Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young North Indian children
Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young North Indian children
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DOI：
10.1542/peds.109.6.e86
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发表时间：
2002-06-01
期刊：
影响因子：
8
通讯作者：
Bhan, MK
中科院分区：
文献类型：
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作者：
Bhandari, N;Bahl, R;Bhan, MK
Objective.评价每日补锌4个月对6 ~ 30个月儿童重度和复发性腹泻发病率的影响。对居住在新德里Dakshinpuri城市贫民窟的6 ~ 30个月的儿童进行了一项双盲、随机、安慰剂对照试验。他们被随机分配每天接受葡萄糖酸锌（婴儿10毫克，年龄较大的儿童20毫克）或安慰剂。一名现场服务员每天在家里服用糖浆，持续4个月，除了星期天，当时母亲这样做。一瓶含250 mL的药物保存在儿童家中，每月更换一次。在4个月的跟踪期间，实地工作人员每隔7天访问一次家庭。在每次访视时，获得前7天的发热史、粪便数量和粘稠度以及是否存在咳嗽的信息。当孩子生病时，确定疾病特征和寻求家庭外的治疗。如果孩子出现腹泻或呕吐，则评估脱水。在家访时，当一名儿童腹泻时，给予2包口服补液盐。根据标准国家项目指南，对因疾病自发前往研究诊所或由现场工作人员转诊的儿童进行治疗。抗生素仅用于腹泻伴血便或相关疾病。为了使用广义估计方程对腹泻等复发事件进行纵向分析，将每名儿童的随访数据分为17个儿童期，每个儿童期7天，并对每个7天期内是否发生腹泻或重度腹泻事件进行编码。这种分析方法不假设事件的独立性，因此可以防止由于同一儿童发病率的相关性而导致的方差低估。然后用具有可交换相关协方差-方差矩阵的Logistic广义估计方程模型估计效应量。在4个月随访期间，分别在88.8%和91.2%的研究日给予锌或安慰剂剂量。锌组的平均呕吐天数略有增加，但具有显著性（4.3 [标准差（SD）：5.8] vs 2.6 [SD 3.9]天;平均值差异：1.7 [95%置信区间（CI）：1.3-2.1]天）。基线时，锌组的平均血浆锌为62.0 mug/dL（标准差：14.3 mug/dL），安慰剂组为62.0 mug/dL（标准差：11.2 mug/dL）;分别有45.8%和42%的患者血浆锌水平低于60 mug/dL。研究结束时，锌组的血浆锌水平显著较高（几何平均值比：1.94 [95% CI：1.86-2.03]），血浆锌水平较低的比例较低（比例差异：-46.7% [95% CI：-41.8%至-51.4%]）。与安慰剂组相比，补锌组随访期间腹泻的发生率较低（比值比[OR]：0.88; 95% CI：0.82-0.95）。锌对腹泻发生率的有益影响更大，持续时间逐渐增加：腹泻发作持续1至6天（OR：0.92; 95%CI：0.85-1.00）、7至13天（OR：0.79; 95%CI：0.65-0.95）和> 14天（OR：0.69; 95%CI：0.48-0.98）。对排便频率逐渐升高的发作发生率的影响也更大：每天排便3至5次（OR：0.90; 95% CI：0.83-0.98），每天排便6至9次（OR：0.87; 95% CI：0.77-0.98），每天> 10次（OR：0.77; 95% CI：0.63-0.94）。在锌组中，在研究期间有更多的儿童没有出现腹泻发作（风险比[RR]：1.22; 95%CI：1.02-1.44）。此外，与安慰剂组的儿童相比，显著更少的儿童（RR：0.51; 95%CI：0.36-0.73）经历了复发性腹泻，定义为在随访期间>6次腹泻发作。锌治疗组因任何原因住院的儿童人数往往较低，但差异无统计学意义（1.79% vs 2.43%; RR：0.74; 95%CI：0.43-1.27）。两组的基线平均血浆铜（mug/dL）相似（平均值差异：1.6; 95% CI：-2.9至6.1）。锌组研究结束时血浆铜水平显著较低（平均差异：-15.5; 95% CI：-19.9至-11.1）。锌的补充大大降低了严重和长期腹泻的发生率，这是与腹泻有关的死亡率和营养不良的两个重要决定因素。这项干预措施还大大降低了反复腹泻的儿童比例。应及时采取措施改善缺锌人群的锌营养状况。实现这一目标的潜在办法包括食品强化、饮食多样化、种植锌含量高或锌吸收抑制剂浓度低的植物，以及为选定的儿童群体提供补充剂。未来的研究应评估增加锌摄入量对发展中国家儿童死亡率的影响。为了便利干预，需要获得对缺锌的可靠估计，特别是在发展中国家。不同剂量的锌对血浆铜水平的影响的功能后果值得进一步研究。
Objective. To evaluate the impact of 4 months of daily zinc supplementation on the incidence of severe and recurrent diarrhea in children 6 to 30 months of age.Methods. A double-blind, randomized, placebo-controlled trial was conducted on children who were identified by a door-to-door survey to be aged 6 to 30 months and residing in the urban slum of Dakshinpuri, New Delhi. They were randomized to receive daily zinc gluconate (elemental zinc 10 mg to infants and 20 mg to older children) or placebo. A field attendant administered the syrup daily at home for 4 months except on Sundays, when the mother did so. One bottle that contained 250 mL was kept in the child's home and replaced monthly. Field workers visited households every seventh day during the 4-month follow-up period. At each visit, information was obtained for the previous 7 days on history of fever, number and consistency of stools, and presence of cough. When the child was ill, illness characteristics and treatment seeking outside the home were determined. If the child had diarrhea or vomiting, then dehydration was assessed. At household visits, 2 packets of oral rehydration salts were given when a child had diarrhea. Children who visited the study clinic spontaneously for illness or were referred by the field workers were treated according to the standard national program guidelines. Antibiotics were advised only for diarrhea with bloody stools or for associated illnesses. For using generalized estimating equations for longitudinal analysis of a recurring event such as diarrhea, the follow-up data for each child was divided into 17 child-periods of 7 days each and presence or absence of an incident episode of diarrhea or severe diarrhea within each 7-day period was coded. This method of analysis does not assume independence of events and therefore prevents underestimation of variance that results because of correlation of morbidity within the same child. A logistic generalized estimating equations model with exchangeable correlation covariance-variance matrix was then used to estimate the effect size.Results. Zinc or placebo doses were administered on 88.8% and 91.2%, respectively, of study days during the 4 months of follow-up. There was a small but significant increase in the average number of days with vomiting in the zinc group (4.3 [standard deviation (SD): 5.8] vs 2.6 [SD 3.9] days; difference in means: 1.7 [95% confidence interval (CI): 1.3-2.1] days). At the baseline, mean plasma zinc was 62.0 mug/dL (SD: 14.3 mug/dL) in the zinc and 62.0 mug/dL (SD: 11.2 mug/dL) in the placebo group; 45.8% and 42%, respectively, had low plasma zinc levels below 60 mug/dL. At the end of the study, plasma zinc levels were substantially higher in the zinc group (ratio of geometric means: 1.94 [95% CI: 1.86-2.03]) and the proportion with low plasma zinc was lower (difference in proportions: -46.7% [95% CI: -41.8% to -51.4%]). The incidence of diarrhea during follow-up was lower in the zinc-supplemented as compared with the placebo group (odds ratio [OR]: 0.88; 95% CI: 0.82-0.95). The beneficial impact of zinc was greater on the incidence of diarrhea with progressively increasing duration: episodes of diarrhea that lasted 1 to 6 days (OR: 0.92; 95% CI: 0.85-1.00), 7 to 13 days (OR: 0.79; 95% CI: 0.65-0.95), and > 14 days (OR: 0.69; 95% CI: 0.48-0.98). The impact was also greater on the incidence of episodes with progressively higher stool frequency: 3 to 5 stools per day (OR: 0.90; 95% CI: 0.83-0.98), 6 to 9 stools per day (OR: 0.87; 95% CI: 0.77-0.98), and > 10 per day (OR: 0.77; 95% CI: 0.63-0.94). In the zinc group, significantly more children experienced no diarrheal episode during the study period (risk ratio [RR]: 1.22; 95% CI: 1.02-1.44). Furthermore, substantially fewer children (RR: 0.51; 95% CI: 0.36-0.73) experienced recurrent diarrhea, defined as >6 diarrheal episodes in the follow-up period as compared with children in the placebo group. The number of children who were hospitalized for any cause tended to be lower in the zinc group, but the difference was not statistically significant (1.79% vs 2.43%; RR: 0.74; 95% CI: 0.43-1.27). The baseline mean plasma copper ( mug/dL) was similar in the 2 groups (difference in means: 1.6; 95% CI: -2.9 to 6.1). The end study plasma copper levels were significantly lower in the zinc group (difference in means: -15.5; 95% CI: -19.9 to -11.1).Conclusions. Zinc supplementation substantially reduced the incidence of severe and prolonged diarrhea, the 2 important determinants of diarrhea-related mortality and malnutrition. This intervention also substantially reduced the proportion of children who experienced recurrent diarrhea. Prompt measures to improve zinc status of deficient populations are warranted. The potential approaches to achieve this goal include food fortification, dietary diversification, cultivation of plants that are zinc dense or have a decreased concentration of zinc absorption inhibitors, and supplementation of selected groups of children. Future studies should assess the impact of increased zinc intakes on childhood mortality in developing countries. For facilitating intervention, there is a need to obtain reliable estimates of zinc deficiency, particularly in developing countries. The functional consequences of the effect of various doses of zinc on plasma copper levels merits additional study.