key: cord-0921461-24dtun4u
authors: Tang, Qiaoling; Hao, Yu; Song, Jia; Sun, Lingzhi; He, Juan
title: Does the traditional Chinese medicine theory of five circuits and six qi improve treatment effectiveness? A systematic review of randomized controlled trials
date: 2018-10-31
journal: Journal of Traditional Chinese Medical Sciences
DOI: 10.1016/j.jtcms.2018.12.004
sha: ac217c7b1b49cbf59928200e285ba2a9186b32b6
doc_id: 921461
cord_uid: 24dtun4u

Abstract Objective To evaluate whether the traditional Chinese medicine (TCM) theory of five circuits and six qi (FCSQ) is beneficial in terms of improving clinical effectiveness. Methods Randomized controlled trials (RCTs) evaluating the clinical value of FCSQ theory were reviewed. Multiple databases (China Network Knowledge Infrastructure, Chinese Scientific Journals Database, Wanfang Data, SinoMed, Cochrane Library, PubMed, and Embase) were systematically searched from inception to June 12, 2018. Two authors independently extracted the data and performed a methodological quality assessment of the RCTs. RevMan 5.3 software was used for the data analysis. The effect sizes for the primary outcome measures were expressed as relative risks or mean differences with 95% confidence intervals. Results A total of 13 RCTs were selected, involving 12 types of diseases and 4695 patients. The methodological quality of the RCTs was generally low. Five studies compared the effectiveness of TCM treatments guided by FCSQ theory with conventional TCM therapies, and the remaining eight studies compared the effectiveness of TCM treatments guided by FCSQ theory with biomedical treatments. All of the RCTs reported that the effectiveness of the treatment intervention was better than that of the intervention in the control group. Conclusion Because of many methodological problems in existing clinical studies, it remains impossible to definitively conclude that FCSQ theory can improve clinical effectiveness. It is difficult to unify the clinical application of FCSQ theory. The feasibility and repeatability of FCSQ as an intervention should be given more attention in future clinical research. Future work should also follow international norms for clinical research implementation and reporting to provide high-quality evidence for evaluating the clinical value of FCSQ theory.

The theory of five circuits and six qi (FCSQ; five circuits refers to wood, fire, earth, metal, and water; six qi indicate wind, cold, summer heat, dampness, dryness, fire) is an essential part of traditional Chinese medicine (TCM). The theory represents a holistic view held by early doctors based on the correspondence between heaven and humankind. It is a doctrine for understanding the laws of nature and climate change, as well as their impact on human diseases. FCSQ theory, which is based on the theory of yin and yang and uses symbols such as "heaven" and "earth" as deductive tools, has been passed down from the era of Yellow Emperor's Canon of Medicine. Using current meteorological data and data on the incidence of diseases, scholars have conducted a series of studies to evaluate the correlations between FCSQ and climate change, occurrence of diseases, and TCM patterns. 1À4 These studies have found varying levels of correlation between the complete meteorological data, based on continuous modern meteorological observations, and the climate mode deduced from FCSQ. Furthermore, a relationship between FCSQ and common diseases has been found in some internal medicine and TCM patterns. All of this previous work has objectively proven that FCSQ exerts an influence on human life activities and provided a basis for using FCSQ theory to treat diseases in TCM clinical practice. Unique effects were observed for TCM treatments guided by FCSQ theory for epidemic cerebrospinal meningitis in North China in the 1950s and severe acute respiratory syndrome in China in 2003. 5 In recent years, a number of studies on FCSQ have been published.

Nevertheless, the clinical value of FCSQ theory is very controversial in the field of TCM, and doubts have existed since the theory's emergence. Some medical doctors have explicitly opposed FCSQ theory. For example, in the Ming Dynasty, Xiyong Miu wrote a chapter entitled "On the falseness of FCSQ" in his book, Commentary on Shen Nong's Classic of the Materia Medica. He believed that what was called FCSQ theory by later generations was not beneficial for treatment, because there was no mention of FCSQ recorded in the books written by Zhongjing Zhang, Tuo Hua, Shuhe Wang, and others. Xiyong Miu therefore denied the significance of FCSQ theory in TCM. During the Republic of China era (1911e1949), two important controversies regarding FCSQ occurred in the field of TCM, and stances denying or proposing the abolishment of FCSQ theory were predominant. Yuanlei Lu, one of the representatives of this view, published an article entitled "Overthrowing FCSQ fundamentally" in 1934 to express the idea that there is no reason for FCSQ theory to exist. 6 Currently, the body of work on FCSQ is increasing, but applications of the theory have not been given much importance in mainstream TCM clinical practice. Is FCSQ theory beneficial for improving the effectiveness of treatments? To answer this question, it is insufficient to rely on traditional literature reviews, theoretical derivations, or medical reports. Therefore, to provide evidence-based medical evidence on this controversial issue in the field of TCM, we systematically collected and evaluated randomized controlled trials (RCTs) that examined FCSQ theory in the treatment of diseases.

The databases searched included China Network Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database, Wanfang Data, SinoMed, Cochrane Library, PubMed, and Embase, which were queried from their inception to June 12, 2018. The search terms were "yunqi" (circuit and qi), "wuyun" (five circuits), "liuqi" (six qi), "keqi" (guest qi), "zhuqi" (dominant qi), "sitian" (celestial control), "zaiquan" (terrestrial effect), "suiyun" (circuit of year, that's the characteristics of one circuit in the whole year), "suiji" (random), and "zhongyi" (TCM). These terms were selected as MeSH terms, free words, or keywords in combinations for comprehensive retrieval based on different characteristics of the selected databases. For example, in CNKI, a Chineselanguage database, we retrieved records with "yunqi," "wuyun," "liuqi," "zhuqi," "keqi," "sitian," "zaiquan," or "suiyun" in the title field in addition to "suiji" and "zhongyi" in the full text. In the PubMed database, the search string was "(( (((((five yun and 

The inclusion criteria were as follows: (i) study design type: randomized controlled trials aimed at evaluating the clinical effectiveness of FCSQ; (ii) study subject: any disease type; (iii) intervention: experimental group receiving TCM treatments guided by FCSQ theory, including traditional Chinese herbal medicine, acupuncture and moxibustion, and tuina massage and control group receiving conventional TCM treatments without FCSQ, biomedicine, or placebo; and (iv) outcomes: because of the varying disease types covered, we selected primary outcomes such as effectiveness rate for evaluating the improvement of symptoms, signs, and laboratory tests, as well as mentions of adverse reactions.

Exclusion criteria included the following aspects: (i) duplicate publications (only the original publication was included); (ii) publications including only "yunqi" (circuit and qi) in intervention measures (e.g., the Wenzhen Yunqi Formula), without including or reflecting on FCSQ thought; and (iii) publications of abstracts only that did not provide the details of the research design or access to the full-text report of the study.

For the methodological quality evaluation, we adopted the Cochrane Collaboration's tool for assessing risk of bias. 7 The items included random sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment, as well as incomplete outcome data, selective reporting, and other biases. The possible evaluations for each item were applicable, nonapplicable, and unclear, corresponding to low, high, and unclear risks of bias, respectively. Two investigators (YH and JS) assessed the quality of each study independently and cross-checked their assessments. In case of disagreement, the evaluation was determined through discussion or submission to a third researcher (JH).

After discussion, we designed the data extraction form. The data were extracted independently by two authors. The extracted contents included titles, characteristics of the research methods, basic information on the subjects, interventions applied in the treatment and control groups, courses of treatment, consideration of FCSQ in the intervention for the treatment group, outcomes, and adverse events.

The data analysis included an analysis of the consideration of FCSQ in the treatment and a statistical analysis of outcomes. For the analysis of FCSQ being considered in the treatment, descriptive methods were used. For the statistical analysis of outcomes, RevMan 5.3.5 analysis software, provided by the Cochrane Collaboration, was adopted to quantify the primary outcomes. For measurement data, weighted mean differences are expressed. For enumeration data, relative risks and their 95% confidence intervals are presented. When two or more studies had good clinical homogeneity in terms of researched diseases, intervention measures, and outcomes, we planned to conduct a pooled meta-analysis, applying the corresponding model based on the results of the heterogeneity test. Where possible, subgroup analyses were performed according to the different modes of FCSQ application and the type of control measures. If not, only the effect sizes (expressed as relative risks or mean differences with 95% confidence intervals) of the individual studies are described.

After searching the above-mentioned databases, 143 articles were obtained. Of these articles, 130 were removed because of duplication, irrelevance, or failure to meet the inclusion criteria. The remaining articles included 13 RCTs, which were included for further analysis. All studies were conducted in China and published in Chinese (Fig. 1) .

A total of 13 RCTs 8À20 involving 4695 patients were included in the analysis. In these studies, 12 categories of diseases/ patterns were mentioned, including cough, 8 rheumatoid arthritis, 9 post-menstruation deficiency, 10 psoriasis, 11, 12 peptic ulcer, 13 hypertension, 14 hand-foot-and-mouth disease, 15 menopausal insomnia, 16 dizziness, 17 externally contracted cough, 18 insomnia after stroke, 19 and chronic fatigue syndrome. 20 The average sample size in these studies was 361, with a maximum of 3666 and a minimum of 60 subjects. The longest course of treatment was 1 year, and the shortest was 5 days. Outcomes reported in these studies included symptom scores, laboratory test indicators, morbidity, and recurrence rate. Symptom scores were the primary outcome of 11 studies. Seven articles reported the occurrence of adverse reactions. 8,9,12,14,16À18 With regard to interventions in the treatment group, 10 studies used oral administration of traditional Chinese herbal medicine 8À12,14À18 (combined with the regular biomedicine or external treatment in four for these studies), and the other three studies used acupuncture therapy, 19 tuina massage, 20 or acupoint application therapy. 13 The interventions using FCSQ theory can be divided into three categories: TCM prescriptions or external therapy devised by the researchers based on the theory of FCSQ, 8À13,19,20 the use of an FCSQ formula taken directly from the work of early medical doctors, 14, 15 and formulas conforming to the "heavenly stems and earthly branches" from Sanyin Sitian Fang, an FCSQ monograph written by Wuze Chen in the Northern Song Dynasty (960e1127 AD). 16À18 As for the control group, in six studies, control subjects were treated with conventional biomedicine, 9, 10, 12, 14, 16, 18 and three studies 13 Figure 1 Selection of randomized controlled trial studies on the five circuits and six qi. Effectiveness evaluation of five circuits and six qi external treatments to compare the effectiveness between external treatments under the guidance of FCSQ with external treatments that were not guided by FCSQ. Chinese patent medicine, 8 prescription based on conventional pattern identification and treatment, 11 and diet therapy 15 were each applied as the control treatment in one study, and an external treatment combined with Chinese patent medicine was the control treatment in one study. 17 The basic characteristics of each study are shown in Table 1 .

The FCSQ thought included and the basis for FCSQ as an intervention in the treatment group are displayed in Table 2 . reported the study dropout rate, but they did not analyze these subjects' data. We cannot judge whether there was selective reporting bias because there was no clinical protocol registration in the examined studies. With regard to other research biases, seven studies 9,13,15À17,19,20 reported receiving funding for related projects. All of the included studies reported consistent baseline data for the treatment and control groups. None of the studies reported the method of sample size calculation. The methodological quality of the included RCTs is displayed in Fig. 2 .

Of the 13 included studies, the disease types, intervention measures, and outcomes of 10 varied. Although the disease type (i.e., insomnia) was the same in two RCTs, the interventions were different, and there was significant heterogeneity. Pooling the studies into a meta-analysis was therefore not possible, and only estimates of effects from single study are described. Our results showed that all of the included studies reported that the effectiveness of the FCSQ treatment was superior to the control treatment (Table 3 ).

Four RCTs 8, 9, 12, 16 reported specific adverse reactions. Loose stools occurred among children receiving an FCSQ-formula treatment for cough 8 ; nausea and loss of appetite occurred among those treated with methotrexate for rheumatoid arthritis 9 ; and skin or mucous dryness, desquamation, and itching occurred among those treated with traditional Chinese herbal medicine for psoriasis vulgaris. 12 Mild diarrhea occurred in the menopausal insomnia treatment group, whereas drowsiness, dizziness, headache, and diarrhea occurred in the control group. 16 Three RCTs reported that there were no adverse reactions, 14, 17, 18 and the remaining six RCTs 10, 11, 13, 15, 19, 20 did not report on adverse events.

In this study, 13 RCTs evaluating the safety and effectiveness of applying FCSQ theory to treat diseases were systematically reviewed. The effectiveness of TCM treatments in the FCSQ treatment groups was higher, compared with the effectiveness of either conventional TCM treatments without guidance from FCSQ theory or Western medicine treatments, and these differences were significant. However, because of the low methodological quality of the included studies and inability to rule out publication bias, we cannot definitively conclude that FCSQ theory improves the effectiveness of TCM. The results in our study are similar to those of a 2014 narrative review by Liu et al, 21 which evaluated four RCTs and two case reports that used FCSQ theory. This previous review pointed out that there have been few evaluations of the effectiveness of applications of FCSQ theory in clinical trials, that the research quality has been low, that there has been obvious publication bias in case reports, and that the demonstration of causal relationships has been weak; therefore, a precise conclusion on FCSQ treatment could not be drawn. In contrast to this previous article, we adopted the Cochrane Collaboration's tool for assessing risk of bias and included all published RCTs on the evaluation of the clinical effectiveness of FCSQ, thus avoiding selection bias in our literature search. Additionally, we summarized the ways in which FCSQ theory has been applied in existing clinical research. We found that the methodological quality of relevant studies published in recent years had not significantly improved, compared with earlier work. Two types of methodological problems were common in the included RCTs. The first type includes common problems in TCM clinical research. 22e24 For example, the examined studies do not design, perform, or report on research in accordance with international standards on clinical research; the details of the random allocation are inappropriately concealed (or may even not be reported at all); there is a lack of information on the sample size calculation; the studies do not report on study dropouts or provide intention-to-treat analyses of their data; evaluations of subjective outcomes are performed without blinding; and there is no clinical trial registration, resulting in an inability to judge publication bias, selective reporting bias, and other biases. The other type of problem is specific to the formulation of control treatments and FCSQinformed interventions. First, the main FCSQ-specific problem is the unreasonable design of control treatments. Western medicine alone has been used in the control group in many studies, without including a group receiving conventional TCM treatment without FCSQ as a control. In this case, even if the effectiveness of the FCSQ treatment is higher than that of the treatment in the control group, we can only reach the conclusion that the effectiveness of TCM is better than that of Western medicine; with this study design, it is impossible to prove whether or not the observed effectiveness is the result of guidance by FCSQ theory. Second, no reliable evidence is provided on the formulation of interventions for FCSQ treatment groups, leading to problematic performance and poor repeatability. In most studies, the FCSQ treatment interventions were based on the researchers' own experience or prescriptions devised by the researchers with consideration of the features of FCSQ. These studies have usually not reported the rules applied for herbal prescription or even defined whether their interventions were related to FCSQ theory. For instance, in a clinical trial for treating hypertension based on FCSQ theory, 14 the Wumei Pill from Treatise on Cold Damage was used in the FCSQ treatment group. The authors analyzed the FCSQ characteristics only in the year of the study and stated that the Wumei Pill was effective for hypertension occurring in that year; they did not clarify the evidence for formulating prescriptions based on aspects of FCSQ theory. In terms of how FCSQ theory is applied, we can conclude that applications considering the characteristics of the "heavenly stems and earthly branches" are the most common in clinical practice. The various problems that occurred in designing interventions for FCSQ treatment groups suggest that the feasibility and repeatability of FCSQ interventions should be given more attention in future clinical research to provide high-quality evidence for assessing the clinical value of FCSQ theory.

For future clinical practice and research, it remains meaningful to explore how to apply FCSQ theory to guide disease diagnosis and treatment. There is a need for highquality trials to evaluate the clinical value of FCSQ theory and answer whether TCM diagnoses and treatments based on FCSQ theory are beneficial for improving effectiveness. 26 ) , to avoid various biases and to obtain reliable outcomes. Furthermore, the particularity of FCSQ clinical research should be fully considered. First, future work should select diseases that are strongly correlated with FCSQ. Second, it is important to design a reasonable control treatmentdA conventional TCM treatment without FCSQ is usually needed as a control intervention, and, if possible, a Western medicine treatment or placebo control is desirable. Third, the determination of FCSQ interventions should have sufficient justification, good operability, and repeatability. We recommend referring to well-recognized FCSQ formulae recorded in the early FCSQ literature, such as the therapeutic principles in the "seven great chapters" on FCSQ in Yellow Emperor's Canon of Medicine and the monograph on FCSQ theory, Sanyin Sitian Fang, produced during the Northern Song Dynasty. Corresponding intervention measures should then be determined in accordance with the specific characteristics of the "heavenly stems and earthly branches" during that month and year.

In this study, we systematically evaluated the clinical value of FCSQ theory based on 13 selected RCTs, finding that positive results were reported in all of the studies. Although there are many methodological shortcomings in the current literature and the value of FCSQ theory cannot be fully affirmed, its application value in clinical practice is undeniable. The present study provides a reference for the clinical application of FCSQ theory in TCM in the future. Only by combining the characteristics of FCSQ theory in TCM, adopting appropriate clinical research methods, designing reasonable study protocols, and following international guidelines for designing and reporting clinical research can we provide more substantial evidence for the clinical application of FCSQ theory.

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This research was supported by the National Natural Science Foundation of China (81503678).