Traditional Chinese medicine for intestinal adhesion : A meta-analysis of randomized controlled trials

only articles, and thesis were not limited as long as they met the inclusion criteria.


INTRODUCTION
Intestinal adhesion is a medical condition characterized by connected loops of intestine with other abdominal organs via fibrous tissue bands.It remains an inevitable event of abdominal operations which can cause a large amount of complications (Valerio, 2014).Literature has reported that the incidence of post-operative intestinal adhesion accounts for 79 to 90% of the patients who are undergoing or underwent laparotomy, and it is still on rise (over 90%) (Valerio, 2014).Postsurgical adhesions are a principal factor that contributes to the increase in mortality and morbidities with operated patients, who may experience other related conditions such as lifethreatening ileus, chronic abdominal pelvic discomfort, chronic pelvic pain, infertility, dyspareunia, and intestinal obstruction, accounting for approximately 75% of all the cases (Ozogul et al., 1998).The pathological mechanism is associated with tissue ischemia, injury, and local overstimulated inflammatory response which are caused by foreign bodies and reduced fibrinolytic activity.The inflammatory response to surgical injury is thought to be one of the factors that result in the formation of adhesion because it leads to the decrease in gastrointestinal activities including contractile activity and gastrointestinal transit.Tumor necrosis factor alpha (TNF -α), interleukin (IL), transforming growth factor beta 1 (TGF-β1) and other cytokines play an important role in regulating the formation of adhesion, which follows the sequence of tissue inflammation, fibrin deposition, fibrin organization, collagen formation and maturation with the formation of adhesions (Singer et al., 1996a).
Injury, in any form, results in the depression of fibrinolytic activity by releasing the plasminogen activator inhibitors 1 and 2 (PAI1 and PAI2) from mesothelial, endothelial, and inflammatory cells.So medicines that interfere with fibrinolytic activity can cause adhesion formation at the fibrin organization phase.Whereas antiinflammatory drugs such as steroids can affect later phases and interfere with collagen formation.The mechanisms involved in this process were demonstrated to be secondary to their anti-inflammatory effects inhibition of fibroblast emigration, or depression of procollagen gene expression through the decreased transforming growth factor-beta (TGF-â) secretion (Murata et al., 2006;Singer et al., 1996b).In brief, researchers have identified the four main aspects of the methods to prevent intestinal adhesions formation: 1. Adoption of minimally invasive surgical procedures like laparoscopic surgery to reduce peritoneal trauma; 2. Prevention of fibrin formation with pharmacological agents, such as corticosteroids, heparin or tissue plasminogen activator, sodium hyaluronate, urokinase, application of anti-adhesive film modified chitosan (Murata et al., 2006;Singer et al., 1996b); 3. Reduction of the contact between organs and intraabdominal contents by using biodegradable barriers such as sodium hyaluronate (SHA), seprafilm, seprafilm antiadhesion film (Akyildiz et al., 2008); 4. Use of various biologically active substances such as intraoperative use of biological polysaccharide flushing liquid.In order to avoid side effects, an ideal barrier should be biocompatible, biodegradable, and surgically easy to handle and should act locally.Unfortunately, only certain materials meet those requirements.Besides there exist no large prospective, randomized, double-blind human studies which can demonstrate their efficacy; 5. Some of them are only effective in the short term.Some have no impact on inflammation activity, while others have severe detrimental impacts (Akyildiz et al., 2008).
Therefore, the development of new available drugs to combat intestinal adhesion is of great clinical significance.For the past decades, physicians in Asia have accumulated a tremendous amount of knowledge and experiences in treating adhesive adhesion for decades.This shows that traditional Chinese medicine (TCM) can reduce the production, inflammatory factors and the effusion of fibrin, as well as increase the activity of plasminogen activators, which demonstrates sound effect in stimulating post operational gastrointestinal peristalsis and preventing the occurrence of post operational intestinal adhesion (Wang and Shao, 2010).Oral TCM, in vitro application of TCM, acupuncture or electroacupuncture point injection, and therapeutic TCM enema are performed as indicated, which have been perceived to be less expensive, safer, and more effective than conventional western therapies (Li et al., 2016).At present, no published meta-analysis has been previously done to the benefits of applying TCM as adjuvant treatment in patients with intestinal adhesion.Therefore, this meta-analysis is conducted to quantitatively summarize the add-on effect of TCM in patients with this condition on the basis of the available randomized controlled trials (RCTs).

Data sources and searches
To identify relevant randomized clinical trials (RCTs), two reviewers (Lian Liu and Song Wei Su) have systematically searched the Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica data BASE (EMBASE), Cochrane Central Register, China National Knowledge Infrastructure Database, Chinese Scientific Journals Full Text Database, Wanfang Data Knowledge Service Platform, and the Chinese Biomedical Literature Service System with search keywords including -"Traditional Chinese medicine" "traditional Chinese herb" "Chinese herb" "TCM" "herbal medicine" "ointment" "TCM enema" "acupuncture", "electro-acupuncture" "intestinal adhesion," and "randomized controlled trial," "RCT".In this study, papers dating from the earliest citation in the databases until August 2016 were included.The references of all the selected publications and reviews were manually searched for further relevant articles.Publication languages and types like conference proceedings, *Corresponding author.abstract-only articles, and thesis were not limited as long as they met the inclusion criteria.

Studies
RCTs were included.Trials were excluded if any of the following factors was identified: (1) Inadequate information relevant to evaluation rates; (2) Quasi-RCTs, non-RCTs, or randomized trials with false randomization methods; (3) Mixed interventions in the experimental group; (4) Researches of pharmacological mechanism of TCM; (5) Animal trials (Figure 1).

Participants
Patients diagnosed with intestinal adhesion based on any set of explicit criteria were included.Also peritoneal adhesion and intestinal adhesion obstructions were excluded.No limitations were set regarding the participant"s age, gender, and surgical types or TCM application.The classification of the degree of intestinal adhesion was governed by Nair"s standard 5-level classification (Nair et al., 1974): (1) Absence of intestinal adhesion (grade 0); (2) Intestinal adhesion of grade I, with an adhesion band observed between the bowels or between the bowel and the abdominal wall; (3) Intestinal adhesion of grade II, where two adhesion bands are observed; (4) Intestinal adhesion of grade III, where more than two adhesion bands are observed but the bowel is not adherent to the abdominal wall; (5) Intestinal adhesion of grade IV in which the bowel is adherent to abdominal wall regardless of the number of adhesion bands.

Interventions
The focused experimental groups received any type of TCM therapy.No limitations had been set on dosages, formulations, routes of administration of TCM, or the types of conventional therapy.
The comparison of TCM with conventional therapy included nothing by mouth (NPO), maintaining the balance of electrolyte and acid-base, continuous gastrointestinal decompression, nutritional support and symptomatic treatment, intra peritoneal pharmacological treatment (medical chitosan and biological polysaccharide flushing liquid etc) and pharmacological treatment (antibiotics dexame thasone, immune potentiator and mosapride etc (Table 1).

Control group treatments
Control groups were defined as patients who received any type of conventional western therapy for intestinal adhesion, instead of TCM treatments.

Outcome measures
The primary outcomes that were taken into in this study were the incidence of intestinal adhesion, the total effective rates after intervention for the duration of treatment and the recovery of gastrointestinal function which was defined as the recovery time of borborygmic, anal exhaust time and anal defecation time by clinical evaluation.Two reviewers also evaluated the average time of incision healing, the termination time of gastrointestinal decompression and blood plasma fibrinogen (FIB) as secondary outcomes.

Data extraction
Two reviewers extracted data independently in a predefined data extraction form.Disagreements were resolved by discussion and consensus with a third reviewer.The extracted data included the first author; study characteristics; participant characteristics (that is, mean age, gender, sample size, surgical procedures, and systemic therapy); the therapy of the experimental and control group treatments; measured outcomes.For studies with insufficient information, the reviewers contacted the primary authors, when possible, to acquire and verify the data.

Risk of bias assessment
Two independent authors assessed the risk of bias in each study via the tool named cochrane risk of bias (Higgins et al., 2011) (Figure 2).

Data synthesis and analyses
In case of meta-analysis, the total effective rates of dichotomous data were pooled by using risk ratios (RRs).All statistical analyses were performed via Review Manager 5.3.1 software (Cochrane Community, London, United Kingdom).The results were compared to tell the differences between experimental and control groups.Cochrane"s  2 and  2 tests were used to assess the degree of heterogeneity between studies.In the  2 and  2 tests, there was considerable heterogeneity for  values less than 0.10 or  2 value above 50% respectively (Higgins et al., 2011).In this case, a random-effects model was used to compute the global RR, MD or SMD.Otherwise, with  values greater than 0.10 and  2 less than 50%.The between-study heterogeneity was not substantial, and the fixed-effect models were suitable.Clinical heterogeneity was assessed by reviewing the differences in the distribution of participants" characteristics among trials (that is, age, gender, and duration of disorder and surgical procedures, TCM formulas).

Study selection
From a total of 169 titles, the full text of 24 potentially relevant studies was reviewed to confirm their eligibility.Liu et al. 463 Among these 169 studies, 88 were excluded, including insufficient information relevant to evaluation rates (n=6), quasi-RCTs, non-RCTs, or randomized trials with false randomization methods (n=16), mixed interventions in the experimental group (n=7), and researches of pharmacological mechanism of TCM (n=16), animal trials (n=12).

Risks of bias assessment
The methodological qualities of all the included trials were poor (Figure 2).Although all these trials had reported randomization, only three trails adequately depicted the randomization method: one through throwing dice (Li et al., 2016), one with a random number table (Zheng et al., 2013), and another one with operation time sequence number (Yang et al., 2007).Moreover, none of the studies reported information such as the allocation concealment or blinding of participants as well  as study personnel; none reported the details of the blinding of outcome assessment.All the relevant trials did not address incomplete outcome data and selective reporting.No other biases were found and high risk bias was not present in these trials; however, considering their poor methodological quality, it was determined that an unclear risk of bias should be given to all the included trials.

Incidence of intestinal adhesion
12 studies contained 1489 subjects (882 in experimental groups and 667 in the control groups).All subjects from the two groups adopted basic intervention strategies.The pool of the results from these trials showed there existed a great difference in the incidence of intestinal adhesion between the TCM and conventional therapy groups (RR = 0.33, 95% confidence interval [CI]=0.26,0.42, and P < 0.00001) using the fixed-effects model (Heterogeneity: P = 0.74, I² = 0%) (Table 2).

Average time of incision healing
Only three studies which involved 270 participants reported average time of incision healing (139 in experimental groups and 131 in the control groups).With random-effects modeling (Heterogeneity: P = 0.009, I² = 79%), the pooled data for the 3 studies showed there existed a difference between the experimental (139) and the control groups (131) in terms of the average time of incision healing (MD = -1.90,95% CI = -2.69,-1.10, and p < 0.00001) (Table 7).

Adverse events
No studies reported adverse events in the experimental groups or the control groups.It seemed to be safe to use TCM in clinical practice.However, this point needed further investigation.

Assessment of Publication Bias
In this review, funnel plots of incidence, total effective rate, the recovery time of borborygmus and anal exhaust time were evaluated in Figure 3. Visual inspection of funnel plots was not substantially symmetrical, suggesting some evidences of publication bias.

Summary of evidence
Even though most of the trials were small in terms of size with poor methodological quality, the analysis of the pooled data showed a consistently superior effect of TCM in terms of incidence, total effective rate, and the recovery of gastrointestinal function and incision healing as compared with to the control groups.However, the pooled data for the two studies showed no difference in the blood plasma fibrinogen (FIB), which was not in accordance with the included research.In addition, only one study reported the prothrombin time (PT) and the activated partial thromboplast in time (APTT) of TCM group was longer than that of control group after TCM therapy (Yang et al., 2007).Additionally another study reported that the whole blood viscosity, plasma viscosity were significantly lower in the TCM group than that in the control group (Zhang et al.,1999), which demonstrated that TCM could prevent postoperative intestinal adhesion through anticoagulation, fibrinolysis and the reduction of abdominal fibrinogen concentration (Yang et al., 2007;Zhang et al., 1999).Furthermore, only one study reported that the serum IL-2 of the TCM enema group was significantly higher than that of the control group, which meant that TCM enema could promote the immune response after abdominal surgery and improve antiinfection ability.Also results showed that the blood gastrin and motilin levels in the enema group were significantly higher than those in the control group, both of which can enhance gastrointestinal motility (Shi et al., 2011).However, these evaluation indexes were not analyze due to the unavailability of more available studies, more sensitive and effective physiological and biochemical indexes.And seroimmunological indicators needed further evaluation in the future.There were few adverse effects, and no patients dropped out of their trials due to adverse effects.

Possible rationales for EA-TCM for treatment of intestinal adhesion
TCM holistic medical system has developed through accumulating intelligence from ancient theories (such as the seminal text of TCM titled the "Yellow Emperor's Inner Canon") and daily life experiences as well as continuous refining and experimenting by generations of practitioners.The comprehensive approach of TCM emphasizes focuses more on disease prevention through the restoration of syndromes (Zheng) or "pathophysiologic" status.From the TCM perspective of TCM, body constitution is transient in nature and a disease may ensue when the inner harmony of a human body is disrupted in response to the external environment (Low et al., 2016).According to principle of determination of treatment based on the TCM of differentiation syndrome, intestinal adhesion of the patients were divided into stagnation of qi and blood stasis type, syndrome of intestinal heat and fu-organ excessiveness type and accumulation of cold evil in the intestines type, the scholars added or subtracted some kinds of TCM herbs according to various clinic manifestation in clinical practice, which were based on the TCM principles.Although the components and methods of TCM used in each trial in our meta-analysis varied, the treatment principles were consistent: purging the bowels and activating blood circulation, reduce the production or inflammatory factors and the effusion of fibrin, increase the activity of plasminogen activators and so on and so forth (Xie et al., 2014).
The most common compositions in these TCM formulas were Berberine Hydrochloride (Berberine), a natural plant alkaloid derived from Rhizoma Coptidis, since research results showed it could significantly lower expression of inflammatory cytokines interleukin-1β(IL-1β), Interleukin 6(IL-6), transforming growth factorβ(TGF-β), tumor necrosis factor-α (TNF-α), and clinical TCM practioners used it as a promising strategy to prevent adhesion by down regulating intercellular adhesion molecule-1(ICAM-1) and reduce inflammation by inhibiting the transforming growth factor-activated kinase 1(TAK1)/c-Jun N-terminal kinase (JNK) and TAK1/nuclear factork B (NF-kB) signaling (TAK1/JNKand TAK1/NF-kB signaling) after abdominal surgery, which brought out a good therapeutic approach for the management of postoperative abdominal adhesion and inflammation (Zhang et al., 2014).
Rhein-arginine (RhA), which is derived from rhubarb, could prevent the formation of postoperative intestinal adhesion in two ways: (1) Reducing vascular permeability, reducing seepage, inhibiting connective tissue proliferation and suppressing excessive expression of inflammatory cytokines; (2) Reducing the hydroxyproline (Hyp) contents of cecal, reducing the expression of transforming growth factor beta 1(TGF-â1), inhibiting increased activity of plasminogen activator inhibitor (PAI) and increasing tissue-type-plasminogen activator (t-PA) activity.As a result, the activity of plasminogen was enhancing the fibrinogen effusion to dissolved (Yin, 2009).
Ligustrazine was extracted from Rhizoma Chuanxiong.It was a piece of herbal medicine which could promote blood circulation, increase the amount of opened tiny blood vessel, speed up the blood circulation, resist blood platelet congregation, and restrain the smooth muscle constriction showing prominent anti-inflammatory property.Furthermore, reduce the percentage of the blood WBC as well as the concentration of the plasma fibrinogen(FIB), and the serum levels of IL-1â, IL-6, TNFα, inhibit the proliferation of hypertrophic scar fibroblasts and decrease the degree of peritoneal adhesions (Shi, 2007).
Paeonol was the main effective constituent in Cortex Moutan, which could significantly reduce the blast of fibrocyte proliferation which was affected by the inflammatory factor lipopolysaccharide (LPS) and tumor necrosis factor (TNF).It also has the up-regulation effects in mesothelial cell proliferation, while mesothelial cell and blast of fibriocyte are very important cells in the process of peritoneal adhesion.This Chinese herb can also modulate the excreting of tissue-type plasminogen activator (t-PA) /plasminogen activator inhibitor (PAI) by changing the interaction of macrophages and mesothelial cells.Furthermore, this Chinese herb could also promote fibrin dissolving.Thus, it can prevent peritoneal adhesion from occurring (Yang, 2007).
Salvianolate, which was derived from Salvia Miltiorrhiza, significantly reduces the extent of postoperative intestinal adhesion by obviously decreasing the levels of IL-lβ, TNF-α and TGF-β1 expression levels, and inhibiting fibrous connective tissue hyperplasia.And Salvia Miltiorrhiza, had been shown to prevent intestinal adhesion in rat models due to its pharmacological effects to minimize postoperative depression of local fibrinolytic activity, reduce the severity of postoperative adhesions, and alleviate the pathological injuries at the site of adhesion (Sui et al., 2007) In addition to the aforementioned single compositions of herbs, the compound TCM formula, which based on the functional classification principle of junchenzuoshi rules, and the traditional principle of syndrome differentiation, lay emphasis on holistic health care, demonstrated more remarkable curative effect.The pharmacodynamics molecules in TCM ingredient molecules could be divided into jun-component, chencomponent, zuo-component, and shi-component in each decoction (Long et al., 2008).For example, Salvia Magnolia mixture, had enterokinetic and decreasing peristalsis affection, and significantly lower blood viscosity and reduce plasma fibrinogen levels to effectively prevent the occurrence of adhesion (Wang and Shao, 2010).Dahuangmudanpi decoction could suppress growth and proliferation of peritoneal adhesion fibroblasts and promote apoptosis (Zhang, 2015).TaozhiZhipu mixture has good effect on stimulating post operational gastrointestinal peristalsis and preventing the occurrence of post operational intestinal adhesion (Su et al., 2000;Zhang et al., 1999).Modified Da Cheng Qi decoction could obviously decrease the concentration of the fibrinogen in abdominal exudates and accelerate the decomposition of the fibrinogen, and could evidently reduce the severity of adhesion (Wu and Li, 2014;Yu, 2015).Zhi Pu hollow type suppositories has good antiinflammatory effect, affect blood WBC,TNF-αcontent, FIB level and can adjust moiling, gastrin, glucagon levels to promote peristalsis, maintain and protect the integrity of intestinal serosa to protect the outer layer of mesothelial cells, forming a layer of barrier, but also may control the proliferation of fibroblasts (Zhang, 2009); Xue Fu Zhu Yu prescription, the promoting blood flow principle representative prescription, could treat abdominal accretion effectively through anti-oxidation, improving hemorrheology situation (Wu and Li, 2014;Yu et al., 2015).Huoxuetong luoliqitongbian decoction could decrease fibrinogen(FIB) in plasma and celiac liquid, increase fibrin degradation products(FDP) density, suppress transforming growth factor (TGF-b) mRNA expression in the adhesion tissue, improve exudation and fibrosis, and decrease the degree of peritoneal adhesion significantly etc (He et al., 2014).
Apart from TCM decoction, to some extent, enema with TCM could decrease the expression of the IgG antigen and serum TNF-á levels (Liu, 2013;Xie et al., 2014).The result suggested the TCM enema could lower fibrinogen and cut down fibrin and lessen inflammatory effect in tissue (He et al., 2014).On the other hand, it increased blood glutathione peroxidase (GSH-Px) content which was against the destroying of strong oxidative free radical to tissues and strengthened the second line of defense against free radical.All these effects contributed to the prevention of inflammatory and preventive of postoperative intestinal adhesions (Shi et al., 2011;Tai et al., 2005;Zhang, 2015).
TCM form acupuncture was known to inhibit pain and promote gastrointestinal motility.Those acupoints (e.g.zhusanli, shangjuxu, neiguan, gongsun, zhongwan) were selected because they were well-known meridians for treating gastrointestinal disorders.Acupuncture could relieve the edema of the obstructive intestinal tissues, improve the ultrastructure injury of the obstructive intestinal tissues, and promote the recovery of the function and morphology of the mitochondria as well as rough surface endoplasmic reticulum (RSER).Acupuncture could also elevate the synthesis and secretion of SIgA, increaseCD 4 + lymphocytes and ratio of CD 8 + /CD 8 + , enhance the intestinal local immunity and reduce the intestinal bacteria translocation (Chen et al., 2014;Li et al., 2016).Early postoperative electroacupuncture could significantly lower the elevated levels of inflammatory mediators such as tumor necrosis factorα (TNF-α), nitric oxide (NO), nitric oxide synthase (NOS), and the expression of vascular endothelial growth factor (VEGF) to decrease angiogenesis.The activation of cholinergic anti-inflammatory pathway might be another mechanism through which electro-acupuncture exerts the anti-inflammatory and inhibitive effects on abdominal adhesion (Li et al., 2014).

Conclusion
Our study highlights that searching on complementary and alternative therapies may have potential benefits for common diseases.Unfortunately, there exist considerable knowledge deficits about TCM especially in western world.Therefore, in the modem clinical practice, in order to make TCM serve people all over the world better and to accelerate the promising TCM-based new drug development, future studies should be based on the classical medical prescriptions, which refers to those recorded in the books before Han dynasty and "Treatise on Febrile and Miscellaneous Diseases" written by Zhang Zhongjing.Furthermore, it is necessary to bring the ancient practice of TCM into line with modern western medicine standards governed by the principle of "unification, simplification, coordination, and optimization" (Liu et al., 2016).While the fact that TCM may be effective in treating intestinal adhesion is encouraging, it is not conclusive due to the low methodological quality of the RCTs.However, this study hope to provide useful experience for further studies on TCM and more highquality RCTs, with low risk of bias and adequate sample sizes, in order to demonstrate its true effects.

Figure 1 .
Figure 1.Summary of the literature identification and selection process.CNKI indicates the Chinese National Knowledge Infrastructure Database; CQVIP, the Chinese Scientific Journals Full Text Database; Sino Med, the Chinese Biomedical Literature Service System; TCM, traditional Chinese Medicine; RCTs, Randomized Clinical Trials.

Table 1 .
Basic characteristics of the included studies.

Table 2 .
Meta-analysis of incidence of intestinal adhesion of TCM versus conventional therapy.

Table 3 .
Meta-analysis of incidence of intestinal adhesion of TCM versus conventional therapy.

Table 4 .
Forest plot of comparison: Total effective rates.

Table 5 .
Forest plot of comparison: Recovery time of Borborygmus.

Table 6 .
Forest plot of comparison: Anal exhaust time.

Table 7 .
Forest plot of comparison: Anal defecation time.

Table 8 .
Forest plot of comparison: Average time of incision healing.