联合益生菌治疗小儿胃肠炎的多中心试验

Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis

The New England Journal of Medicine(2018)

DOI 10.1056/NEJMoa1802597

Abstract

Background: Gastroenteritis accounts for approximately 1.7 million visits to the emergency department (ED) by children in the United States every year. Data to determine whether the use of probiotics improves outcomes in these children are lacking.

Methods: We conducted a randomized, double-blind trial involving 886 children 3 to 48 months of age with gastroenteritis who presented to six pediatric EDs in Canada. Participants received a 5-day course of a combination probiotic product containing Lactobacillus rhamnosus R0011 and L. helveticus R0052, at a dose of 4.0×10^9 colony-forming units twice daily or placebo. The primary outcome was moderate-to-severe gastroenteritis, which was defined according to a post-enrollment modified Vesikari scale symptom score of 9 or higher (scores range from 0 to 20, with higher scores indicating more severe disease). Secondary outcomes included the duration of diarrhea and vomiting, the percentage of children who had unscheduled physician visits, and the presence or absence of adverse events.

Results: Moderate-to-severe gastroenteritis within 14 days after enrollment occurred in 108 of 414 participants (26.1%) who were assigned to probiotics and 102 of 413 participants (24.7%) who were assigned to placebo (odds ratio, 1.06; 95% confidence interval [CI], 0.77 to 1.46; P=0.72). After adjustment for trial site, age, detection of rotavirus in stool, and frequency of diarrhea and vomiting before enrollment, trial-group assignment did not predict moderate-to-severe gastroenteritis (odds ratio, 1.06; 95% CI, 0.76 to 1.49; P=0.74). There were no significant differences between the probiotic group and the placebo group in the median duration of diarrhea (52.5 hours [interquartile range, 18.3 to 95.8] and 55.5 hours [interquartile range, 20.2 to 102.3], respectively; P=0.31) or vomiting (17.7 hours [interquartile range, 0 to 58.6] and 18.7 hours [interquartile range, 0 to 51.6], P=0.18), the percentages of participants with unscheduled visits to a health care provider (30.2% and 26.6%; odds ratio, 1.19; 95% CI, 0.87 to 1.62; P=0.27), and the percentage of participants who reported an adverse event (34.8% and 38.7%; odds ratio, 0.83; 95% CI, 0.62 to 1.11; P=0.21).

Conclusions: In children who presented to the emergency department with gastroenteritis, twice-daily administration of a combined L. rhamnosus-L. helveticus probiotic did not prevent the development of moderate-to-severe gastroenteritis within 14 days after enrollment. 

在美国，每年约有170万儿童因肠胃炎前往急诊科就诊。尽管越来越多的消费者使用益生菌来治疗肠道感染，但益生菌的疗效并没有的到充分验证。大多数已发表的益生菌研究在方法学或样本量上存在局限性、对致病菌的调查有限、且未报告不良事件。

本研究旨在评估益生菌在3 - 48个月大的急性胃肠炎患儿中的有效性，借以阐明益生菌在儿童急性胃肠炎门诊治疗中的意义。 

研究对象：3至48个月大的加拿大婴幼儿

入组标准：前往急诊科就医的3至48个月的婴幼儿；在24小时内出现三次或三次以上的水样大便；在少于72小时内有呕吐或腹泻症状；由医生确诊为急性肠胃炎；排除有留置的血管通路导管的患儿或其家庭成员有留置血管通路导管的患儿；排除患有结构性心脏病、免疫功能受损或正在接受免疫抑制治疗的患儿；排除有便血、胆汁性呕吐、慢性胃肠疾病(如炎症性肠病或短肠综合征)、胰腺功能障碍或功能不全的患儿；排除前14天使用益生菌、对大豆过敏以及无法完成随访的患儿；排除前7天内接受过口腔或胃肠道手术或以前参与过试验的患儿。

实验方法：这是一项多中心、随机、双盲试验，涉及886名3 - 48个月大的胃肠炎患儿。参与者被随机分为对照组和益生菌组，对照组接受安慰剂治疗，益生菌组接受每天两次的联合益生菌治疗（含有4X10^9 CFU的鼠李糖乳酸杆菌Lactobacillus rhamnous R0011和瑞士乳酸杆菌 Lactobacillus helveticus R0052，两种菌株比例为95：5），治疗为期5天并在急诊科完成。研究人员收集了人口统计学和临床特征数据，父母或监护人每24小时完成一次电子或电话随访调查，直到受试者呕吐和腹泻症状停止24小时。研究人员在受试者入组时采集直肠拭子或粪便标本，或两者皆采。样本进行细菌培养及15种肠道细菌、病毒和寄生虫检测。

检测方法：细菌培养和多重核酸面板检测

研究结论：

• 在因胃肠炎而就诊于急诊科的儿童中，每日 2 次给予联合鼠李糖乳杆菌和瑞士乳杆菌不能预防入组后 14 天内中重度胃肠炎的发生；

• 对照组和益生菌组在腹泻和呕吐的持续时间上没有显著差异；

• 对照组和益生菌组在总腹泻发作次数上没有显著差异，但益生菌组的总呕吐发作次数明显高于对照组；

• 尽管益生菌的使用只做了了单一剂量，但所选数值高于厂家的推荐数值，并且在保质期结束时，益生菌的数量仍在目标范围内，因此不存在剂量过低导致疗效不明显的问题；

• 本研究的局限在于无法排除回忆偏差，益生菌菌株的选择和单一的剂量以及地域差异使本研究的结果不具备普适性。

Figure 2. Episodes of Diarrhea and Vomiting, According to Trial Group. Shown are the mean numbers of episodes of diarrhea (Panel A) and vomiting (Panel B) per 24‐hour period after enrollment. Data on all participants are included, irrespective of the number of vomiting episodes that occurred before enrollment. I bars denote the standard error. 

图2. 试验组腹泻和呕吐的发作次数。图中所示为入组后24小时内腹泻(A图)和呕吐(B图)的平均发作次数。所有参与者的数据都包括在内，与入组前发生的呕吐次数无关。I条表示标准误差。

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