Zinc versus placebo for children with acute diarrhoea, outcome: 1.12 Diarrhoea on day 7.

Sensitivity analysis

The sensitivity analysis against markers of methodological quality did not affect the direction of results. There was some loss of significance with diarrhoea duration, but overall the analysis did not change the point estimate of effects. The ITT analysis for worst-case/best-case scenarios did not alter the statistical significance of the results.

Comparison 2: Zinc versus placebo for children with persistent diarrhoea

All trials of persistent diarrhoea enrolled children aged over six months.

Diarrhoea duration

On average, zinc supplementation reduced the duration of persistent diarrhoea by around 16 hours (MD −15.84 hours, 95% CI −25.43 to −6.24 hours; 529 children, 5 trials; Analysis 2.1), with no evidence of heterogeneity.

Diarrhoea on days 3, 5, and 7

There was no evidence of a benefit with zinc in the one trial that reported on diarrhoea at days three (Analysis 2.2) and five (Analysis 2.3) (Penny 1999), and two trials that reported on diarrhoea at day seven (Analysis 2.4; Penny 1999; Khatun 2001).

Stool frequency

One small trial reported on stool frequency, Sachdev 1990, but the result did not reach statistical significance (40 participants, Analysis 2.5).

Stool output

Stool output was measured using different units at different time points, thus we could not pool results (Table 4). We expressed the results as the AMD or GMR. Two trials, Bhutta 1999 and Khatun 2001, reported on children greater than six months of age, with five comparisons (Additional tables). Of these, one trial reported a significant reduction in cumulative stool output at day seven in the zinc group (AMD −338 mg/kg bodyweight, 95% CI −413.6 to −262.4 mg/kg bodyweight; P ≤ 0.001) (Khatun 2001).

Table 4. Stool output: persistent diarrhoea
  1. 1Arithmetic mean difference (95% CI) for means.

    Abbreviations: CI: confidence interval; ID: identification.

Trial IDOutcomeZincPlaceboMean difference 1Statistical test
NMean (95% CI)NMean (95% CI)
Age > 6 months
Bhutta 1999Per day of diarrhoea, day 1 (g/kg/day)43

116.8

(85.8 to 147.8)

44

141.9

(91.2 to 192.6)

−25.1

(−84.5 to 34.3)

Not significant
Per day of diarrhoea, day 7 (g/kg/day)43

66.7

(40.9 to 92.4)

44

43.9

(32.1 to 55.7)

22.8

(−5.5 to 51.1)

Not significant
Per day of diarrhoea, day 14 (g/kg/day)43

24.9

(20.1 to 29.7)

44

27.8

(18.5 to 37.1)

-2.9

(−13.4 to 7.6)

Not significant
Khatun 2001Cumulative day 1 (mg/kg)24

127

(113 to 141)

24

137

(121 to 153)

−10

(−31.6 to 11.6)

Not significant
Cumulative day 7 (mg/kg)24

528

(472 to 584)

24

866

(815 to 917)

−338

(−413.6 to −262.4)

P ≤ 0.001
Hospitalization

The only community trial that reported on hospitalization did not observe any hospitalizations in the zinc or placebo group (Penny 1999; 275 participants).

Death

One trial reported one death in the zinc group compared to five deaths in the placebo group, out of 95 participants in each group (Roy 1998). Two trials did not observe deaths in any participants, irrespective of their allocated group (Penny 1999; Khatun 2001).

Adverse events

Four trials that reported on vomiting (505 children) showed no difference between the zinc and placebo groups (Analysis 2.6): three of the trials reported no incidences of vomiting in either group (Khatun 2001; Roy 1998; Sachdev 1990); one trial that used 3 mg/kg/day zinc for 14 days in moderately malnourished and severely malnourished children reported a significantly lower plasma copper levels in the zinc-treated group by the end of the second week of therapy (56.2 ± 17.8 µg/dL versus 72.7 ± 18.3 µg/dL, P = 0.02; Bhutta 1999, 87 children).

Statistical heterogeneity

There was heterogeneity between two trials for diarrhoea at day seven. This may be explained by differences in the geographical regions (India and Peru) or to other factors not explored in this Cochrane Review. Reporting of vomiting was heterogeneous between trials, and this may be due to difference in the population or in the definition of event, or to reporting bias.

Sensitivity analysis

The sensitivity analyses did not affect the direction of results. There was some loss of significance with diarrhoea duration, but no changes in the point estimate of effects. An ITT analysis for worst-case/best-case scenarios did not alter the point estimate or the significance of results.

Discussion

Summary of main results

Thirty-three trials, enrolling 10,841 children, met our inclusion criteria. Most included trials were conducted in Asian countries where the risk of zinc deficiency is high.

Acute diarrhoea

There is currently not enough evidence from well conducted trials to be able to say whether zinc supplementation during acute diarrhoea reduces the number of deaths or the number of children hospitalized (very low certainty evidence).

In children aged greater than six months, zinc supplementation may shorten the duration of diarrhoea by around half a day (low certainty evidence), and probably reduces the number of children whose diarrhoea persists until day seven (moderate certainty evidence). In children with signs of moderate malnutrition the effect appears greater, reducing the duration of diarrhoea by around a day (high certainty evidence).

Conversely, in children less than six months of age, the available evidence suggests zinc supplementation may have no impact on the duration of diarrhoea (low certainty evidence), and may increase the proportion of children whose diarrhoea persists until day seven (low certainty evidence).

No trials reported serious adverse events, but zinc supplementation during acute diarrhoea causes vomiting in both age groups (moderate certainty evidence).

Persistent diarrhoea

In children with persistent diarrhoea, zinc supplementation probably shortens the duration of diarrhoea by around 16 hours (moderate certainty evidence).

Overall completeness and applicability of evidence

This Cochrane Review showed that zinc overall reduced the duration of acute diarrhoea. However, most trials were conducted in populations with moderate to high risk of zinc deficiency (Asia, Africa, children over six months of age and with some degree of malnutrition). Transferability of these results to other countries is therefore likely to depend on local risk of zinc deficiency and other population characteristics such as the degree of malnutrition and breastfeeding habits. The few trials conducted in populations at low risk of zinc deficiency, namely well-nourished children in countries and continents where zinc deficiency is uncommon (Europe, Australia), overall showed no benefit of zinc.

Most trials were conducted in hospital where participants are more likely to adhere to the intervention, but some community trials also showed a benefit with zinc, which suggests that zinc could be used both at hospital and at community level.

The observed increase in vomiting was consistent across trials in all age groups with one large trial reporting that vomiting was limited to one episode in most children and mainly occurring within 10 minutes of administration (Larson 2005). Zinc has a metallic after-taste, and development of a more palatable formulation may minimize this adverse effect.

Quality of the evidence

We assessed the certainty of the evidence using the GRADE methodology and displayed it in three 'Summary of findings' tables (Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3).

In general, the methodological quality of the trials included in this review was good.

The evidence for benefits on diarrhoea duration in children aged greater than six months of age is of low to moderate certainty. This implies that we can have some confidence in the results but further research may alter the estimates of benefit and harm. The main reasons to downgrade were 'quality of trials' and 'inconsistency' in the results. Heterogeneity between trials was often high. This is perhaps not surprising given the variations in populations, settings, and interventions. We were unable to completely explain this heterogeneity through subgroup analysis, and so our confidence that zinc supplementation can be broadly applied was decreased.

Most trials were conducted in hospitals where death rates were low, and were consequently not powered to detect an effect on mortality. Large community trials are needed to explore whether zinc treatment for diarrhoea reduces hospitalization and death.

Potential biases in the review process

We attempted to limit bias by following the rigorous methods provided by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We conducted an extensive search for studies, including ongoing studies. We only included peer-reviewed trials in this review. Two review authors independently scrutinized the studies, assessed them for eligibility, extracted data, inserted data into RevMan 5 (Review Manager 5), and double checked the final version of the review. The findings of the funnel plots may suggest publication bias. However, asymmetry in the funnel plots may also be due to other reasons, such as poor methodological quality in smaller studies leading to spuriously inflated effects, true heterogeneity in the treatment effect, sampling variation, or chance (Higgins 2011).

Agreements and disagreements with other studies or reviews

Our results agree with those of other systematic reviews of zinc for treating children that have diarrhoea (Bhutta 2000b; Lukacik 2008; Patro 2008; Haider 2009; Liberato 2015; Zou 2015), except for the finding of no effect of zinc in children aged less than six months, and in populations at low risk of zinc deficiency. Compared to the other recent reviews (Liberato 2015; Zou 2015; Lazzerini 2016), this Cochrane Review includes several new trials, includes a more extensive subgroup analysis, and reports on diarrhoea at different time points, diarrhoea severity, death, and adverse events.

The results of this Cochrane Review in children over six months of age support the current WHO/UNICEF policy to give zinc to children with diarrhoea (WHO/UNICEF 2004), while currently there are no evidence from randomized controlled trials to provide zinc in children younger than six months of age.

Authors' conclusions

Implications for practice

In areas where diarrhoea is an important cause of child mortality, and the prevalence of zinc deficiency or mild/moderate malnutrition is high, zinc may be of benefit in children with diarrhoea aged six months or more.

Implications for research

Causes of heterogeneity in the effect of zinc in children over six months should be further explored, and further research is necessary to justify continued supplementation in children less than six months of age and in children with low risk of zinc deficiency.

Acknowledgements

We thank Victoria Lutje for support in the search strategy, and Deirdre Walshe and David Sinclair for their help in reviewing the text. We acknowledge Luca Ronfani for his contributions to previously published versions of this Cochrane Review. The editorial base of the Cochrane Infectious Diseases Group is funded by UK aid from the UK Government for the benefit of developing countries (Grant: 5242). The views expressed in this review do not necessarily reflect UK government policy.

Data and analyses

Download statistical data

Comparison 1. Zinc versus placebo for children with acute diarrhoea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Diarrhoea duration (hours)245096Mean Difference (IV, Random, 95% CI)-13.42 [-20.52, -6.31]
1.1 Age < 6 months51334Mean Difference (IV, Random, 95% CI)5.23 [-2.00, 14.45]
1.2 Age > 6 months92581Mean Difference (IV, Random, 95% CI)-11.46 [-19.72, -3.19]
1.3 Ages both < and > 6 months101181Mean Difference (IV, Random, 95% CI)-22.18 [-32.57, -11.78]
2 Diarrhoea duration (hours): subgrouped by nutritional status173518Mean Difference (IV, Random, 95% CI)-17.54 [-25.49, -9.58]
2.1 Nutritional status: only well-nourished2406Mean Difference (IV, Random, 95% CI)-6.79 [-23.84, 10.26]
2.2 Nutritional status: well-nourished plus moderately malnourished102693Mean Difference (IV, Random, 95% CI)-15.46 [-25.55, -5.36]
2.3 Nutritional status: malnourished5419Mean Difference (IV, Random, 95% CI)-26.39 [-36.54, -16.23]
3 Diarrhoea duration (hours): subgrouped by sex183621Mean Difference (IV, Random, 95% CI)-17.33 [-25.03, -9.62]
3.1 Sex: male3430Mean Difference (IV, Random, 95% CI)-22.35 [-36.40, -8.31]
3.2 Sex: male and female153191Mean Difference (IV, Random, 95% CI)-16.13 [-24.71, -7.55]
4 Diarrhoea duration (hours); subgrouped by continent183621Mean Difference (IV, Random, 95% CI)-17.33 [-25.03, -9.62]
4.1 Continent: Africa160Mean Difference (IV, Random, 95% CI)-2.40 [-33.25, 28.45]
4.2 Continent: Asia133205Mean Difference (IV, Random, 95% CI)-19.01 [-28.19, -9.82]
4.3 Continent: South America174Mean Difference (IV, Random, 95% CI)-31.20 [-46.43, -15.97]
4.4 Continent: Europe2224Mean Difference (IV, Random, 95% CI)-10.19 [-34.29, 13.91]
4.5 Continent: Australia158Mean Difference (IV, Random, 95% CI)-2.40 [-20.93, 16.13]
5 Diarrhoea duration (hours): subgrouped by national risk of zinc deficiency163253Mean Difference (IV, Random, 95% CI)-16.99 [-25.49, -8.50]
5.1 Region: countries ranked as high risk of zinc deficiency82535Mean Difference (IV, Random, 95% CI)-14.97 [-26.21, -3.72]
5.2 Region: countries ranked as medium risk of zinc deficiency5436Mean Difference (IV, Random, 95% CI)-25.92 [-44.80, -7.04]
5.3 Region: countries ranked as low risk of zinc deficiency3282Mean Difference (IV, Random, 95% CI)-7.63 [-22.74, 7.48]
6 Diarrhoea duration (hours): subgrouped by zinc dose132018Mean Difference (IV, Random, 95% CI)-20.24 [-28.84, -11.63]
6.1 Zinc dose:≤ 20 mg9976Mean Difference (IV, Random, 95% CI)-18.45 [-30.19, -6.71]
6.2 Zinc dose: > 20 mg41042Mean Difference (IV, Random, 95% CI)-23.33 [-38.30, -8.35]
7 Diarrhoea duration (hours): subgrouped by zinc type163454Mean Difference (IV, Random, 95% CI)-16.50 [-25.11, -7.89]
7.1 Zinc type: zinc acetate3875Mean Difference (IV, Random, 95% CI)-30.55 [-49.29, -11.82]
7.2 Zinc type: gluconate2908Mean Difference (IV, Random, 95% CI)-14.51 [-30.84, 1.81]
7.3 Zinc type: zinc sulphate111671Mean Difference (IV, Random, 95% CI)-13.21 [-24.16, -2.27]
8 Diarrhoea duration (hours): subgrouped by study setting183621Mean Difference (IV, Random, 95% CI)-17.33 [-25.03, -9.62]
8.1 Study setting: hospital152468Mean Difference (IV, Random, 95% CI)-17.86 [-27.01, -8.70]
8.2 Study setting:community31153Mean Difference (IV, Random, 95% CI)-12.65 [-21.76, -3.54]
9 Diarrhoea duration (hours): subgrouped by concomitant treatment183777Mean Difference (IV, Random, 95% CI)-15.68 [-23.53, -7.82]
9.1 Concomitant treatment: zinc alone173394Mean Difference (IV, Random, 95% CI)-16.95 [-24.85, -9.05]
9.2 Concomitant treatment: zinc plus copper1383Mean Difference (IV, Random, 95% CI)2.20 [-5.08, 9.48]
10 Diarrhoea on day 392063Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.69, 0.86]
10.1 Age > 6 months41599Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.72, 0.94]
10.2 Ages both < and > 6 months5464Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.56, 0.79]
11 Diarrhoea on day 582307Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.64, 0.91]
11.1 Age > 6 months31384Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.52, 1.01]
11.2 Ages both < and > 6 months5923Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.64, 0.96]
12 Diarrhoea on day 7135528Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.94]
12.1 Age < 6 months31074Risk Ratio (M-H, Fixed, 95% CI)1.24 [0.99, 1.54]
12.2 Age > 6 months63865Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.61, 0.88]
12.3 Ages both < and > 6 months4589Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.18, 0.52]
13 Diarrhoea on day 7: subgrouped by nutritional status10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
13.1 Nutritional status: only well-nourished1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]
13.2 Nutritional status: well-nourished plus moderately malnourished64075Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.60, 0.86]
13.3 Nutritional status: malnourished3238Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.22, 0.61]
14 Diarrhoea on day 7: subgrouped by sex10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
14.1 Sex: male1266Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 0.88]
14.2 Sex: male and female94188Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.58, 0.81]
15 Diarrhoea on day 7: subgrouped by continent10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
15.1 Region: Asia94313Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.56, 0.79]
15.2 Region: Europe1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]
16 Diarrhoea on day 7: subgrouped by national risk of zinc deficiency10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
16.1 Region: countries ranked as high risk of zinc deficiency63240Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.62, 0.92]
16.2 Region: countries ranked as medium risk of zinc deficiency31073Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.35, 0.68]
16.3 Region: countries ranked as low risk of zinc deficiency1141Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.04, 3.26]
17 Diarrhoea on day 7: subgrouped by zinc dose9 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
17.1 Zinc dose: 20 mg83154Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.51, 0.74]
17.2 Zinc dose: >20mg1805Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.19]
18 Diarrhoea on day 7: subgrouped by zinc type10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
18.1 Zinc type: zinc acetate31628Risk Ratio (M-H, Fixed, 95% CI)0.60 [0.45, 0.79]
18.2 Zinc type:gluconate1805Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.38, 1.19]
18.3 Zinc type: zinc sulphate62021Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.57, 0.90]
19 Diarrhoea on day 7: subgrouped by study setting10 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
19.1 Study setting: hospital82758Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.56, 0.84]
19.2 Study setting: community21696Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.44, 0.85]
20 Diarrhoea on day 7: subgrouped by concomitant treatment11 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
20.1 Concomitant treatment: zinc alone104330Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.55, 0.78]
20.2 Concomitant treatment: zinc plus copper1383Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.43, 2.45]
21 Stool frequency (stools /day)102643Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.25, 0.04]
21.1 Age < 6 months51334Mean Difference (IV, Fixed, 95% CI)0.0 [-0.17, 0.17]
21.2 Age > 6 months41235Mean Difference (IV, Fixed, 95% CI)-0.32 [-0.58, -0.06]
21.3 Ages both < and > 6 months174Mean Difference (IV, Fixed, 95% CI)-5.9 [-9.44, -2.36]
22 Death82609Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.09, 1.07]
22.1 Age < 6 months21334Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.06, 15.89]
22.2 Age > 6 months51134Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.04, 2.20]
22.3 Ages both < and > 6 months1141Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.02, 1.55]
23 Adverse events (vomiting)155942Risk Ratio (M-H, Random, 95% CI)1.54 [1.28, 1.85]
23.1 Age < 6 months31334Risk Ratio (M-H, Random, 95% CI)1.54 [1.05, 2.24]
23.2 Age > 6 months62605Risk Ratio (M-H, Random, 95% CI)1.57 [1.32, 1.86]
23.3 Ages both < and > 6 months62003Risk Ratio (M-H, Random, 95% CI)1.63 [1.14, 2.34]
24 Difficulties in treatment administration187Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.44, 2.41]
Analysis 1.1.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 1 Diarrhoea duration (hours).

Analysis 1.2.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 2 Diarrhoea duration (hours): subgrouped by nutritional status.

Analysis 1.3.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 3 Diarrhoea duration (hours): subgrouped by sex.

Analysis 1.4.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 4 Diarrhoea duration (hours); subgrouped by continent.

Analysis 1.5.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 5 Diarrhoea duration (hours): subgrouped by national risk of zinc deficiency.

Analysis 1.6.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 6 Diarrhoea duration (hours): subgrouped by zinc dose.

Analysis 1.7.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 7 Diarrhoea duration (hours): subgrouped by zinc type.

Analysis 1.8.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 8 Diarrhoea duration (hours): subgrouped by study setting.

Analysis 1.9.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 9 Diarrhoea duration (hours): subgrouped by concomitant treatment.

Analysis 1.10.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 10 Diarrhoea on day 3.

Analysis 1.11.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 11 Diarrhoea on day 5.

Analysis 1.12.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 12 Diarrhoea on day 7.

Analysis 1.13.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 13 Diarrhoea on day 7: subgrouped by nutritional status.

Analysis 1.14.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 14 Diarrhoea on day 7: subgrouped by sex.

Analysis 1.15.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 15 Diarrhoea on day 7: subgrouped by continent.

Analysis 1.16.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 16 Diarrhoea on day 7: subgrouped by national risk of zinc deficiency.

Analysis 1.17.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 17 Diarrhoea on day 7: subgrouped by zinc dose.

Analysis 1.18.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 18 Diarrhoea on day 7: subgrouped by zinc type.

Analysis 1.19.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 19 Diarrhoea on day 7: subgrouped by study setting.

Analysis 1.20.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 20 Diarrhoea on day 7: subgrouped by concomitant treatment.

Analysis 1.21.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 21 Stool frequency (stools /day).

Analysis 1.22.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 22 Death.

Analysis 1.23.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 23 Adverse events (vomiting).

Analysis 1.24.

Comparison 1 Zinc versus placebo for children with acute diarrhoea, Outcome 24 Difficulties in treatment administration.

Comparison 2. Zinc versus placebo for children with persistent diarrhoea
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Diarrhoea duration (hours)5529Mean Difference (IV, Fixed, 95% CI)-15.84 [-25.43, -6.24]
1.1 Age > 6 months4388Mean Difference (IV, Fixed, 95% CI)-16.01 [-26.16, -5.86]
1.2 Ages both < and > 6 months1141Mean Difference (IV, Fixed, 95% CI)-14.40 [-43.77, 14.97]
2 Diarrhoea on day 31 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2.1 Age > 6 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Diarrhoea on day 51 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Age > 6 months1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Diarrhoea on day 72221Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.02]
4.1 Age > 6 months2221Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.27, 1.02]
5 Stool frequency (stools/day)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5.1 Age > 6 months1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Adverse events (vomiting)4505Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.37, 10.59]
6.1 Age > 6 months3364Risk Ratio (M-H, Fixed, 95% CI)1.97 [0.37, 10.59]
6.2 Ages both < and > 6 months1141Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 1 Diarrhoea duration (hours).

Analysis 2.2.

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 2 Diarrhoea on day 3.

Analysis 2.3.

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 3 Diarrhoea on day 5.

Analysis 2.4.

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 4 Diarrhoea on day 7.

Analysis 2.5.

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 5 Stool frequency (stools/day).

Analysis 2.6.

Comparison 2 Zinc versus placebo for children with persistent diarrhoea, Outcome 6 Adverse events (vomiting).

What's new

DateEventDescription
25 April 2017AmendedWe have amended the GRADE assessment for two outcomes, duration of diarrhea and diarrhea on day 7 for children aged less than 6 months with acute diarrhoea and treated with zinc, which we had scored incorrectly in the review update. We had stated that these outcomes had a GRADE score of moderate. However, we had downgraded the certainty of the evidence by 2, and thus the certainty of the evidence was low. We have amended the certainty of the evidence for these two outcomes to low in 'Summary of findings' table 2 and the review text.

History

Protocol first published: Issue 3, 2005
Review first published: Issue 3, 2008

DateEventDescription
19 December 2016New citation required but conclusions have not changedWe included 33 trials in total in this review update, of which nine were new trials. We updated the 'Summary of findings' tables according to the GRADE approach, and included a PRISMA study flow diagram and funnel plots.
19 December 2016New search has been performedWe amended the author team. Luca Ronfani stepped down as an author, and Humphrey Wanzira joined as an author. We updated the literature search to 30 September 2016, and nine new trials met the inclusion criteria of the review update.
6 December 2012New citation required but conclusions have not changedWe corrected the Abstract.
6 December 2012AmendedAn error was spotted in the abstract (number of participants and number of studies was incorrect). We have corrected this and republished the review to ensure the correct details are documented.
22 March 2012New search has been performedWe updated the search on 20 February 2012, and included two new trials. We updated the Background and undertook a more detailed assessment of the risk of bias in all included trials. We updated the 'Summary of findings' tables according to the GRADE methodology.
22 March 2012New citation required but conclusions have not changedUpdate.
11 February 2011New search has been performedWe updated the search on 1 December 2010, and included four new trials. We updated the Background and performed a more detailed assessment of the risk of bias in all included trials. We added 'Summary of findings' tables according to the GRADE methodology.

Contributions of authors

Both ML and HW contributed equally to the preparation of this Cochrane Review update.

Declarations of interest

Marzia Lazzerini has no known conflicts of interest.
Humprey Wanzira has no known conflicts of interest.

Sources of support

Internal sources

  • Liverpool School of Tropical Medicine, UK.

External sources

  • Department for International Development (DFID), UK.

    Grant: 5242

Differences between protocol and review

2016

We included a PRISMA study flow diagram and funnel plots.

2011

We used GRADE profiler, version 3.2.2 to create 'Summary of findings’ tables for the primary outcomes in the review.

2007, Issue 4 (first review version)

We made the following modifications to the review.

  • We changed the inclusion criteria for participant age to "children over one month old" (rather than "two months") to avoid arbitrarily losing trials.

  • We amended death to a secondary outcome measure following feedback from referees.

  • We stratified the results by age categories since we observed significant heterogeneity when trials were pooled, and a clear difference in zinc effect was evident according to age.

  • For subgroup analysis by nutritional status, it was not possible to refer to the definition of malnutrition given in the protocol (weight/height) as most included trials used another definition (weight/age), which is easier to measure. The difference between the two definition is that the first identifies children with acute weight loss or 'wasted', while the second includes both children with acute and chronic malnutrition ('wasted' and 'stunted').

  • Two categories of 'zinc dose' were used (20 mg and > 20 mg) as most trials used zinc 20 mg/day, and only two trials used more than 20 mg/day.

  • We added sex (male, female) as a subgroup as it was identified as a possible effect modifier (Garenne 2005).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Al-Sonboli 2003

MethodsRandomized controlled trial (RCT)
Participants

Number of participants (N): 81 participants

Inclusion criteria: age 3 to 60 months; diarrhoea < 7 days, or 1 or more loose stool containing blood in the previous 24 hours and at least mild dehydration

Exclusion criteria: suspected or confirmed severe systemic infections; antimicrobial or antidiarrhoeal treatment within 72 hours before admission; severe malnutrition (< 60% median for weight for age of the National Center for Health Statistic (NCHC) standards)

Interventions
  1. Zinc sulphate: 22.5 mg (3 to 6 months) or 45 mg (7 to 60 months).

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Stool frequency.

Notes

Location: Brazil

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used a random numbers table to randomize participants.
Allocation concealment (selection bias)Unclear riskThe trial authors did not provide any details regarding allocation concealment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThis trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk8.6% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no further information available.

Bahl 2002

MethodsRCT
Participants

N: 1219 participants

Inclusion criteria: age 6 to 35 months; acute diarrhoea (less than 4 days duration)

Exclusion criteria: visible blood in stools; likely to emigrate in the next 4 weeks; required hospitalization; previously enrolled; sibling concurrently enrolled; refusal of consent

Interventions
  1. Zinc gluconate 30 mg (≥ 12 months) or 15 mg (< 12 months).

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Diarrhoea at day 3.

  3. Diarrhoea at day 5.

  4. Diarrhoea at day 7.

  5. Stool frequency.

  6. Adverse events (vomiting).

Notes

Location: India

Setting: community

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThis trial used computer-generated randomization lists.
Allocation concealment (selection bias)Low riskAn independent individual who was not involved in participant enrolment labelled the glass bottles that contained the products with the participant’s number that corresponded to the randomization list. Randomization codes were secured until the completion of data collection and initial analysis. There was no difference between zinc and the placebo in appearance; a minor metallic aftertaste of zinc was hardly detectable.
Blinding (performance bias and detection bias)
All outcomes
Low riskFour-blinded (participant, intervention provider, data collector, data analyst).
Incomplete outcome data (attrition bias)
All outcomes
Low risk2% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no available protocol.
Other biasUnclear riskThere was no further information available.

Bhatnagar 2004a

MethodsRCT
Participants

N: 287 participants

Inclusion criteria: male; 3 to 36 months; acute diarrhoea (< 72 hours) with mild dehydration

Exclusion criteria: severe malnutrition (weight/height < 65% of NCHS median); visible blood in stool; severe systemic illness

Interventions
  1. Zinc sulphate: 15 mg (< 12 months) or 30 mg (> 12 months) syrup.

  2. Placebo.

Both groups: multivitamin

Outcomes
  1. Average duration of diarrhoea.

  2. Diarrhoea at day 5.

  3. Diarrhoea at day 7.

  4. Stool output.

  5. Adverse events (vomiting).

  6. Adverse events (copper levels).

Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial authors used a table of random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskCentral randomization was performed at a site remote from trial location (World Health Organization (WHO), Geneva).
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk7% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no available protocol.
Other biasUnclear riskThere was no further information available on other risks of bias.

Bhutta 1999

MethodsRCT
Participants

N: 87 participants

Inclusion criteria: 6 to 36 months; persistent diarrhoea (> 4 unformed stools/day for at least 14 days); malnutrition (weight-for-age z score < −2.0)

Exclusion criteria: kwashiorkor; clinical signs of vitamin A or zinc deficiency; needing intravenous fluids or unable to tolerate oral feeds after a 24-hour period of stabilization

Interventions
  1. Zinc sulphate: 3 mg/kg/day.

  2. Placebo.

Both groups: multivitamins

Outcomes
  1. Average duration of diarrhoea.

  2. Stool output.

  3. Adverse events (copper levels).

Notes

Location: Pakistan

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers table.
Allocation concealment (selection bias)Low riskAn independent pharmacy performed central randomization; the pharmacy maintained the table block randomization.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
High risk11% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no further information available.

Boran 2006

MethodsRCT
Participants

N: 280 participants

Inclusion criteria: acute diarrhoea of <14 days presenting at the paediatric emergency and outpatient clinic

Exclusion criteria: refusal of consent, malnutrition, medical condition requiring hospitalization, received anti-diarrhoea medication or antibiotics

Interventions
  1. 3 RDA zinc sulphate in a syrup once daily (15 mg zinc for 6 to 12 months children and 30 mg for 12 to 60 months) for 14 days + ORS.

  2. ORS.

Outcomes
  1. Duration of diarrhoea.

  2. Adverse events (vomiting).

NotesWe requested additional information from the trial author, but did not receive any reply
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used block randomization with 8 numbers in each block.
Allocation concealment (selection bias)Unclear riskThe trial did not mention these details.
Blinding (performance bias and detection bias)
All outcomes
High riskThere was no blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskFifteen participants (5.36%) were lost to follow-up
Selective reporting (reporting bias)Unclear riskThe trial authors did not include the RCT protocol registration number.
Other biasUnclear riskThere was no further information available on other sources of bias.

Brooks 2005a

MethodsRCT
Participants

N: 275 participants

Inclusion criteria: male, 1 to 6 months; onset < 72 hours; some dehydration or > 100 mL of watery stool within a 4-hour observation period

Exclusion criteria: clinical signs of zinc deficiency; kwashiorkor, weight/age < 60% NCHS; grossly bloody stool comorbidity; cholera

Interventions
  1. Zinc acetate: 20 mg.

  2. Zinc acetate: 5 mg.

  3. Placebo.

Outcomes
  1. Death.

  2. Average duration of diarrhoea.

  3. Stool output.

  4. Stool frequency.

  5. Adverse events (vomiting).

Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used a random numbers table to randomize participants to treatment.
Allocation concealment (selection bias)Unclear riskThe trial used bottles labelled with randomization numbers; but did not provide any other details.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk5% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no information available on other sources of bias.

Brooks 2005a (20 mg)

MethodsSee Brooks 2005a
ParticipantsN: 91 participants (5% lost to follow-up)
Interventions
  1. Zinc acetate: 20 mg.

  2. Placebo.

OutcomesSee Brooks 2005a
NotesSee Brooks 2005a
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Brooks 2005a for all descriptions.
Allocation concealment (selection bias)Unclear riskSee Brooks 2005a for all descriptions.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Brooks 2005a for all descriptions.
Incomplete outcome data (attrition bias)
All outcomes
Low risk5% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskSee Brooks 2005a for all descriptions.
Other biasUnclear riskSee Brooks 2005a for all descriptions.

Brooks 2005a (5 mg)

MethodsSee Brooks 2005a
ParticipantsN: 91 participants (7% lost to follow-up)
Interventions
  1. Zinc acetate: 5 mg.

  2. Placebo.

OutcomesSee Brooks 2005a
NotesSee Brooks 2005a
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Brooks 2005a for all descriptions.
Allocation concealment (selection bias)Unclear riskSee Brooks 2005a for all descriptions.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Brooks 2005a for all descriptions.
Incomplete outcome data (attrition bias)
All outcomes
Low risk7% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskSee Brooks 2005a for all descriptions.
Other biasUnclear riskSee Brooks 2005a for all descriptions.

Crisinel 2015

MethodsRCT
Participants

N = 148 participants

Inclusion criteria: children 2 months to 5 years of age, acute diarrhoea (3 or more stools a day for < 72 hours) at emergency department

Exclusion criteria: severe malnutrition (−3 standard deviations (SDs)), ongoing zinc treatment, overwhelming chronic medical condition, non-French speaking parents, hypersensitivity to component of zinc or placebo, phenylketonuria

Interventions
  1. Zinc tablets of 10 mg (children < 6 months) or 20 mg (children ≥ 6 months) once a day for 10 days plus ORS.

  2. Placebo plus ORS.

Outcomes
  1. Diarrhoea at day 3 and day 5.

  2. Adverse events (vomiting, difficulties in treatment administration).

NotesResults recorded as medians with IQR because data was not normally distributed.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskWHO performed block randomization.
Allocation concealment (selection bias)Low riskAn institutional pharmacy assigned a study number to each package of zinc or placebo.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe same packaging and dosage were used for the intervention and control groups.
Incomplete outcome data (attrition bias)
All outcomes
High riskOver 40% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThis RCT was not registered.
Other biasUnclear riskNo information.

Dalgic 2011

MethodsRCT
Participants

N: 120 participants

Inclusion criteria: 1 to 28 months and, on admission, stool positive for rotavirus antigen.  

Exclusion criteria: severe malnutrition (weight for height < −3SD as for WHO standards): duration of diarrhoea > 96 hours; severe dehydration; exclusively breast-feeding; toxic clinical appearance; immunosuppression; any known allergies to any drugs or foods.

Interventions
  1. Zinc 20 mg/day.

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Hospitalization.

Notes

Location: Turkey

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated.
Allocation concealment (selection bias)Unclear riskAllocation concealment was not specified.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial authors stated the trial was "single blind", but did not provide further details.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll children completed the study.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no further information available.

Dutta 2000

MethodsRCT
Participants

N: 80 participants

Inclusion criteria: male, 3 to 24 months; malnourished (< 80% Harvard Standard weight for age); clinical signs of dehydration

Exclusion criteria: antibiotics; systemic infections; chronic diseases; need for intensive care; exclusively breastfed

Interventions
  1. Zinc sulphate: 40 mg/day.

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Diarrhoea at day 5.

  3. Stool output.

Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskThe trial kept code numbers in a sealed envelope; zinc and placebo bottles were identical.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial did not specify the number of participants lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no further information available on other sources of bias.

Dutta 2011

MethodsRCT
Participants

N: 84 participants

Inclusion criteria: age 6 to 24 months, history of acute watery diarrhoea, moderate dehydration

Exclusion criteria: severe malnutrition (weight on height < −3SD WHO reference); systemic illness; chronic underlying disease (for example, tuberculosis, liver diseases) or needing intensive care; exclusively breastfed; antibiotics before enrolment or vitamin A within the previous 6 months

Interventions
  1. Zinc 20 mg/day.

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Diarrhoea at day 5.

  3. Stool output.

Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskThe trial kept code numbers in a sealed envelope; zinc and placebo bottles were identical.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe number of participants lost to follow-up was < 10%.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no further information available on sources of bias.

Fajolu 2008

MethodsRCT
Participants

N: 60 participants

Inclusion criteria: age 6 to 24 months; acute diarrhoea (less than 14 days duration)

Exclusion criteria: refusal of consent; protein energy malnutrition; use of stool hardeners, antimotility drugs ant antibiotics; other medical condition requiring hospitalization

Interventions
  1. Zinc sulphate 20 mg (>12 months) or 10 mg (< 12 months).

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Stool frequency.

Notes

Location: Nigeria

Setting: hospital (follow-up in the community)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial authors did not provide these details.
Allocation concealment (selection bias)Unclear riskThe trial authors did not provide these details.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial authors did not provide these details.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial authors did not specify the number of participants lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no further information available on other sources of bias.

Faruque 1999

MethodsRCT
Participants

N: 684 participants

Inclusion criteria: children 6 to 24 months with acute diarrhoea, some dehydration and no severe dehydration; underweight or stunted children were not excluded

Exclusion criteria: marasmus; kwashiorkor; systemic illnesses

Interventions
  1. Zinc acetate: 14.2 mg (first 417 children) or 40 mg (other 273 children randomized).

  2. Placebo.

Both groups: vitamin A

Outcomes
  1. Average duration of diarrhoea.

  2. Diarrhoea at day 7.

Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskThe trial used bottles serially numbered according to the randomization schedule to correspond to the serial number of the participant; a pharmaceutical company prepared the supplements and provided them in dark-coloured bottles.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk4% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no information available on other sources of bias.

Fischer Walker 2006

MethodsRCT
Participants

N: 1110 participants

Inclusion criteria: infants 1 to 5 months of age with acute diarrhoea (< 72 hours)

Exclusion criteria: severe malnutrition (< −3 z score weight for age); signs of pneumonia if < 2 months (cough and difficult or fast breathing with a respiratory rate of > 60 breaths/minute); signs severe pneumonia if 2 to 5 months of age (cough or difficult fast breathing and chest indrawing, nasal flaring, or grunting); required hospitalization (overnight stay at a healthcare facility) for any reason; known major congenital malformation; any other serious pre-existing medical condition; lived out of or planned to move out of study area within following 3 months; previously enrolled in the study

Interventions
  1. Zinc sulphate: 10 mg.

  2. Placebo.

Outcomes
  1. Death.

  2. Average duration of diarrhoea.

  3. Diarrhoea at day 7.

  4. Stool frequency.

  5. Hospitalization.

  6. Adverse events (vomiting).

Notes

Location: Ethiopia, India, and Pakistan

Setting: community

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskThe trial assigned the randomization scheme in Geneva and kept it secure until completion of data collection and initial analysis; upon enrolment, infants were assigned chronological study identifiers corresponding to a prelabelled blister pack of either zinc or placebo tablets.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk3% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no further information available on other sources of bias.

Fischer Walker 2006 ETH

MethodsSee Fischer Walker 2006
ParticipantsN: 177 participants (8% lost at follow-up)
InterventionsSee Fischer Walker 2006
OutcomesSee Fischer Walker 2006
NotesLocation: Ethiopia
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Fischer Walker 2006.
Allocation concealment (selection bias)Low riskSee Fischer Walker 2006.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006.
Incomplete outcome data (attrition bias)
All outcomes
Low risk8% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006.
Other biasUnclear riskSee Fischer Walker 2006.

Fischer Walker 2006 IND

MethodsSee Fischer Walker 2006
ParticipantsN: 373 participants (1% lost to follow-up)
InterventionsSee Fischer Walker 2006
OutcomesSee Fischer Walker 2006
NotesLocation: India
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Fischer Walker 2006.
Allocation concealment (selection bias)Low riskSee Fischer Walker 2006.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006.
Incomplete outcome data (attrition bias)
All outcomes
Low risk1% participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006.
Other biasUnclear riskSee Fischer Walker 2006.

Fischer Walker 2006 PAK

MethodsSee Fischer Walker 2006
ParticipantsN: 560 participants (3% lost to follow-up)
InterventionsSee Fischer Walker 2006
OutcomesSee Fischer Walker 2006
NotesLocation: Pakistan
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Fischer Walker 2006.
Allocation concealment (selection bias)Low riskSee Fischer Walker 2006.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Fischer Walker 2006.
Incomplete outcome data (attrition bias)
All outcomes
Low risk3% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskSee Fischer Walker 2006.
Other biasUnclear riskSee Fischer Walker 2006.

Jiang 2016

MethodsRCT
Participants

N: 103 participants

Inclusion criteria: children diagnosed with acute diarrhoea,duration within 48 hours, age 3 months to 3 years, rotavirus enteritis (colloidal gold method should be used to detect RV antigen expression) and informed consent

Exclusion criteria: mucous and bloody stool, stool routine shows white blood cells > 5 /high power field or red blood cells > 5 /high power field, total white blood cells > 12 × 109/L, C reactive protein > 10 mg/L, children with some underlying diseases such as congenital heart disease, hepatopathy and epilepsy

Interventions
  1. Zinc gluconate granules (10mg) in children 3 to 6 months, and 20 mg in children over 6 months.

  2. Microecologic products with some extra treatments for myocardial nutrients, protect liver, relieve cough, reduce phlegm, and improve microcirculation (vitamin C) for children with abnormal laboratory indexes.

Outcomes
  1. Duration of diarrhoea.

  2. Diarrhoea at day 3.

NotesNone
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial authors did not mention how allocation sequence was generated.
Allocation concealment (selection bias)Unclear riskThe trial authors did not mention how allocation concealment was conducted.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial authors did not mention how blinding was achieved for participants, intervention providers, and assessors.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThere was no loss to follow-up of participants.
Selective reporting (reporting bias)Unclear riskThere was no number of protocol registration.
Other biasUnclear riskThe trial was not registered.

Jin 2013

MethodsRCT
Participants

N: 103 participants

Inclusion criteria: 4 to 40 months of age; infants with acute rotavirus diarrhoea; parental consent

Exclusion criteria: not reported

Interventions
  1. Zinc gluconate (20 mg of zinc/day).

  2. Montmorillonite.

Outcomes
  1. Diarrhoea at day 3.

  2. Average number of hospitalization (days).

NotesWe requested additional information from the trial author, but received no reply
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThere was no mention of how random sequence was generated.
Allocation concealment (selection bias)Unclear riskThere was no mention of how allocation concealment was performed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskIt was unclear whether or not blinding was done.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThere was no loss of participants to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no RCT protocol registration number.
Other biasUnclear riskThere was no information available on other sources of bias.

Karamyyar 2013

MethodsRCT
Participants

N: 379 participants

Inclusion criteria: children aged 9 months to 5 years, admission to hospital with acute watery diarrhoea and moderate dehydration

Exclusion criteria: chronic diseases (cystic fibrosis, inflammatory bowel disease, malabsorption), severe malnutrition (weight curve under 3% for age), dysentery and bloody diarrhoea with red blood cells (RBCs) or white blood cells (WBCs) in stool, recent consumption of antibiotics, severe dehydration, persistent vomiting, consumption of zinc supplements (in the last month), drug intolerance, refusal to consent

Interventions
  1. Zinc supplementation (syrup 1ml/kg/day with 1 mg zinc sulphate divided into two doses) + ORS.

  2. ORS.

Outcomes
  1. Stool frequency.

NotesWe requested additional information from the trial author, but received no reply
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used computer-generated allocation sequence.
Allocation concealment (selection bias)Low riskA randomization list (simple randomly allocation of two group) was given to the pharmacist prior to enrolment. Randomization codes were secured until the completion of data collection and neither the physician, participants (or their parents), nor nurse were unaware of the drug or placebo.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe glass bottles that contained the products (zinc Sulfate or placebo) were labelled with participants’ code (with keeping the names of participants) by pharmacists who was not involved in the treatments. A placebo with similar taste, colour, and smell and with a similar option (1 mL/kg/day) was given to the control group.
Incomplete outcome data (attrition bias)
All outcomes
High risk15.5% of participants were lost to follow-up (> 10%).
Selective reporting (reporting bias)Low riskThe outcomes were reported according to the protocol. The RCT was registered (IRCT201201241580N2).
Other biasUnclear riskThere was no information available on other sources of bias.

Khatun 2001

MethodsRCT
Participants

N: 100 participants

Inclusion criteria: 6 to 36 months; moderately malnourished (61% to 75% of the median NCHS median weight for age); persistent diarrhoea

Exclusion criteria: systemic infection; clinical signs of vitamin A deficiency; received vitamin A supplementation within 3 months; received prior antibiotics therapy; bloody mucoid diarrhoea; kwashiorkor; no longer received breast milk

Interventions
  1. Zinc acetate: 20 mg.

  2. Placebo.

Both groups: multivitamins

Outcomes
  1. Death.

  2. Average duration of diarrhoea.

  3. Diarrhoea at day 7.

  4. Stool output.

  5. Adverse events (vomiting).

Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial authors did not provide these details.
Allocation concealment (selection bias)Unclear riskThe trial authors did not provide these details.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial authors did not provide these details.
Incomplete outcome data (attrition bias)
All outcomes
Low risk4% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no further information available on other sources of bias.

Larson 2005

MethodsRCT
Participants

N: 1067 participants

Inclusion criteria: children aged 3 to 59 months; acute diarrhoea; having taken ORS as instructed; no vomiting in the past 2 hours for the short-stay ward or 30 minutes in the outpatient clinic, and no longer dehydrated

Exclusion criteria: returning to the hospital with diarrhoea; receiving zinc

Interventions
  1. Zinc sulphate: 20 mg.

  2. Placebo.

Outcomes
  1. Adverse events (vomiting).

Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskThe trial used opaque envelopes, numbered, in which the assigned zinc tablet, placebo tablet, or a similar-sized button was placed; and kept the randomization schedule in a locked cabinet.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskThere was no information available on other sources of bias.

Passariello 2015

MethodsRCT
Participants

N: 83 participants

Inclusion criteria: children aged between 5 to 36 months, diarrhoea lasting less than 24 hours with mild-moderate dehydration

Exclusion criteria: malnutrition ( weight/height ratio) < 5th percentile), severe dehydration, concomitant severe or chronic systemic illness, immunodeficiency, cystic fibrosis, food allergy, chronic gastrointestinal disease, endocrine disease, use of pre/pro/symbiotic antibiotics, any anti-diarrhoea medication in the previous 3 weeks

Interventions
  1. Hypotonic super ORS containing zinc in a gel formulation.

  2. Standard hypotonic ORS.

Outcomes
  1. Duration of diarrhoea.

  2. Diarrhoea on day 3.

  3. Adverse events (vomiting).

NotesWe requested additional information from the trial authors, but received no reply
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used computer-generated randomization to assign participants to treatment.
Allocation concealment (selection bias)Low riskThe hospital pharmacy produced identical white aluminium fold sachets contained in a blank blinded code-labelled paper box for intervention and controls.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskWe requested additional information from the trial authors, but received no reply.
Incomplete outcome data (attrition bias)
All outcomes
Low riskThere was no loss of participants to follow-up.
Selective reporting (reporting bias)Unclear riskThe RCT was registered retrospectively (ACTRN12614000028606).
Other biasUnclear riskThere was no further information available on other sources of bias.

Patel 2009

MethodsRCT
Participants

N: 808 participants

Inclusion criteria: age 6 to 59 months; acute diarrhoea (duration up to 72 hours); ability to accept oral fluids or feeds  

Exclusion criteria: severe dehydration and unable to drink, chronic or severe complicating illness, known positive HIV status, kwashiorkor, residing outside a radius of 30 km around the hospital, participating in another study or already enrolled in this study

Interventions
  1. Zinc sulcates 2 mg/kg/day.

  2. Zinc sulphate 2 mg/kg/day + copper 0.2 mg/kg/day.

  3. Placebo.

Outcomes
  1. Death.

  2. Average duration of diarrhoea.

  3. Diarrhoea at day 3.

  4. Diarrhoea at day 5.

  5. Diarrhoea at day 7.

Notes

Location: India

Setting: hospital (follow-up in the community)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSingle-site, blocked randomization procedure with blocks of sizes 3, 6, and 9 in equal proportions.
Allocation concealment (selection bias)Low riskRandomization list generated off site by an investigator not directly involved in the data collection. The code list of the placebo and the treatment groups was secured and held only by the pharmacist at the Universal Medicaments Pvt. Ltd, Nagpur, until initial data analysis was completed.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: bottle packs sequentially labelled according to the treatment allocation list and assigned to participants by the research physician.
Incomplete outcome data (attrition bias)
All outcomes
Low risk7% lost at follow-up.
Selective reporting (reporting bias)Low riskThe protocol was available. The trial was registered in the metaRegister of Controlled Trials (ISRCTN85071383).
Other biasUnclear riskThere was no information available on other sources of bias.

Patel 2009a (zinc)

MethodsRCT
Participants

N: 808 participants

Inclusion criteria: age 6 to 59 months; acute diarrhoea (duration up to 72 hours); ability to accept oral fluids or feeds  

Exclusion criteria: severe dehydration and unable to drink,chronic or severe complicating illness, known positive HIV status, kwashiorkor, residing outside a radius of 30 km around the hospital, participating in another study or already enrolled in this study

Interventions
  1. Zinc sulphate 2 mg/kg/die.

  2. Zinc sulphate 2 mg/kg/die + copper 0.2 mg/kg/die.

  3. Placebo.

Outcomes
  1. Death.

  2. Average duration of diarrhoea.

  3. Diarrhoea at day 3.

  4. Diarrhoea at day 5.

  5. Diarrhoea at day 7.

Notes

Location: India

Setting: hospital (follow-up in the community)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Patel 2009.
Allocation concealment (selection bias)Low riskSee Patel 2009.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Patel 2009.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Patel 2009.
Selective reporting (reporting bias)Low riskSee Patel 2009.
Other biasUnclear riskSee Patel 2009.

Patel 2009b (zinc + copper)

MethodsSee Patel 2009a (zinc)
ParticipantsSee Patel 2009a (zinc)
InterventionsSee Patel 2009a (zinc)
OutcomesSee Patel 2009a (zinc)
NotesSee Patel 2009a (zinc)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Patel 2009.
Allocation concealment (selection bias)Low riskSee Patel 2009.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Patel 2009.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Patel 2009.
Selective reporting (reporting bias)Low riskSee Patel 2009.
Other biasUnclear riskSee Patel 2009.

Patel 2015

MethodsRCT
Participants

N: 100 participants

Inclusion criteria: children < 12 years (but all enrolled had ≤ 5 years), presentation to hospital with diarrhoea

Exclusion criteria: serious illness, intensive care admission, use of ventilators, impossibility of communication

Interventions
  1. Oral zinc sulphate (10 mg for < 6 months a day or 20 mg for ≥ 6 months) per 14 days + standard of care (ORS, intravenous fluid, antibiotics).

  2. Standard of care (ORS, intravenous fluid, antibiotics).

Outcomes
  1. Diarrhoea at day 3 and 5.

NotesWe requested additional information from the trial authors, but received no reply
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom sequence generation was computer generated.
Allocation concealment (selection bias)Unclear riskThe trial authors did not clearly describe allocation concealment.
Blinding (performance bias and detection bias)
All outcomes
High riskThis was an open label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low risk4% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no RCT registration number.
Other biasUnclear riskThere was no information on other sources of bias.

Patro 2010

MethodsRCT
Participants

N: 160 participants

Inclusion criteria: age 3 to 48 months diagnosed with acute diarrhoea lasting less than 5 days, with at least some degree of dehydration

Exclusion criteria: diarrhoea lasting <1 day or >5 days, recent history of diarrhoea (last 2 weeks before enrolment day), chronic gastrointestinal disease with diarrhoea manifestation, (for example, food allergy, coeliac disease), weight-to-height ratio < 5th percentile, severe dehydration, coexistence of serious systemic disease(s), coadministration of antibiotics, exclusive or > 50% breastfeeding, immunodeficiency, immunosuppressive therapy.

Interventions
  1. Zinc sulphate (20 mg in children > 6 months or 10 mg in children < 6 months).

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Diarrhoea at day 7.

Notes

Location: Poland

Setting: hospital (90% of children) and outpatient (10%)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAn investigator at the Medical University of Warsaw computer-generated 2 different randomization lists for each centre.  
Allocation concealment (selection bias)Low riskThe glass bottles containing the products were labelled with the participant’s number corresponding to the randomization list by an independent individual who was not involved in participant enrolment. Randomization codes were secured until the completion of data collection and initial analysis. The placebo was identically supplied and formulated. There was no difference between zinc and the placebo in appearance; a minor metallic aftertaste of zinc was hardly detectable.
Blinding (performance bias and detection bias)
All outcomes
Low riskInvestigators, participants, outcome assessors, and data analysts were blinded.
Incomplete outcome data (attrition bias)
All outcomes
High risk11.8% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no protocol available.
Other biasUnclear riskNote: the source of funding was Nutricia.

Penny 1999

MethodsRCT
Participants

Number: 413

Inclusion criteria: 6 to 36 months, persistent diarrhoea

Exclusion criteria: vitamins or minerals within 6 weeks; major congenital malformation affecting growth; severe dehydration; requiring hospitalization

Interventions
  1. Zinc gluconate: 20 mg.

  2. Placebo.

Outcomes
  1. Death.

  2. Hospitalization.

  3. Diarrhoea at day 3.

  4. Diarrhoea at day 5.

  5. Diarrhoea at day 7.

  6. Adverse events (vomiting).

Notes

Location: Peru

Setting: community

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used computer-generated random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskRandomization numbers were linked to letter codes, each indicating 1 treatment group; codes were kept secret; independent laboratories provided supplements.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskNo protocol was available.
Other biasUnclear riskNo information was available on other sources of bias.

Polat 2003

MethodsRCT
Participants

N: 200 participants

Inclusion criteria: 2 to 29 months; malnourished children (weight for age scale, score < 76% according to NCHS standards); acute non-bacterial diarrhoea

Exclusion criteria: concomitant illness or oedema

Interventions
  1. Zinc sulphate: 20 mg.

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Diarrhoea at day 3.

  3. Diarrhoea at day 7.

  4. Adverse events (vomiting).

Notes

Location: Turkey

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskBottles were labelled with randomization numbers.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk9% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskNo protocol was available.
Other biasUnclear riskNo information was available on other sources of bias.

Polat 2003 (low Zn)

MethodsSee Polat 2003
Participants

N: 76 participants

Children with low zinc serum levels

InterventionsSee Polat 2003
OutcomesSee Polat 2003
NotesSee Polat 2003
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Polat 2003.
Allocation concealment (selection bias)Low riskSee Polat 2003.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Polat 2003.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Polat 2003.
Selective reporting (reporting bias)Unclear riskSee Polat 2003.
Other biasUnclear riskSee Polat 2003.

Polat 2003 (normal Zn)

MethodsSee Polat 2003
Participants

N: 106 participants

Children with normal zinc serum levels

InterventionsSee Polat 2003
OutcomesSee Polat 2003
NotesSee Polat 2003
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSee Polat 2003.
Allocation concealment (selection bias)Low riskSee Polat 2003.
Blinding (performance bias and detection bias)
All outcomes
Low riskSee Polat 2003.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSee Polat 2003.
Selective reporting (reporting bias)Unclear riskSee Polat 2003.
Other biasUnclear riskSee Polat 2003.

Roy 1997

MethodsRCT
Participants

N: 111 participants
Inclusion criteria: 2 to 24 months; weight below the 76th centile of weight-for-age according to the NCHS standard 18 (by Gomez classification, protein energy malnutrition grades II and III included)

Exclusion criteria: systemic infection or oedema

Interventions
  1. Zinc acetate: 20 mg.

  2. Placebo.

Both groups: multivitamin

Outcomes
  1. Average duration of diarrhoea.

  2. Stool output.

Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used a table of random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskBottles were labelled with randomization numbers.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
High risk32.4% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskNo protocol was available
Other biasUnclear riskNo information was available on other sources of bias.

Roy 1998

MethodsRCT
Participants

N: 190 participants

Inclusion criteria: 3 to 24 months; persistent diarrhoea; underweight (low weight-for-age) using a cut-off of 70% weight/age of the 50th centile of the NCHS standard; wasted (low weight/height) using a cut-off of 80%; short (low height/age) using a cut-off of less than 95% of the height/age standard

Exclusion criteria: none stated

Interventions
  1. Zinc acetate: 20 mg.

  2. Placebo.

Both groups: multivitamin

Outcomes
  1. Death.

  2. Average duration of diarrhoea.

  3. Adverse events.

Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Unclear riskThe trial did not provide any details on allocation concealment.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIt was unclear whether or not any participants were lost to follow-up; 11% discontinued the intervention.
Selective reporting (reporting bias)Unclear riskNo protocol was available.
Other biasUnclear riskNo information was available on other sources of bias.

Roy 2008a

MethodsRCT
Participants

N: 56 participants

Inclusion criteria: aged 12 to 59 months; moderately malnourished (weight/age 61% to 75% of NCHS median); history suggestive of dysentery (for example, bloody-mucoid diarrhoea or febrile diarrhoea less than 5 days' duration); with culture-proven shigellosis

Exclusion criteria: severe malnutrition; receiving zinc supplementation; measles in the last 6 months; living beyond 2 hours of travel time; complications such as haemolytic uraemic syndrome or other systemic illness, including pneumonia, meningitis, and septicaemia

Interventions
  1. Zinc acetate: 10 mg.

  2. Placebo.

Both groups: multivitamins

Outcomes
  1. Death.

  2. Average duration of diarrhoea.

  3. Diarrhoea at day 7.

Notes

Location: Bangladesh

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used a table of random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskBottles were identical and labelled with sequential numbers that had earlier been allocated to either intervention or control according to the randomization.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
High risk11% of participants were lost to follow-up.
Selective reporting (reporting bias)Low riskThe trial was registered at ClinicalTrials.gov (NCT00321126).
Other biasUnclear riskNo information was available on other sources of bias.

Sachdev 1988

MethodsRCT
Participants

N: 50 participants

Inclusion criteria: children 6 to 18 months; dehydration secondary to acute diarrhoea of < 4 days' duration

Exclusion criteria: antibiotics; severe malnutrition (grades III and IV); concomitant features (meningitis, pneumonia, liver disease, otitis media, fever > 39°C)

Interventions
  1. Zinc sulphate: 20 mg.

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Stool frequency.

  3. Adverse events (vomiting).

Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial authors did not provide any details.
Allocation concealment (selection bias)Unclear riskThe trial authors did not provide any details.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial authors did not provide any details.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial authors did not provide any details.
Selective reporting (reporting bias)Unclear riskNo protocol was available.
Other biasUnclear riskNo information was available.

Sachdev 1990

MethodsRCT
Participants

N: 40 participants

Inclusion criteria: 6 to 18 months; persistent diarrhoea

Exclusion criteria: another diarrhoeal episode 1 month prior; critically ill; obvious parenteral infections; severe malnutrition (grade III and IV)

Interventions
  1. Zinc sulphate: 20 mg.

  2. Placebo.

Outcomes
  1. Average duration of diarrhoea.

  2. Stool frequency.

  3. Adverse events (vomiting).

Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial authors did not provide any details.
Allocation concealment (selection bias)Unclear riskThe trial authors did not provide any details.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial authors did not provide any details.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe trial authors did not provide any details.
Selective reporting (reporting bias)Unclear riskNo protocol was available.
Other biasUnclear riskNo information was available on other sources of bias.

Sazawal 1995

MethodsRCT
Participants

N: 947 participants

Inclusion criteria: 6 to 35 months; diarrhoea for 7 days; permanent resident in study area; stunted defined (length for age less than −2 SD)

Exclusion criteria: second visit; malnutrition requiring hospitalization; not provide consent

Interventions
  1. Zinc gluconate: 20 mg.

  2. Placebo.

Both groups: multivitamin

Outcomes
  1. Diarrhoea at day 7.

  2. Stool frequency.

  3. Adverse events (vomiting).

Notes

Location: India

Setting: hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskChildren were allocated to sequential numbers indicating zinc or placebo; the WHO kept the code, which was not available to the trial investigators.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk2% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskNo protocol was available.
Other biasUnclear riskNo information was available.

Shimelis 2008

MethodsRCT
Participants

N: 414 participants

Inclusion criteria: children 2 to 59 months, presented at the hospital with acute watery diarrhoea for less than 7 days

Exclusion criteria:children living far or unsafe areas for follow-up, children requiring antimicrobial for other conditions, immunocompromised (severely malnourished or with known primary immune deficiency) excluding cases of measles or those with HIV positive status, special fluid requirements (that is, renal disease, health hepatic failure), chronic or persistent diarrhoea and dysentery requiring hospitalization or admitted for in-patient care, on zinc supplementation, no consent

Interventions
  1. Zinc (2 tablets each containing 10 mg zinc) and ORS.

  2. ORS.

Outcomes
  1. Diarrhoea at day 5.

  2. Adverse events: vomiting.

NotesWe requested additional information from the trial author, but received no reply
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskThe trial used randomly selected days to assign participants to treatment.
Allocation concealment (selection bias)High riskThere was no randomization concealment since participants were randomized depending on the day they reported to the health facility.
Blinding (performance bias and detection bias)
All outcomes
High riskThis was an open label trial.
Incomplete outcome data (attrition bias)
All outcomes
Low risk3% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskThere was no RCT registration number. We requested additional information from the trial authors but received no reply.
Other biasUnclear riskThere was no information available on other sources of bias.

Strand 2002

MethodsRCT
Participants

N: 899 participants

Inclusion criteria: 6 to 35 months; diarrhoea < 96 hours

Exclusion criteria: massive dose of vitamin A; requiring hospitalization; family intended to leave Bhaktapur within 2 months

Interventions
  1. Zinc gluconate: 15 mg for infants; 30 mg for older children.

  2. Placebo.

Outcomes
  1. Diarrhoea at day 3.

  2. Diarrhoea at day 7.

  3. Adverse events (vomiting).

  4. Adverse events (copper levels).

Notes

Location: Nepal

Setting: community

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe trial used random numbers to assign participants to treatment.
Allocation concealment (selection bias)Low riskPacking with serial number; the list was kept in Copenhagen; capsules were identical in appearance; the syrup was identical in appearance and taste.
Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was double blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk1% of participants were lost to follow-up.
Selective reporting (reporting bias)Unclear riskNo protocol was available.
Other biasUnclear riskNo information was available.

Tran 2015

  1. a

    Abbreviations: N: number of participants; NCHS: National Center for Health Statistics; ORS: oral rehydration solution; RCT: randomized controlled trial; WHO: World Health Organization.

MethodsRCT
Participants

N: 76 participants

Inclusion criteria: children 6 months to 12 years,clinically diagnosed with diarrhoea and tolerate oral feed

Exclusion criteria: other gastrointestinal symptoms, history of gastrointestinal surgery with organic disease (excluding previous gastrostomy, pyloric stenosis), phenylketonuric or diabetic, taking gastric acid-neutralizing antacids, drugs to suppress gastric acid secretion or anti-diarrhoeal drugs, probiotics or zinc supplement, immunocompromised, proven sucrose intolerance, or previously participated in the study

Interventions
  1. ORS (Gastrolyte-R sachets) with zinc sulphate fortification (3 mg elemental zinc in total) to be mixed with 200 mL water for 4 days up to a maximum of 4 sachets in 24 hours).

  2. ORS (Gastrolyte-R sachets).

Outcomes
  1. Duration of diarrhoea.

NotesWe requested additional information from the trial author, but received no reply
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated random sequence.
Allocation concealment (selection bias)Unclear riskNot clearly described.
Blinding (performance bias and detection bias)
All outcomes
Low riskAll bottles packaged by the manufacturing pharmacy.
Incomplete outcome data (attrition bias)
All outcomes
High riskLost to follow-up in both study arms = 23.7% (> 10%).
Selective reporting (reporting bias)Unclear riskNo RCT registration number. We did not receive a response from the trial authors.
Other biasUnclear riskNo information available.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    Abbreviations: AIDS: acquired immune deficiency syndrome; HIV: human immunodeficiency virus; ORS: oral rehydration solution; RCT: randomized controlled trial.

Abraham 2016This study did not concern the intervention of interest to this review
Adu-Afarwuah 2007This study did not concern the intervention of interest (3 types of micronutrients for food fortification)
Adu-Afarwuah 2008This study did not concern the intervention of interest (zinc fortification)
Aggarwal 2007Randomized controlled trial (RCT) on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Agustina 2007This study did not concern the intervention of interest (probiotic, prebiotic, fibre, and micronutrient mixture)
Alam 2010Prevention study
Alarcon 2004A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Awasthi 2006This study did not concern the intervention of interest (zinc in oral rehydration solution (ORS))
Baqui 2002A community RCT without a placebo group
Baqui 2003A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Baqui 2006This study did not concern any outcome of interest (serum zinc) to this review
Baum 2010This study did not concern the population of interest (adults, HIV-positive)
Becquey 2016This study did not concern the intervention of interest to this review
Behrens 1990This study did not concern any outcome of interest (nutritional status)
Bhandari 2002A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Bhandari 2005This was not a RCT
Bhandari 2007A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Bhandari 2008A RCT without a placebo group
Bhatnagar 2004bThis was not a RCT
Bhutta 2000aThis study did not concern any outcome of interest (appetite)
Bilenko 2010This study did not concern the intervention of interest (multiple micronutrients in sprinkles)
Black 2001Not a RCT
Bobat 2005This study did not concern the population of interest (only children with HIV enrolled)
Borges 2007This was not a RCT
Brooks 2005bA RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Brown 2007This study did not concern the Intervention of interest (food fortification)
Bruzzese 2016This study did not concern the intervention of interest to this review
Chandyo 2010A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chang 2010A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chen 2010This study did not concern the intervention of interest (food fortification with multiple micronutrients)
Chhagan 2009A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Chhagan 2010A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Christian 2009A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, on a different population (pregnant women)
CIGNIS 2010This study did not concern the intervention of interest (food fortification with multiple micronutrients)
Colgate 2016This study did not concern the intervention of interest to this review
Coronel Carbajal 2000This was not a placebo-controlled RCT
Cross 2009Not a RCT
Cárcamo 2006This study did not concern the population of interest (adults with HIV)
Dhingra 2009Not a RCT
Doherty 1998This was not a placebo-controlled RCT, and the criterion for inclusion of children was malnutrition, not diarrhoea
Ebrahimi 2006Thist study did not concern any outcome of interest (growth) to this review
Ellis 2007Not a RCT
Ferraz 2007Not a RCT
Ferrufino 2007Not a RCT
Fischer Walker 2008Secondary analysis of a previously excluded study (Baqui 2002)
Gardner 2005Not a RCT
Garenne 2007A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Gebremedhin 2016This study did not concern the outcomes of interest to this review
Gregorio 2007This study did not concern the intervention of interest (zinc-fortified ORS)
Gupta 2003A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Gupta 2007A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Habib 2010A longitudinal cohort study
Habib 2013A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Heinig 2006This study did not concern any outcome of interest (growth, morbidity, and motor development)
Hess 2015A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Hettiarachchi 2008This study did not concern the population of interest (children 12 to 16 years), nor the outcomes
Hidayat 1998A community RCT, but we could not compare the results with other studies because of methodological problems (enrolling the same children more than once) and types of outcomes (episodes of diarrhoea and not children with diarrhoea)
Hoque 2006Not a RCT (review)
Hyder 2007This study did not concern the population of interest (adolescent girl), the intervention (multiple micronutrients), nor the outcomes
Iannotti 2010This study did not concern the population of interest (pregnant women)
Islam 2010This study did not concern the population of interest (preterm infants), nor any outcome of interest (growth)
Jimenez 2000This study did not concern any outcome of interest (growth)
Kelly 1999The intervention and the population (micronutrient supplementation in AIDS diarrhoea-wasting syndrome) considered in this RCT were not relevant to this review
Kelly 2010This study did not concern any outcome of interest (intestinal function) to this review
Kianmehr 2016This study did not concern any interventions of interest to this review
Larson 2010A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lin 2008This study was not placebo controlled, and did not report outcomes of interest (weight)
Lind 2004A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Lind 2008A secondary analysis of a previously excluded study (Lind 2004)
Lira 1998This study did not concern the population of interest (low birthweight infants)
Long 2006A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Long 2007A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (specific intestinal infections)
Lopez 2005This study did not concern the intervention of interest (multiple micronutrient), nor the outcomes (anaemia, micronutrient status, growth, and morbidity) of interest to this review
Luabeya 2007A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Makonnen 2003aThis study did not concern any outcome of interest to this review
Makonnen 2003bThis study did not concern any outcome of interest to this review
Manger 2008No placebo control, different intervention (multiple micronutrients), prevention study
Maragkoudaki 2016This study did not concern any intervention of interest to this review
Martinez-Estevez 2016This was a prevention study
Mazariegos 2010This study did not concern any outcome of interest (linear growth) to this review
Mazumder 2010This was a secondary analysis of a previously excluded study (Bhandari 2008)
Mda 2010This study did not concern a population of interest (only children with HIV), and used a different intervention (multiple micronutrient)
Meeks Gardner 1998A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Müller 2001A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Naheed 2009A secondary analysis of a previously excluded study (Baqui 2002)
Nasrin 2005Not a RCT
Negi 2014The study participants were above 5 years (age range 5 to 12 years)
Nga 2009A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Osendarp 2002A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Ouedraogo 2008A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Passariello 2010This study did not concern the intervention of interest (zinc in ORS) to this review
Patel 2005This study did not concern the intervention of interest (zinc and copper in ORS)
Patel 2010aSecondary analysis of an included study (Patel 2009), with no outcome of interest (by isolated microorganism)
Patel 2010bNot a RCT (review)
Patel 2012A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Penny 2004aA RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Penny 2004bNot a RCT
Polat 2006Not a placebo-controlled RCT
Prado 2016This study used a different intervention that was not of interest to this review
Rahman 2001A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rahman 2005This study did not concern any outcome of interest to this review
Raqib 2004This study did not concern any outcome of interest (immune and inflammatory responses) to this review
Richard 2006A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rollins 2007This study did not concern the population of interest (only HIV-infected children), and different outcomes (growth, immunity)
Rosado 1997A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Rosado 1998Not a RCT
Rosado 2009A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (specific intestinal infections)
Roy 1992This study did not concern any outcome of interest (intestinal permeability) to this review
Roy 1999A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Roy 2007A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Roy 2008bThis study did not concern the population of interest (children aged between 3 and 14 years)
Ruel 1997A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sabatier 1997Not a placebo-controlled RCT
Samuel 1995Not a RCT
Sazawal 1996A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 1997aA RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 2004A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sazawal 2007aThis study did not concern the intervention of interest to this review(milk fortification)
Sazawal 2007bThis study did not concern any outcome of interest to this review (plasma retinol)
Sazawal 2007cA RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Shamir 2005Different intervention (zinc and probiotics)
Shankar 1998Not a RCT (review)
Sharieff 2006A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sheikh 2010Not a RCT
Sur 2003A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Sáenz De Pipaón 2007Not a RCT (review)
Taneja 2009A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, in a different population (low birthweight infants)
Taneja 2010A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment, with different outcomes (growth)
Tielsch 2006A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Tielsch 2007A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Umeta 2000A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Untoro 2005This study did not concern the intervention of interest (multiple micronutrient), nor any outcome of interest to this review (anaemia, micronutrient status, growth, and morbidity)
Valery 2005This study did not concern the population of interest (all children aged under 11 years)
Veenemans 2011This was a prevention study
Wadhwa 2011This was a study on zinc-enriched ORS
Walden 2004Not a RCT
Walker 2007A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment
Wieringa 2010This study did not concern the population of interest to this review (pregnant women)
Winch 2006Not a RCT
Winch 2008Not a RCT
Wuehler 2008A RCT on zinc supplementation for prevention of diarrhoea episodes, not for diarrhoea treatment

Characteristics of ongoing studies [ordered by study ID]

NCT01140074

Trial name or titleEfficacy of zinc sulfate with probiotics for the treatment of acute diarrhoea in children
MethodsRCT
Participants

Inclusion criteria: age 1 to 36 months; a

cute diarrhoea defined as 3 or more watery stools per day; informed consent (parents)

Exclusion criteria: severe dehydration (> 10%); coexisting severe infection (for example, sepsis, pneumonia, meningitis); immune deficiency; chronic digestive tract disease (for example, coeliac disease, food allergy); on antibiotic therapy

Interventions
  1. Zinc sulphate 10 to 20 mg per day orally plus probiotics.

  2. Zinc sulphate 10 to 20 mg per day orally.

  3. Placebo.

Outcomes
  1. Period of diarrhoea in hours (time frame: 15 days) (designated as safety issue: no).

  2. Number of stools in consequent days (time frame: 15 days).

  3. Hospitalization.

  4. Tolerability.

  5. Adherence to the therapy.

Starting dateJuly 2010 (not yet recruiting in December 2010)
Contact information

Contact: Leszek Szenborn, Prof szenborn@zak.am.wroc.pl (principal investigator)

Contact: Ernest P. Kuchar, MD kuchar@zak.am.wroc.pl

Notes

Location: Poland

Registration number: NCT01140074

Source of funding: unclear

Sponsor: University Hospital No 1 Wroclaw

NCT01198587

  1. a

    Abbreviations: MD: medical doctor; RCT: randomized controlled trial.

Trial name or titleA double blind randomized placebo controlled trial of oral zinc for children with acute diarrhoea in a developed nation
MethodsRCT
Participants

Inclusion criteria

  • Healthy children with non-bloody diarrhoea illness defined as loose or watery stools.

  • Symptoms must be present for greater than 24 hours but less than 72 hours.

  • Comorbid conditions including: asthma, gastroesophageal reflux (unless followed by a gastroenterologist), mild speech, language, motor delays, benign heart murmurs, isolated atrial septal defect (ASD) or ventricular septal defect VSD, epilepsy (unless developmentally delayed), children born prematurely between 33 to 37 weeks without long term sequelae, repaired tetralogy of Fallot (no cardiac issues for > 6 months), diabetes may be enrolled in the study.

Exclusion criteria

  • Children with symptoms less than 24 hours.

  • Children with symptoms greater than 24 hours.

  • Failure to thrive.

  • G or J tube.

  • Major surgery within last 3 months.

  • Minor surgery (e.g. tonsillectomy, ear tubes, skin lesion removal) within last 1 month.

  • Followed by gastrointestinal service for any reason (Crohn, ulcerative colitis, constipation.

  • Developmental delay, patient > 1 year behind milestones.

  • Current brain tumour.

  • Currently being treated for cancer or in remission < 6 months.

  • Intussuception.

  • Antibiotics in the last 14 days or currently taking antibiotics for any reason.

  • Autism.

  • Children born premature < 33 weeks.

  • Cystic fibrosis.

  • Major congenital heart disease (any disease where child's baseline oxygen saturations < 93%).

  • Short gut.

  • Liver disease.

  • History of bowel resection.

Age minimum: 6 months
Age maximum: 6 years
Gender: both

Interventions
  1. Zinc sulfate:

    1. for children aged 6 months to 1 year, 12.5 mg orally daily for 14 days mixed in 60 mL of fluid;

    2. for children aged 1 year and above 25mg orally daily for 14 days mixed in 60 mL of fluid.

  2. Placebo.

Outcomes
  1. Duration of diarrhoea in acute diarrhoeal illnesses in a developed nation while taking zinc or placebo (time frame: 14 days)

Starting dateSeptember 2010
Contact information

Michelle L Niescierenko, MD

michelle.niescierenko@childrens.harvard.edu

Children's Hospital Boston

Notes

Location: USA

Registration number: NCT01198587

Source of funding: unclear

Sponsor: Children's Hospital Boston