Efficacy and safety of integration of traditional and Western medicine for the treatment of spontaneous bacterial peritonitis in liver cirrhosis: a systematic review

Background

Liver cirrhosis is the end stage of liver diseases with a high morbidity and mortality (1). Ascites is the most common complication of liver cirrhosis. Nearly 60% of patients diagnosed with liver cirrhosis will develop ascites within 10 years (2). Spontaneous bacterial peritonitis (SBP) is a common bacterial infection in cirrhotic patients with ascites. The morbidity and in-hospital mortality of SBP in patients with ascites is 7–30% and 10–50% (3-5).

Several guidelines unanimously recommend third-generation cephalosporins for the treatment of SBP (6-8). However, antibiotic resistance is increasing year by year in SBP patients (9-11). The effectiveness of antibiotics alone for the treatment of SBP is unsatisfactory.

Traditional Chinese medicine (TCM) refers to the drugs and compounds used under the guidance of the TCM theory. Integration of traditional and Western medicine (ITWM) refers to the combination of TCM with Western medicine, which has a great potential for the treatment of many diseases in China (12-14). More and more studies have focused on the ITWM for the treatment of SBP in China.

The aim of this study was to systematically evaluate the efficacy and safety of ITWM for the treatment of SBP.

Materials and methods

Eligibility and exclusion criteria

Eligibility criteria: randomized controlled trials (RCTs) about ITWM for the treatment of SBP in patients with cirrhosis. ITWM group should be patients who received TCM drugs combined with Western medicine drugs. Control group should be patients who received Western medicine drugs alone. Exclusion criteria: (I) incomplete data; (II) reviews; (III) case reports; (IV) duplicate publications; (V) commentaries; (VI) non-RCTs; and (VII) ITWM in the prevention of SBP. No limits on publication status or language.

Literature search

PubMed, China National Knowledge Infrastructure, Wanfang, and VIP databases were searched electronically from inception to July 2016 to collect all RCTs about ITWM for the treatment of SBP in patients with liver cirrhosis. All databases were searched using key words: TCM, SBP, and ITWM.

Data extraction

Data were extracted as follows: title, author’s information, year of publication, study design, method of intervention, effectiveness of treatment, and adverse event.

Effectiveness rate was defined as the proportion of patients in whom SBP-related symptoms and/or laboratory data improved after treatment.

Cure rate was defined as the proportion of patients in whom SBP-related symptoms disappeared and laboratory data normalized after treatment.

Ineffectiveness rate was defined as the proportion of patients without any response to treatment.

Quality of studies

Jadad quality score was used to assess the quality of studies (Table S1) (15).

Randomization: studies using the method of randomization appropriately were graded as 2 points; studies without any description about the method of randomization were graded as 1 point; studies using the method of randomization inappropriately were graded as 0 point.

Double blinding: studies using and describing the double blinding method appropriately were graded as 2 points; studies in which the use of double blinding was just mentioned but the detailed method was lacking were graded as 1 point; studies in which the double blinding method was not used or the method of double blinding was inappropriate were graded as 0 point.

Withdraws and dropouts: studies in which both withdraws and dropouts were described were graded as 1 point; studies in which withdraws and dropouts were not described were graded as 0 point.

Results

Basic information

A total 628 studies were identified. Finally, 42 RCTs including 3,227 SBP patients were enrolled into this study (Figure 1). Information of the included studies is depicted in the Table S2. The distributions of included studies according to the region of China are described in the Figure S1.

Figure 1 Flow diagram.

Medications

Components of TCM-drugs

The most commonly used TCM drugs were demonstrated in Figure 2. Overall, 77 kinds of TCM drugs were used, including Rhubarb (N=24), Red Peony Root (N=20), Danshen Root (N=16), Baical Skullcap Root (N=14), Dahurian Patrinia Herb (N=11), Honeysuckle Flower (N=11), Golden Thread (N=10), Mongolian Dandelion Herb (N=10), Spreading Hedyotis Herb (N=8), Chinese Angelica (N=8), Largehead Atractylodes Rhizome (N=7), Indian Buead (N=7), Safflower (N=7), Officinal Magnolia Bark (N=7), Cape Jasmine Fruit (N=7), Weeping Forsythiae Capsule (N=6), Oriental Waterplantain Rhizome (N=6), Liquoric Root (N=5), Areca Peel (N=4), Sargent Gloryvine (N=4), Radix Astragali (N=4), Lightyellow Sophora Root (N=4), Virgate Wormwood Herb (N=4), Bitter Orange (N=4), Green Tangerine Peel (N=4), Agaric (N=4), Plantain Seed (N=3), Pilose Asiabell Root (N=3), Giant Knotweed Rhizome (N=3), Ginseng (N=3), Peach Seed (N=3), Heartleaf Houttuynia Herb (N=3), Indigowoad Root (N=2), Turtle Shell (N=2), Tangerine Peel (N=2), Myrrh (N=2), Frankincense (N=2), Common Yam Rhizome (N=2), Yanhusuo (N=2), Coix Seed (N=2), Turmeric Root-tuber (N=2), Hiraute Shiny Bugleweed Herb (N=2), Medicinal Indianmulberry Root (N=1), White Hyacinth Bean (N=1), Chinese Pulsatilla Root (N=1), Barbed Skullcap Herb (N=1), Pinellia Tuber (N=1), Areca Seed (N=1), Borneol (N=1), Chinese Thorowax Root (N=1), Halloysit (N=1), Rice Bean (N=1), Common Andrographis Herb (N=1), Indigowoad Leaf (N=1), Zedoary (N=1), Turmeric (N=1), Platycodon Root (N=1), Semen Nelumbinis (N=1), Beautiful Sweetgum Fruit (N=1), European Verbena (N=1), Parslane Herb (N=1), Dwarf Lilyturf Tuber (N=1), Mirabilite (N=1), Oyster Shell (N=1), Bezoar (N=1), Goat Horn (N=1), Common Clubmoss Herb (N=1), Garden Balsam Stem (N=1), Ground Beeltle (N=1), Cowherb Seed (N=1), Bear Gall Powder (N=1), Figwort Root (N=1), Dragon’s Blood (N=1), Motherwort Herb (N=1), Epimedium Herb (N=1), Pearl Powder (N=1), and Common Anemarrhena Rhizome (N=1).

Figure 2 The most commonly used TCM drugs for the treatment of SBP.

There were 12 categories of TCM drugs, including formula for heat-clearing and toxicity-relieving (N=20), formula for blood circulation promoting (N=13), formula for energy-restoring (N=12), formula for water-disinhibiting damp-percolating (N=8), desiccating formula (N=4), carminative formula (N=4), astringent formula (N=3), superficies-resolving formula (N=2), formula for purgation (N=2), formula for rheumatism (N=2), formula for expectorants, antitussives and dyspnea-relieving (N=2), and formula for resuscitation (N=1).

Western medicine drugs

The third-generation cephalosporins, including cefoperazone and ceftriaxone, were the most commonly used Western medicine drugs for the treatment of SBP (71.43%, 30/42).

Form of TCM drugs

Of all included studies, 38.10% (16/42) used the TCM decoction (16-31), 28.57% (12/42) used the Chinese patent medicine (32-43), 21.43% (9/42) used the TCM enema (44-51), 9.52% (4/42) used the TCM umbilicus compression (52-55), and 2.38% (1/42) used the TCM peritoneal lavage (56).

Of all included studies, 4.76% (2/42) used the single-TCM drug (27,57), 30.95% (13/42) used the TCM compounds that have been proven by the China Food and Drug Administration (CFDA) (22,32-43), 16.67% (7/42) used the classical TCM compounds (16-19,25,31,54), and 47.62% (20/42) used the self-made TCM compounds (20,21,23,24,26,28-30,44-53,55,56).

Effectiveness rate

All included studies reported the effectiveness rate. The effectiveness rate was 58.33–96.00% and 32.20–93.75% in ITWM and control groups, respectively (Figure 3). Of all included studies, 97.62% (41/42) reported a higher effectiveness rate in ITWM group; and 92.69% (38/41) of them found a significant difference.

Figure 3 The effectiveness rate. In the study by Li et al. (16), the red bar refers to the control group that used Norfloxacin, the green bar refers to the control group that used Cefazolin.

Cure rate

All included studies reported the cure rate. The cure rate was 9.00–95.00% and 3.00–77.00% in ITWM and control groups, respectively (Figure 4). Of all included studies, 97.62% (41/42) reported a higher cure rate in ITWM group and 24.39% (10/41) of them found a significant difference.

Figure 4 The cure rate. In the study by Li et al. (16), the red bar refers to the control group that used Norfloxacin, the green bar refers to the control group that used Cefazolin.

In-hospital mortality

Four studies reported the in-hospital mortality. The in-hospital mortality was 5.10–18.33% and 7.69–52.78% in ITWM and control groups, respectively (Figure 5). All of the four included studies reported a lower in-hospital mortality in ITWM group; and 50% (2/4) of them found a significant difference.

Figure 5 The in-hospital mortality.

Adverse events

Six studies reported the adverse events, including abdominal pain, diarrhea, vomiting, headache, and rash. The rate of adverse events was 0.00–13.33% and 0.00–59.52% in ITWM and control groups, respectively (Figure 6). Five of them (83.33%, 5/6) reported a lower rate of adverse events in ITWM group; and 80% (4/5) of them found a significant difference.

Figure 6 The rate of adverse events. In the study by Li et al. (16), the red bar refers to the control group that used Norfloxacin, the green bar refers to the control group that used Cefazolin.

Study quality

Of all included studies, 30.95% (13/42) didn’t describe any method of randomization; 64.29% (27/42) used the randomization but didn’t describe any method of randomization; and 4.76% (2/42) used the random number table (Table S1). No studies used the double-blind method. No studies reported the withdrawal/dropout rates.

Discussion

TCM drugs have been used for the treatment of many diseases for over 2,000 years in China and Eastern Asian countries (58). TCM theory is based on the ancient Chinese philosophy, aiming to correct the maladjustments, restore the self-regulatory ability, and remove the harms (59). Due to the language barrier, studies that reported the effectiveness of ITWM for the treatment of SBP are rarely noticed in the Western world. As far as we concern, no review explored the ITWM for the treatment of SBP. Our systematic review found the following: 92.69% (38/41) and 24.39% (10/41) of included studies reported a significantly higher effectiveness and cure rate in ITWM group, respectively; 50% (2/4) showed a significantly lower in-hospital mortality in ITWM group; and 66.67% (4/6) showed a significantly lower proportion of adverse events in ITWM group. Thus, ITWM should be a promising treatment for SBP. Additional benefits of ITWM might be attributed to the inhibition of inflammation, improvement of immunity, regulation of intestinal microflora, improvement of antibiotics bioavailability, and inhibition of drug resistance. However, the accurate mechanisms remained unclear.

Our study also showed that Rhubarb was the most commonly used TCM drug, followed by Red Paeony Root and Danshen root. First, Rhubarb was used in 57.14% (24/42) of studies, which has a role in defecation-accelerating, heat-clearing, blood-cooling, toxin-relieving, blood stasis-dredging, dampness-dredging, and jaundice-resolving according to the TCM theory. Modern pharmacological studies conclude that Rhubarb can protect the digestive tract mucosa and promote the gastrointestinal peristalsis (60). Second, Red Paeony Root was used in 83.33% (20/42) of studies. The dry root of Paeonia Lactiflora Pallas has a role in heat-clearing, blood-cooling, toxin-relieving, and blood stasis-dredging according to the TCM theory. Third, Danshen root was used in 38.10% (16/42) of studies, which has a role in blood circulation-promoting, blood stasis-dredging, and blood-nourishing according to the TCM theory. Anti-inflammatory functions of Red Paeony Root and Danshen Root have been proved (61,62). Additionally, both Red Paeony Root and Danshen Root are the main components of Xuebijing injection, which is the ethanol extract derived from Chuanxiong, Red Paeony Root, Danshen Root, and Honghua. It is the most commonly used Chinese herb compound in all included studies, well-known by its anti-inflammatory function (63). Seven (16.67%) studies used Xuebijing injection for the treatment of SBP.

There are many different forms of TCM drugs, including decoction, enema, sticking, and compound injection. Decoction is the most commonly used form of TCM drugs. It has some advantages: (I) the composition of a decoction can be modified according to the patient’s condition; (II) water is the main carrier to promote the absorption of TCM drugs; and (III) TCM decoction is widely used in China and becomes more and more popular worldwide. However, it also has some disadvantages: (I) TCM decoction is a complex composition that is composed by different TCM drugs. However, the interaction among TCM drugs after boiling and taking remains unclear; (II) the process of preparing a TCM decoction is complex; (III) the quality of TCM drugs after decocted is variable; and (IV) TCM compounds are highly individualized, the indications for modifying the TCM drugs or compounds are unclear.

Safety of ITWM treatment should be carefully evaluated. However, adverse events related to ITWM treatment were generally lacking. Non-specific adverse events (including abdominal pain, diarrhea, vomiting, headache, and rash) were only reported in six studies. No study described the risk factors, management, and outcome of adverse events. Thus, in future studies, there is a need for more detailed reporting on this matter. Additionally, some TCM drugs, such as Medicinal Indian Mulberry Root and Yanhusuo, have the potential of inducing liver and/or renal injury (64,65). Thus, they might be cautiously used in patients with liver and/or renal diseases. Notably, our systematic review demonstrated neither liver nor kidney toxicity of Medicinal Indian Mulberry Root and Yanhusuo.

We found that 30.95% of studies used the CFDA-proved TCM compounds, 16.67% of studies used the classical TCM compounds, and 47.62% of studies used the self-made TCM compounds. The CFDA-proved TCM compounds can be identified on the CFDA official website (http://www.sda.gov.cn/WS01/CL0001/). The classical TCM compounds can be identified from the classic books of TCM and are recognized by many TCM practitioners. The self-made TCM compounds are invented by some TCM practitioners based on their own clinical experiences. Certainly, the quality of the self-made TCM compounds may be uncertain. Only two studies (27,57) used the single-TCM drug (Rhubarb and Heartleaf Houttuynia Herb).

Some limitations should be pointed out. First, the ITWM treatment strategy and patients’ conditions are different among studies, which cause different rates of effectiveness, cure, and adverse events among studies. Thus, the data was not pooled due to these huge heterogeneities among studies. Second, a uniform definition of “therapeutic effectiveness” was lacking, which might contribute to the heterogeneity. For example, in Zhang’s paper, the definition of “effectiveness” was broad and easy to achieve, but the definition of “cure” was strict (36). This may lead to a higher effectiveness rate and a lower cure rate. Third, the quality of included studies was relatively poor. The quality of TCM RCTs performed in China has been questioned (66). Almost all TCM RCTs claimed a superiority of TCM treatment, but only few of them were of high-quality. Some methodological components of the RCTs were incompletely reported. Wang et al. (67) identified a total of 7,422 RCTs published between 1999 and 2004. Surprisingly, only 17.9% (1,329/7,422) of them were truly randomized. Forth, the risk control of TCM drugs was unavailable (68). Fifth, there are few TCM specialized hospitals in Western countries. Thus, the TCM RCTs were hardly performed in Western countries. It is also hard to extrapolate our conclusions to Western countries. Sixth, only 11 out of the 42 trials used albumin for the SBP treatment. Indeed, the lack of albumin administration in most of the trials included is a reason of concern, because it impairs the subjects’ outcome and makes difficult to compare the results.

In conclusion, ITWM might be effective and safe for the treatment of SBP. However, the quality of studies on ITWM for the treatment of SBP should be improved in future. Further well-randomized, double-blind, and placebo-controlled studies with a strict and uniform definition of effectiveness (i.e., partial response) and cure (i.e., complete response) are needed to explore the benefit/risk of a specific TCM drug or compound (i.e., Rhubarb or Xuebijing injection) for the treatment of SBP.

Figure S1 The distributions of studies regarding ITWM for the treatment of SBP according to the regions in China.

Acknowledgements

Funding: None.

Footnote

Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/amj.2017.08.10). Dr. Qi serves as an Editor-in-Chief of AME Medical Journal. Andrea Mancuso serves as an unpaid editorial board member of AME Medical Journal from Mar 2017 to Mar 2019. Fernando Gomes Romeiro serves as an unpaid editorial board member of AME Medical Journal from Apr 2017 to Apr 2019. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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