| Diarrhea disease is the major cause for maldevelopment, malnutrition and death of children under 5 years old. The development of diarrhea disease is closely associated with physical and pathological features of children, infection, improper diet, and their low immune ability. Although the popularization of Diagnostic and Therapeutic Guide for Diarrhea Disease decreased the mortality of infantile diarrhea, such disease was still one of the main reasons leading to death of children under 5 years old. Therefore, a simple, convenient, effective and inexpensive therapeutic regimen was required in clinical. Traditional Chinese medicine cherished long history and effectiveness in treating infantile diarrhea disease, besides its characteristics and advantages. In order to make an objective evaluation on TCM therapeutic effect and analyze problems and strategies in clinical studies, we conducted a relevant research in these fields at the guide of evidence-based medicine, adopting its methods and thoughts.1. Literature researches1.1 Object:Writer summary TCM and modern medicine recognition on infantile diarrhea, elaborate necessity and feasibility of evidence-based medicine methodology application in Chinese medicine treatment for infantile diarrhea.1.2 Results:(1)TCM believed diarrhea was a disease with the symptoms of loose stool or watery stool and frequent defecation caused by functional disorder of spleen and stomach. In TCM theory, the causes of diarrhea are exogenous pathogenic evil, importer diet, or deficiency of both spleen and stomach more often, and the diseased part locates at spleen and stomach. ZHANG Jing-yue, a famous doctor of Ming dynasty, explored the pathogenesis of diarrhea:"The fundamental cause for diarrhea is the dysfunction of spleen and stomach. Stomach is the sea of water and cereals and spleen is in charge of transportation and transformation. If the functions of spleen and stomach are normal, intake cereals will be digested well and transformed into essence-qi and blood, supplementing Ying qi and Wei qi; while if the functions of spleen and stomach are damaged by improper diets or irregular daily life, water will be turn into pathogenic dampness, cereals will be transformed into stagnation, and essence qi will not be transformed and transported, leading to diarrhea together with filthy things." (JingYue QuanShu). LI Zhong-zhi, a famous doctor of Ming dynasty, made a fully summarization about the treatments of diarrhea on the experiences of his predecessors:"there are nine kinds of major therapeutic methods for diarrhea, which are inducing urine with mild taste medicines, lifting, cooling, dispersing, relaxing with sweet taste medicines, astringing with sour taste medicines, drying spleen, warming kidney and consolidating", manifesting important clinical values for the development of diarrhea therapeutics.There were many kinds of effective therapeutic methods for diarrhea in TCM, including internal medicine, such as treatment based on syndrome differentiation, and external medicine, such as acupuncture, moxibustion, massage, acupoints-application and others. Boosting of agility and few side-effects, TCM has a broad feature for the treatment of infantile diarrhea.(2)Modern medicine considered the development of infantile diarrhea was associated with the features of infant and the factors of infection, diet, immune function. The pathological mechanism of this disease could be summarized into the following four types:osmotic diarrhea, secretory diarrhea, exudative diarrhea and motility disturbance diarrhea. However, now the relative etiological factor, pathological mechanism, pathophysiology were not yet fully understood.Intestinal microecology may have an important significance on the development of infantile diarrhea. The disorder of intestinal microecology balance of infants mainly manifested as the following:one is the serious imbalance of normal proportion of each microbial population due to decreased number of probiotics mainly as Bacillus bifidus; the other is the diseases resulted from normal enteric flora transfer and mass multiplication and growth of some opportunists (mainly as transient flora). Once abnormal changes of kinds, number, and proportion of intestinal flora occurred, they would deviated from normal physiological composition and thansformed into pathologic composition, thus alteration of intestinal flora occurred and in turn resulted in many diseases. Pediatric acute and chronic diarrhea might be both closely associated with alteration of intestinal flora.(3) The necessity of systemic evaluation of Chinese medicine efficacy with Evidence-based medicine methodology is that the methodology characteristics of systemic evaluation advocated by evidence-based medicine was suited to the requirements of the development law of Traditional Chinese Medicine, and there was an urgent need to perform objective evaluation of Chinese medicine efficacy by new research methods for reference; and its feasibility lies on a sufficient number of clinical trials on Chinese medicine were available for the systemic evaluation and there has been some of examples for performing relevant practice.1.3 ProblemsIn the literature of today, there were more experience reports but few clinical studies. And randomized control clinical trials were more less and had unreasonable design and many problems in term of randomization, blind design, selection of control group, inclusion and exclusion criteria of subjects and selection of end point, also whose relative clinical effects were poorly reproduced or could not bear the test of practice again.2. Evidence-based Medicine Research2.1 Object:Writer performed a systemic review of the effect of Eliminating Dampness on clinical efficacy and its antidiarrheal time in infantile acute nonbacterial diarrhea treatment, effect of Dioctahedral smectite on clinical efficacy and its antidiarrheal time in infantile nonbacterial diarrhea treatment. So as to provide the basis on Evidence-based medicine of dioctahedral smectite as control, treatment effect of Chinese Herbal used Eliminating Dampness compound massage for diarrhea in children.2.2 Methods:Writer collected documents,evaluated the quality of the literature and extracted data. On the time, writer used software RevMan 4.2.10 provided by Cochrane Collaboration to do Meta-analysis.2.3 Results:(1)Total 28 literatures were included in the systemic evaluation of Chinese herbal medicine belonging to Therapeutic Principle of Eliminating Dampness in treatment of infantile acute nonbacterial diarrhea, and by the meta-analysis of which we found that:①In the superiority-inferiority assessment with clinical efficacy as evaluation indexes conducted in 27 literatures, results of 16 literatures revealed the efficacy of Chinese Medicine according to Eliminating Dampness for infantile diarrhea treatment was superior to Dioctahedral smectite, while the results of the other 11 literatures denied this opinion.②In 5 literatures used antidiarrheal time as the evaluation index, results of 3 literatures revealed the efficacy of Chinese Medicine according to Eliminating Dampness for infantile diarrhea treatment was superior to Dioctahedral smectite, while the results of the other 2 literatures was opposite to this. Although all literature had report bias, in general, these literatures had little bias. In short, Chinese herbal medicine belonging to Therapeutic Principle of Eliminating Dampness possessed the exact curative effect in infantile acute nonbacterial diarrhea treatment.(2) A preliminary analysis of therapeutic method and the rules for Chinese medicine application in the 28 literatures included in the study. The therapeutic principle mainly was Activating Spleen and Removing Dampness, which was combined with the therapeutic method of Clearing Heat, Eliminate stasis, Dispelling Wind, or Astringe. For herbs prescription and application, the medicine type most widely and frequently used is herbs with the function invigorating spleen and stomach, dissipating dampness, which were in turn Poria (18 times,64.29%), Atractylodes macrocephala Koidz (10 times,35.71%), Atractylodes Polysaccharides (8 times,28.57%), Agastache rugosa (8 times, 28.57%); and other herbs with the function of invigorating spleen included Codonopsis lanceolata or Radix pseudostell (total 7 times), Chinese Yam (4 times), Astragalus (3 times), parched hyacinth bean (2 times); other herbs with the function of removing dampness by promoting diuresis included plantain seed (5 times), Alisma orientale Juzepcz (3 times), prepared Pinellia tuber (3 times), Polyporus (2 times); and simultaneous application of Poria and Polyporus appeared in 8 articles, according to 28.57% of total. The medicine type followed above in term of application extent was Regulating Qi Activity, which included 6 herbs, among them, tangerine peel is most frequently used for 6 times (21.34%), followed by Magnolia officinalis (3 times,10.71%), Radix Aucklandiae (2 times,7.14%), and one time of villous amomum fruit, Cyperus rotundus L., and bitter orange. Five herbs with Astringe function were used, including charred Fructus Crataegi (4 times),3 times of Pomegranate Rind and myrobalan,2 times of guava leaf and halloysitum rubrum. Also the drugs for Remove Stagnated Food and Promote Digestion were used more often, such as roasted byne (5 times), endothelium corneum gigeriae galli (4 times), medicated leaven (3 times), oriental latrine fly larvina (1 time). We concluded that the rule of herbs application revealed in this study was consisted with the etiology and pathogenesis of infantile diarrhea.(3) Dioctahedral smectite appeared exact clinical efficacy in infantile diarrhea treatment, but there were different results in literatures in term of which therapy was superior when compared with Chinese Herbal Compound. In the superiority-inferiority assessment with clinical efficacy as evaluation indexes, the results of systemic evaluation of 11 independent literatures showed the effects of oral Dioctahedral smectite was significantly different when compared with non-drug therapy in Chinese medicine and blank control group, which indicated exact effect of Dioctahedral smectite in infantile diarrhea treatment; however, the results of 60 independent literatures revealed there was no significant difference for clinical efficacy of oral Dioctahedral smectite in infantile diarrhea compared with Western and Chinese medicine or blank control group, and the clinical effect of Dioctahedral smectite in infantile diarrhea treatment was not obviously different to management of Chinese medicine and Western medicine, and had no any treatment advantages; In analysis used antidiarrheal time as the evaluation index, results of systemic evaluation of 6 independent literatures revealed that oral Dioctahedral smectite could significantly decrease the duration of infantile diarrhea compared with non-drug therapy in Chinese medicine and blank control group, which indicated exact effect of reducing duration of infantile diarrhea of Dioctahedral smectite; and the results of 22 independent literatures showed there was no significant difference for decrease of infantile diarrhea duration of oral Dioctahedral smectite compared with Western and Chinese medicine or blank control group, and the decrease of infantile diarrhea-duration of Dioctahedral smectite was not obviously different to management of Chinese medicine and Western medicine, and had no any treatment advantages. All literatures included in the analysis had publication bias. On the whole, when clinical efficacy and antidiarrheal time was used as evaluative index, Dioctahedral smectite could be served as the positive control drug in clinical efficacy evaluation of new Chinese medicine and Western medicine in infantile diarrhea treatment.2.4 ProblemsThe methodology limitation of clinical studies resulted in a serious effect on the quality of studies, in which the present problems mainly included: (1)Principles of randomization and control were not well kept in clinical control trials; (2) Determination of sample size was not rigorous enough; (3) Lack of standardized statistical methods; (4) Standards of clinical evaluation and diagnosis as well as the diagnostic criteria of TCM Syndromes were not unified; (5)Observation of follow-up and adverse effects were not be attended enough.3. Clinical and experimental study of infantile acute nonbacterial diarrhea3.1 Object:A randomized control clinical study of Chinese medicine in infantile diarrhea treatment was conducted to evaluate objectively and standardized the effect of main therapeutic method of Activating Spleen and Dissipating Dampness on infantile acute nonbacterial infectious diarrhea in terms of clinical syndrome appearance and microecological regulation. 3.2 Methods:(1) the clinical study was designed as a prospective, multi-center, randomized, control trial in target population of 6-month to 3-year-old infants with acute nonbacterial diarrhea, who were allocated into Chinese medicine group, Chinese medicine+massage group, Dioctahedral smectite group in proportion of 1:1:1 with Central randomization system. Clinical symptoms observation and detection of intestinal microecology change between pre/post-treatment, follow-up, observation of adverse effect events and drug combination were performed, also treatment safety was evaluated.(2) Real-time Fluorescent Quantitative PCR Technique (FQ-PCR) technique used to perform the detection of Bacillus bifidus, lactobacillus, and Escherichia Coli. 3.3 Results:(1) Post-treatment total effective rates of Chinese medicine, Chinese Herbal Compound massage treatment were superior to Dioctahedral smectite, and there were significant differences when compared these three treatments. The antidiarrheal time of Chinese medicine, Chinese Herbal Compound+massage and Dioctahedral smectite was 2.78±1.54 days,2.36±1.25 days and 2.90±1.73 days, respectively. By analysis only on specific number, although Chinese Herbal Compound massage therapy had the shortest antidiarrheal time, followed by Chinese medicine and Dioctahedral smectite therapy had the longest one, there was no significant difference between the antidiarrheal times of three treatments revealed by statistics analysis.(2) Content of Bacillus bifidus, lactobacillus, and Escherichia Coli in stool specimens were detected in 26 infants with acute nonbacterial diarrhea, and the results showed no significant correlations were revealed between content of Bacillus bifidus, lactobacillus, and Escherichia Coli in post-treatment stool specimens of infants in the three groups and that in pre-treatment stool specimens;further analysis of correlation of main clinical symptoms (stool frequency, character of stool, and score of stool symptoms) and the content of Bacillus bifidus, lactobacillus, and Escherichia Coli indicated there was no significant relation between stool frequency, loose degree of stool as well as score of stool symptoms and the content of Bacillus bifidus, lactobacillus, and Escherichia Coli.3.4 Conlusion:(1)Post-treatment total effective rates of Chinese medicine, Chinese Herbal Compound massage treatment were superior to Dioctahedral smectite in superiority-inferiority assessment. However, there was no significant difference between the three treatments in term of antidiarrheal time.(2) The results showed no significant correlations were revealed between content of Bacillus bifidus, lactobacillus, and Escherichia Coli in post-treatment stool specimens of infants in the three groups and that in pre-treatment stool specimens; and there was no significant relation between stool frequency, loose degree of stool as well as score of stool symptoms and the content of Bacillus bifidus, lactobacillus, and Escherichia Coli.3.5 Analysis of result and ProspectingThe reasons for failure to effectively confirm the efficacy of Chinese medicine therapy in infantile diarrhea treatment in case of strict design of experimental study were consider as following:Limitation of time, effect of compliance of infants and their parents during study as well as lack of understanding of informed content and noncompliance of infants and their parents resulted the present number of patients enrolled in the study was far from the planned sample size, and thus the inadequate sample size might the reason for that no statistical significance was revealed in present study.In view of this, we believed that results of our study could not indicate uncertain clinical efficacy of Chinese medicine in infantile acute nonbacterial diarrhea treatment, and could not come to a conclusion of no correlation between the main clinical symptoms of infants with diarrhea and contents of Bacillus bifidus, lactobacillus, and Escherichia Coli; the same, we also could not infer that interventions of Chinese herbal compound, massage manipulation, and Dioctahedral smectite were not associated with content changes of Bacillus bifidus, lactobacillus, and Escherichia Coli.The force of results could be affected due to the lack of sample size. In present, the study on action mechanism of Traditional Chinese Medicine in the treatment of infantile acute nonbacterial infectious diarrhea was still in exploratory stage, and the data obtained in our study could only be use for conference due to the lack of patient's number, which also was the regret of our study. Based the experience summary of preliminary study, we will continue to conduct the clinical trial in order to obtain objective and scientific conclusions, thus to provide reliable clinical evidences for the Chinese medicine treatment of acute nonbacterial diarrhea in infants.
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