Introduction

Spontaneous intracerebral hemorrhage (ICH) is one of the most detrimental subtypes of stroke. It accounts for 10%–15% of all strokes and is an important public health problem that leads to significant morbidity and mortality1. The epidemiological perspective on ICH remains bleak. ICH affects 24.6 per 100 000 person-years; the median case fatality within 1 month was 40.4%, and the functional dependency after ICH was approximately 75%2. In China, a nation of 1.4 billion, which accounts for almost one-fifth of the world's total population, stroke is already the leading cause of death3. In addition, a recent systematic review showed that the Chinese have higher overall stroke incidence. ICH accounts for a higher proportion of stroke in Chinese than the white population4.

Currently, no specific therapies or treatments improve the outcome after ICH. The updated evidence-based guidelines for the management of ICH from the American Heart Association/American Stroke Association remain multifaceted; most recommendations are symptomatic and supportive5. In the trial in surgery, the results of spontaneous supratentorial lobar intracerebral hematomas (STICH II) confirmed that early surgery did not increase the rate of death or disability at 6 months. This suggested that there is a small survival advantage for patients with ICH who did not have intraventricular hemorrhage6. Acute hemostatic management is not usually recommended to control bleeding in ICH guidelines; the exception is rare cases, such as those including oral anticoagulants, coagulation factor deficiencies, and platelet abnormalities, in which underlying hemostatic abnormalities may contribute to ICH7. Although hemostatic therapy with rFVIIa can limit the extent of hematoma expansion in noncoagulopathic ICH patients, there is an increase in thromboembolic risk with rFVIIa, and the survival or functional outcome after ICH is not increased8. Faced with the limitations of the present available treatments, complementary and/or alternative medicine (CAM) is thus increasingly sought to treat stroke worldwide.

In China, traditional Chinese medicine (TCM), including various forms of herbal medicine, acupuncture, massage (Tuina), exercise (qigong), and dietary therapy, has been used to treat stroke patients for over 2000 years9. In fact, TCM was the major available method of healthcare in the western pacific region of the world before modern Western medicine was introduced. However, stroke was divided into ischemic and hemorrhagic until the end of the Qing Dynasty (1616–1911). A brief history of TCM application in acute ICH has been summarized by Zheng et al10as follows: (1) before the 1950s–1960s, the pathogenesis of acute ICH emphasized up-stirring of the liver and adverse-rising of both blood and qi; (2) from the 1970s, the central pathogenesis of acute ICH has been considered as a blocked passage of the middle Jiao, a disorder of qi in ascending and descending and abnormal flow of qi and blood; (3) from the 1980s, it was claimed that the vital pathogenesis of acute ICH was blood stasis; (4) in recent years, theories of endogenous toxins and deficient vital qi have been developed. However, blood stasis syndrome can be found throughout the pathological process of ICH under the TCM theory of 'abnormal flow of the blood is blood stasis' in Xuezheng Lun (On Blood Syndromes), written by Tang Rong-chuan during the Qing Dynasty. Thus, the key point of the treatment method for ICH was promoting blood circulation for removing blood stasis (PBCRBS). Blood stasis, known as 'Oketsu' in Japanese, 'Xueyu' in Chinese and 'Eohyul' in Korean, refers to whenever the circulation of blood is not smooth or the blood flow is stagnant and forms stasis11. Although the consensus among the interviewed experts was that the definition of blood stasis is rather complicated and that there is no gold standard marker for detecting blood stasis12, blood stasis refers to a group of distinct syndromes. Over the following three decades, there have been a number of clinical trials to evaluate the efficacy and safety of the PBCRBS method for acute ICH. Therefore, the objective of the present systematic review is to assess the current evidence available regarding the PBCRBS method for patients suffering from acute ICH.

Methods

Standard protocol registration

This systematic review was registered in PROSPERO, and the registration identifier of the protocol is CRD4201400900313.

Study criteria

Types of studies

Only randomized controlled clinical trials (RCTs), which evaluate the efficacy and safety of the PBCRBS prescription for acute ICH, were included in the qualitative analyses, regardless of blinding, publication status or language. We included the RCTs assessed in ≥4 domains with 'yes' for the analyses using the Cochrane RoB tool14,15. Quasi-RCTs, taking those using the admission sequence for treatment allocation as example, were not considered.

Types of participants: patients of any gender, age, or race/ethnicity with ICH within 14 d from the onset were included. The ICH was diagnosed according to the Chinese national criteria in Diagnostic Essentials of Various Cerebrovascular Diseases revised at the Fourth National Conference of the China Society of Medicine on Cerebrovascular Diseases in 199516. The diagnosis of ICH was confirmed by CT scan or MRI.

Types of interventions

The patients of the control groups were given Western conventional medication (WCM), WCM plus stereotactic microsurgery (SM), or placebo alone. The patients at the treatment groups were given PBCRBS intervention as add-on therapy, which included PBCRBS prescriptions, Chinese patent herbal oral preparations, and Chinese patent herbal injections. PBCRBS therapy was defined as the use of common blood-invigorating and stasis-removing herbal prescriptions, based on the Eight Principles plus differentiation between qi and blood11, and any Chinese patent herbal preparation that comes from commonly used blood-invigorating and stasis-removing herbs based on both TCM theory and Western medicine. Studies comparing different forms of TCM were excluded. The clinical trials were included regardless of the dosage or duration of treatment. The mode of delivery was the oral route or injection route.

Types of outcome measurements

The primary outcome measures were mortality and dependency at the end of the treatment course or at the end of follow-up. Dependency was defined as needing assistance in the activity of daily living scale (ADL), using the Barthel Index (BI) and modified Rankin Standard (mRS). The secondary outcome measures were the clinical effective rate, the neurological deficit improvement, volume of hematoma, volume of perihematomal edema and adverse events. The neurological deficit improvement was assessed using the Chinese Clinical Neurological Deficit Scale (CCNDS) and National Institutes of Health Stroke Scale (NIHSS) score after treatment.

Literature search

A comprehensive literature search was conducted in CENTRAL (The Cochrane Library), PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), VIP Journals Database and the Wanfang database from inception to December 2013. The search terms used were '(Promoting Blood Circulation OR Removing Blood Stasis) AND (intracerebral hemorrhage OR hemorrhagic stroke)' in English and (Huoxue OR Huayu) AND (Naochuxue OR Chuxuezhongfeng) in Chinese pinyin in the Chinese databases. The search was restricted to clinical trials or reviews. No limitation was placed on publication date, country or language. The reference lists of all relevant articles were also searched for appropriate studies.

Study selection and data collection process

All articles were screened by 2 independent reviewers, who extracted data from the articles according to a standardized data extraction form, including study design, patients' characteristics (age, gender, and onset of ICH), PBCRBS treatment protocol, control intervention, and outcome parameters. The reasons for inclusion and exclusion of studies were recorded at all stages. For eligible studies, 2 authors of this work extracted the data independently. The missing data were obtained by contacting the authors of the original studies. Disagreements were settled through discussion or consultation with corresponding authors.

Risk of bias and grading the quality of evidence

The risk of bias was assessed using the 7 criteria recommended by the Cochrane Handbook17. We included the RCTs assessed in ≥4 domains with 'yes' for the analyses; ie, we excluded those cases assessed in ≥3 domains with 'unclear' or 'no' which were classified as having a high risk of bias14,15. The level of evidence was assessed by the updated GRADE system18. We classified evidence into 4 grades: high quality, moderate quality, low quality and very low quality. The low and very low quality of evidence showed a serious limitation in the study design, study quality, consistency, directness of the evidence and precision of the results.

Description of the herbal medicine and herbal prescription

The selection criteria of high-frequency herbs and herbal prescriptions in the treatment of ICH were those with cumulative frequencies of over 50%.

Data analysis

All data analyses were performed using Review Manager 5.1.0, compiled by the Cochrane Collaboration. The risk ratio (RR), with a 95% confidence interval (CI), was calculated for dichotomous outcomes, whereas weighted mean differences (WMD) or standardized mean differences (SMD) were used for continuous outcomes. Heterogeneity was examined by the chi-square test at a significance level of 0.05. An I2 statistic was also calculated to estimate variation among studies as follows: I2 values of 25%, 50%, and 75% correspond to low, moderate, and high level of heterogeneity, respectively. However, on account of the clinical heterogeneity, all meta-analyses were performed using a random-effect model. Publication bias was detected by funnel plot analyses. Two-tailed P values less than 0.05 were considered statistically significant.

Results

Description of the selection process

We identified 3426 potentially relevant articles from 6 databases. After removal of duplicates, 1330 records remained. After going through the titles and abstracts, we excluded 594 studies for at least one of following reasons: (1) the study was a case report or review, (2) not a clinical trial, or (3) did not include Chinese herbs and formulas for promoting blood circulation and removing blood stasis. By reading the full texts of the remaining 736 articles, we excluded 444 studies for at least one of following reasons: (1) there were no RCTs or no real RCTs, (2) the study did not include the acute phase of intracerebral hemorrhage, or (3) the study compared TCM or acupuncture. The remaining 292 studies examining the efficacy of Chinese herbs and formulas were included for qualitative analysis. Of the 292 studies, 9 studies assessed ≥4 domains with 'yes'; these were selected for detailed assessment and meta-analysis. The flow diagram is shown in Figure 1.

Figure 1
figure 1

PRISMA 2009 flow diagram.

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Description of the studies

The sample sizes of the 9 studies ranged from 21 to 213, with a total of 830 subjects (Table 1). All studies were carried out in China and published in Chinese language journals from 2000 to 2013. The criteria used in these 9 studies for diagnosis of ICH were the Chinese Cerebrovascular Disease Diagnosis Standard 1995 (CCDDS 1995). Of the 9 studies, 5 studies compared PBCRBS plus WCM with WCM alone, 2 studies19,20 compared PBCRBS plus WCM plus SM with WCM plus SM, one21 compared PBCRBS plus WCM plus SM with WCM alone, and only one22 used a placebo control. The subjects' durations of ICH reported in the 9 studies were all within 3 d. The course of PBCRBS treatment lasted 10 d to 8 weeks in the 9 studies. Seven of the 9 studies reported follow-up; follow-up was from 30 d to one year after finishing treatment.

Table 1 The characteristics of included studies.
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Assessment by the Cochrane's risks of bias

Eight of the 9 studies had at least one domain rated as high risk of bias19,20,21,23,24,25,26,27 (Table 2). In the double-blind study, none of the domains were rated as having high risks of bias. In the 2 single-blind studies, the blinding procedure was not described, and there was a high risk of bias in concealment of allocation. In the 6 open-label studies, there were high risks of bias both in concealment of allocation and blinding: neither the subjects nor the evaluators were blinded.

Table 2 Assessment of study quality and risk of bias.
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Description of the PBCRBS herbs and prescriptions

A total of 41 standardized Chinese herbal formulas were examined in 229 (78.4%) of the 292 studies, while the other 63 studies used an individualized approach. The top 8 herbal formulas were used in 142 (48.6%) of the 292 reviewed studies (Table 3). These included Xueshuantong Injection (11.3%), an extract from Sanqi (Radix Notoginseng); Fufang Danshen Injection/**angdan Injection (10.3%), composition of Danshen (Radix Salviae miltiorrhizae) and Jiangxiang (Lignum Dalbergiae Odoriferae); Danshen Injection (7.9%), an extract from Danshen root; Shuxuetong Injection (5.5%), composition of Shuizhi (Hirudo) and Dilong (Lumbricus); Shuxuening injection/Yinxingye Preparations (4.1%), an extract from Yinxingye (Folium Ginkgo); Dengzhan **xin Injection/Dengzhan Huashu Injection (3.8%), an extract from Dengzhan **xin (Herba Erigerontis); Buyang Huanwu decoction (3.1%), and Liangxue Tongyu Injection/Liangxue Tongyu oral liquid (2.7%). These commonly used prescriptions corresponded to syndromes, including the syndrome of blood stasis (due to bleeding), syndrome of stagnation of qi and blood stasis, syndrome of blood stasis due to blood deficiency, syndrome of intermingled phlegm and blood stasis, syndrome of blood stasis, syndrome of blood stasis due to coagulated cold, syndrome of blood stasis due to qi deficiency, and syndrome of blood stasis due to heat toxicity, respectively (Table 3). Seven out of the 8 prescriptions are Chinese herbal patent preparations, which are quality controlled for manufacturing methods. In addition, 6 Chinese herbal patent preparations all have injection preparations, which are more convenient during a stroke emergency. The remaining preparation is a famous Chinese herbal prescription, Buyang Huanwu decoction, which is specifically used to treat stroke, according to the theory of qi deficiency and blood stasis recorded in Yilin Gaicuo (Correction of Errors in Medical Classics), written by Wang Qingren in 1830.

Table 3 The most commonly used prescription corresponding to syndrome and pharmacological study for acute intracerebral hemorrhage.
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The numbers of Chinese herbs in the formulas varied from 1 to 9. The top 15 single herbs are shown in Table 4. Danshen (Radix Salviae miltiorrhizae) was the most frequently used single herb; it was used in 109 (37.3%) of the 292 studies. This was followed by Sanqi (Radix Panax notoginseng) (36.3%), Shuizhi (Hirudo) (30.1%), Chuanxiong (Rhizoma Ligustici Chuanxiong) (27.4%), Taoren (Semen Persicae) (23.3%), Chishao (Radix Paeoniae rubra) (20.2%), Honghua (Flos Cartham) (19.9%), Dilong (Lumbricus) (18.8%), Danggui (Radix Angelicae sinensis) (16.8%), Chuanniuxi (Radix Cyathulae) (13.0%), Jiangxiang (Lignum Dalbergiae Odoriferae) (12.0%), Huangqi (Radix Astragali seu Hedysari) (6.8%), Yu** (turmeric root tuber, Curcuma longa) (5.5%), Shexiang (musk) (5.1%), and Quanxie (scorpion) (4.5%).

Table 4 The most commonly used herbs for acute intracerebral hemorrhage.
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Efficacy assessment

Mortality

The mortality was reported in 7 of the 9 studies. Meta-analysis showed that PBCRBS treatment significantly reduced the mortality rate in the trial group compared with the control group. The risk ratio in the 7 studies varied from 0.24 to 0.86, with an overall risk ratio of 0.50 (95% CI: 0.35 to 0.71, P<0.05, I2=0%, Figure 2). In the double-blind placebo control study22, the risk ratio was 0.41, which was lower than the overall risk ratio.

Figure 2
figure 2

The forest plot: mortality rate.

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ADL score

The Barthel Index was used in 2 studies22,27 and evaluated at 90 d after PBCRBS treatment. There were significant differences between the PBCRBS group and the control group (1.86, 95% CI: 1.39 to 2.49, P<0.05, I2= 0%, Figure 3). In addition, the mRS was used in Chen's study22. At the last time point investigated, there were 60 patients (55.5%) who achieved a good outcome (mRS 0, 1, 2) in the PBCRBS group and 30 patients (28.5%) in the control group; there were significant differences among these studies, according to the Cochran-Mantel-Hansel (CMH) test (P=0.048). For the subjects who began treatment within 24 h after an attack, there were 5 patients (4.6%) who had severe disability (mRS 4, 5, 6) in the PBCRBS group and 9 patients (8.6%) in the control group; there were no significant differences between these groups, according to the CMH test (P=0.741). For the subjects who began treatment between 24 and 48 h after the attack, there were 5 patients (5.1%) who had severe disability (mRS 4, 5, 6) in the PBCRBS group and 15 patients (16.7%) in the control group; there was a significant difference between these two groups, according to the CMH test (P=0.048). For the subjects who began treatment between 48 and 72 h after an attack, there were 7 patients (7.5%) who had severe disability (mRS 4, 5, 6) in the PBCRBS group and 19 patients (21.2%) in the control group; there were significant differences between these groups, according to the CMH test (P=0.031).

Figure 3
figure 3

The forest plot: the barthel index.

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Clinical effective rate

The clinical efficacy was reported in 3 of the 9 studies. The definition of effective rate was not standardized. It was defined according to CCNDS 1995 in 2 studies20,26 and according to the clinical guidelines for new drugs for TCM28 in the remaining 1 study24. The risk ratio of clinical efficacy in the 3 studies varied from 1.35 to 1.59, with an overall risk ratio of 1.44 (95% CI: 1.16 to 1.78, P<0.05, I2=0%, Figure 4); for the SM group20, the risk ratio was 1.35; for the non-SM groups24,26, the risk ratios were 1.47 and 1.59, respectively.

Figure 4
figure 4

The forest plot: Clinical effective rate.

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Volume of hematoma

The volume of hematoma was used as an outcome measure in 3 of the 9 studies; the volume was evaluated at 14 and 28 d after PBCRBS treatment. Meta-analysis showed that PBCRBS treatment significantly reduced the volume of hematoma in the trial group when compared with the control group (−2.72, 95% CI: −4.12 to −1.32, P<0.05, I2=77%). The volume of hematoma in the trial group was more significantly reduced than that in the control group at 28 d (−2.05, 95% CI: −2.89 to −1.22, P<0.05, I2=0%) after PBCRBS treatment, but not at 14 d (−3.21, 95% CI: −6.34 to −0.09, P=0.04, I2=91%, Figure 5).

Figure 5
figure 5

The forest plot: volume of hematoma.

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Volume of perihematomal edema

The volume of perihematomal edema was used as an outcome measure in 3 of the 9 studies and evaluated at 7, 14, and 21 d after PBCRBS treatment. Meta-analysis showed that PBCRBS treatment significantly reduced the volume of perihematomal edema in the trial group compared with the control group (−5.84, 95% CI: −8.62 to −3.06, P<0.05, I2=95%). After PBCRBS treatment, significant differences between the trial group and control group were detected at 21 d (−7.27, 95% CI: −7.91 to −6.64, P<0.05, I2=0%), but not at 7 d (−3.08, 95% CI: −7.23 to 1.07, P=0.15, I2=54%) or 14 d (−7.39, 95% CI: −15.06 to 0.28, P=0.06, I2=88%, Figure 6).

Figure 6
figure 6

The forest plot: volume of perihematomal edema.

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NIHSS score

Two19,26 of the 9 studies used NIHSS scores to determine the effect of PBCRBS on the neurological function of the patients. The NIHSS score was assessed at 14 and 28 d after PBCRBS treatment. The overall results indicate that the PBCRBS group had a measurably better recovery of neurological functions than the control group (−5.34, 95% CI: −7.14 to −3.53, P<0.05, I2=92%). Furthermore, the NIHSS score in the PBCRBS group was significantly lower when compared with the control group at 14 d (−4.75, 95% CI: −5.57 to −3.93, P<0.05, I2=0%) and 28 d (−5.68, 95% CI: −8.87 to −2.49, P<0.05, I2=94%, Figure 7).

Figure 7
figure 7

The forest plot: national institute of health stroke scale (NIHSS) score.

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CCNDS score

The CCNDS score was used in 2 studies25,27 and assessed at 14, 30 and 90 d following PBCRBS treatment. Meta-analysis showed that PBCRBS treatment significantly reduced the CCNDS score in the trial group compared with the control group (−4.50, 95% CI: −6.44 to −2.57, P<0.05, I2=83%). After PBCRBS treatment, significant differences between the trial group and control group were detected at 30 d (−5.38, 95% CI: −7.73 to −3.03, P<0.05, I2=52%) and 90 d (−2.96, 95% CI: −3.99 to −1.92, P<0.05, I2=83%), but not at 14 d (−4.74, 95% CI: −10.49 to 1.01, P=0.11, I2=90%, Figure 8).

Figure 8
figure 8

The forest plot: Chinese clinical neurological deficit scale (CCNDS) score.

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Adverse event reporting

Adverse events were reported in 2 of the 9 studies and not mentioned in the remaining 7 studies. Chen et al

References

  1. Qureshi AI, Mendelow AD, Hanley DF . Intracerebral haemorrhage. Lancet 2009; 373: 1632–44.

    Article  PubMed  PubMed Central  Google Scholar 

  2. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ . Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnicorigin: a systematic review and meta-analysis. Lancet Neurol 2010; 9: 167–76.

    Article  PubMed  Google Scholar 

  3. Liu L, Wang D, Wong KS, Wang Y . Stroke and stroke care in China: huge burden, significant workload, and a national priority. Stroke 2011; 42: 3651–4.

    Article  PubMed  Google Scholar 

  4. Tsai CF, Thomas B, Sudlow CL . Epidemiology of stroke and its subtypes in Chinese vs white populations: a systematic review. Neurology 2013; 81: 264–72.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Morgenstern LB, Hemphill JC 3rd, Anderson C, Becker K, Broderick JP, Connolly ES Jr, et al. American heart association stroke council and council on cardiovascular nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010; 41: 2108–29.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM, et al. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet 2013; 382: 397–408.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Toyoda K, Steiner T, Epple C, Kern R, Nagayama M, Shinohara Y, et al. Comparison of the European and Japanese guidelines for the acute management of intracerebral hemorrhage. Cerebrovasc Dis 2013; 35: 419–29.

    Article  PubMed  Google Scholar 

  8. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. New Engl J Med 2008; 358: 2127–37.

    Article  CAS  PubMed  Google Scholar 

  9. Wang Y, Fan YC, **e CL, Zheng GQ . History of post–stroke epilepsy in ancient China. J Neurol 2011; 258: 1555–8.

    Article  PubMed  Google Scholar 

  10. Zheng GQ, Huang PX . Origin and development of hemorrhagic stroke. Chin J Med Hist 2005; 35: 25–8.

    Google Scholar 

  11. Chen KJ . Blood stasis syndrome and its treatment with activating blood circulation to remove blood stasis therapy. Chin J Integr Med 2012; 18: 891–6.

    Article  PubMed  Google Scholar 

  12. Choi TY, Jun JH, Lee JA, Park B, You S, Jung J, et al. Expert opinions on the concept of blood stasis in China: an interview study. Chin J Integr Med 2014. doi: 10.1007/s11655-014-1983-3.

    Article  PubMed  Google Scholar 

  13. Li HQ, Liu AJ, **a W, Li JH, Wei JJ, Yin SB, et al. Promoting blood circulation for removing blood stasis as therapy for acute intracerebral hemorrhage: a systematic review and meta-analysis [database on the Internet]. York: University of York (UK). c2014 - [cited 2014 Jun 18]. Available from: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014009003

  14. Higgins JP, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, et al. The cochrane collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Chung JH, Lee JW, Jo JK, Kim KS, Lee SW . A quality analysis of randomized controlled trials about erectile dysfunction. World J Mens Health 2013; 31: 157–62.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chen QT . Classification, diagnostic criteria and evaluation of neurological impairment for stroke patients. Chin J Neurol 1996; 29: 379.

    CAS  Google Scholar 

  17. Cochrane.org [www.cochrane-handbook.org]. London: The Cochrane Collaboration (UK); c2008 [updated March 2011; cited 2014 Jun 18]. Available from: www.cochrane-handbook.org

  18. Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, et al. GRADE guidelines: 11. Making an overall rating of confidence in effect estimates for a single outcome and for all outcomes. J Clin Epidemiol 2013; 66: 151–7.

    Article  PubMed  Google Scholar 

  19. Sun JH, Chen W . Clinical study of minimally traumatic puncture drainage of hematoma combined with Salviae Miltiorrhizae injection in treatment of hypertensive cerebral hemorrhage. Chin J Integr Tradit And Western Med 2008; 15: 28–30. Chinese.

    Google Scholar 

  20. Dai MX, **ao YJ, Wang JP, **ao HL, Tang CH, et al. Clinical efficacy of zhuyuxiaozhong decoction combined with Stereotactic microsurgery therapy in treating hypertensive cerebral hemorrhage. J New Chin Med 2002; 3: 40–2. Chinese.

    Google Scholar 

  21. Huang JL, Li YH, Lin ZP . Therapeutic efficacy of stereotactic microsurgery combined with therapy of inducing resuscitation, activating blood and promoting diuresis in treating severe cerebellopontine hemorrhage. J Guangzhou Univ Tradit Chin Med 2010; 27: 445–8. Chinese.

    CAS  Google Scholar 

  22. Chen SH, Zhang XY, Li XG, Wang J, Long CG, **ong Y, et al. Clinical efficacy of zhongfengxingnao oral solution in Chinese subjects with acute cerebral hemorrhage: a randomized, double-blind, placebo-controlled trial [database on the Internet]. Bei**g: Tsinghua Tongfang Knowledge Network Technology Co, Ltd. c2010 - [cited 2014 Jun 18]. Available from: http://cpfd.cnki.com.cn/Article/CPFDTOTAL-ZHZY201008004006.htm.

  23. He D, Liu QR, Zhao JX . Therapeutic efficacy of xueshuantong injection on patients with acute intracerebral hemorrhage in early stage. Chin J Integr Tradit And West Med Intens and Crit Care 2002; 9: 27–9. Chinese.

    CAS  Google Scholar 

  24. Fan Y, Zhou ZY, ** MW . The influence of liangxuetongyu oral solution on early rehabilitation of hypertensive cerebral hemorrhage. Chin J Integr Tradit West Med 2000; 20: 138–40. Chinese.

    Google Scholar 

  25. Wang YQ, Shi Q, Wang WP . Clinical study of xuefuzhuyu decoction on hypertensive intracerebral hemorrhage. J Emerg Tradit Chin Med 2013; 22: 1686–7, 1689. Chinese.

    Google Scholar 

  26. Zhang SQ, Zhang CP, Chen ML, Xu XY, Hou B . Clinical study of bushenhuoxuehuatan decoction on acute cerebral hemorrhage. J Emerg Tradit Chin Med 2012; 4: 529–30, 557. Chinese.

    Google Scholar 

  27. Wang ZF, Wang JY . Efficacy observation of the sequential therapy of traditional Chinese medicine for hypertensive cerebral hemorrhage. China Pharm 2011; 3: 263–5. Chinese.

    Google Scholar 

  28. Ministry of Health of the People's Republic of China. Clinical guideline of new drugs for traditional Chinese medicine. 1993. 35–6.

  29. De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, et al. International Committee of Medical Journal Editors. Clinical trial registration: a statement from the International Committee of Medical Journal. New Engl J Med 2004; 351: 1250–1.

    Article  PubMed  Google Scholar 

  30. Kjaergard LL, Villumsen J, Gluud C . Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001; 135: 982–9.

    Article  CAS  PubMed  Google Scholar 

  31. Kotsirilos V . Complementary and alternative medicine. Part 2-evidence and implications for GPs. Aust Fam Physician 2005; 34: 689–91.

    PubMed  Google Scholar 

  32. Meng LQ, Huang RY, Zhu CL, Wei SG, Li XB, Huang JM . The effect of Panax Notoginseng Saponins on expression of AQP4 and brain edema after intracerebral hemorrhage in rats. Chin J Geriatr Heart Brain Vessel Dis 2007; 9: 53–6. Chinese.

    CAS  Google Scholar 

  33. Zhao XS, Chen ZG, Gao F, Xu ZF . Effect of Panax Notoginseng saponins on cerebral water content and thrombin of intracerebral hemorrhage rats. Chin J Inform on TCM 2014; 21: 46–8. Chinese.

    Google Scholar 

  34. Zhu JH, Wang DK, Dong KQ, Dai XW, He LF . Effects of total panax notoginseng saponins on ultrastructure of mitochondria for intracerebral hemorrhage focus in rats. Chin J Neuroanat 2014; 30: 60–4. Chinese.

    CAS  Google Scholar 

  35. Si YC, Li JW, Zhu PC, Zhang LJ . Effects of Panax Notoginseng saponins on expression of excitatory amino acid receptor GluR2 subunit of AMPA receptor in rat forebrain after intracerebral hemorrhage. Chin J Anat 2005; 28: 535–8. Chinese.

    CAS  Google Scholar 

  36. Zhang ZZ, Zhang BH, Chen M . The study of Danshen Injection for prevention and treatment of brain edema in acute intracerebral hemorrhage. Zhejiang J Integr Tradit Chin West Med 2003; 13: 355–7. Chinese.

    Google Scholar 

  37. Liu HY, Zhang HY, Ma QR, Wang DK, Sun Z, Han JL, et al. Effect of Danshen Injection on neurons apoptosis that surround intracerebral hemorrhage in rats. Chin Tradit Patent Med 2012; 34: 731–3. Chinese.

    Google Scholar 

  38. He YP, Huang JZ, Ying RB, Pan GC . Study on correlation of thrombin and cerebral edema following intracerebral hemorrhage and effects of treated with hirudo powder. Chin J Emerg Med 2002; 11: 172–5. Chinese.

    Google Scholar 

  39. Wu Q, Chen GH, Yang F, Chen ZW . Pathological study of treatment effect of hirudo on experimental intracerebral hemorrhage. J Clin Exp Pathol 1999; 15: 51–3. Chinese.

    Google Scholar 

  40. Wang DK, Zhang HY, Sun Z, Liu HY, Li Q, Zhang LX, et al. Effects of Ginkgo Biloba extract on apoptotic neurons around the early hematoma after intracerebral hemorrhage in rats. J Ningxia Med Univ 2011; 33: 537–9. Chinese.

    Google Scholar 

  41. Ke JF, Du QC, Zhang HY, Qin Y, Li L, Li Q . Effects of injection of ginkgo biloba leave extract on content of IL-8 and ICAM-1in brain of intracerebral hemorrhage in rats. Ningxia Med J 2010; 32: 46–8.Chinese.

    Google Scholar 

  42. Hu JH, Chen HJ, Liu HY, Che P, Qing Y, Zhang LX . The protective effect of erigeron on hemorrhagic brain injury in rats. Chin J Neuroanat 2013; 29: 209–13. Chinese.

    CAS  Google Scholar 

  43. Dai XW, Zhang HY, Wang DK, Qin Y, Zhang Y . Effects of Breviscapine on cerebral edema and expression of intercellular adhension molecular-1 in rats of cerebral hemorrhage. Chin J Neuroanat 2011; 27: 665–9. Chinese.

    CAS  Google Scholar 

  44. Sun H, Guo FQ, Wang DZ, Zhang HY, Wang JY . Effects of Buyang Huanwu decoction on expression of aquaporin-4 in brain tissue of intracerebral hemorrhage rats. J Clin Neurol (China) 2012; 25: 115–8. Chinese.

    Google Scholar 

  45. Luo JK, Tang T, Li XQ . Effect of Buyang Huanwu decoction on activated caspase-3 after intracerebral hemorrhage in rats. J Tradit Chin Med Univ Hunan 2006; 26: 12–4. Chinese.

    Google Scholar 

  46. Liu XJ, Tang T, Luo JK, Huang JF, Yang QD, **ng ZH, et al. Effect of Buyang Huanwu decoction on expression of VEGF mRNA in rat brains following cerebral hemorrhage. Tradit Chin Drug Res Clin Pharmacol 2007; 18: 100–3. Chinese.

    CAS  Google Scholar 

  47. He CY, Huang JH, Zhou XP, ** MW, Ye F, Wu HT, et al. Effect of Liangxue Tongyu Formula on t-PA and MMP-9 expressions in rats with intracerebral hemorrhage. Chin J Tradit Chin Med Pharm 2011; 26: 50–3. Chinese.

    CAS  Google Scholar 

  48. He CY, Huang JH, Wang WJ, ** MW, Ye F, Wu HT, et al. Effect of Liangxue Tongyu Formula on brain edema and expressions of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rats with intracerebral hemorrhage. J Chin Integr Med 2010; 8: 347–51. Chinese.

    Article  Google Scholar 

  49. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006; 66: 1175–81.

    Article  CAS  PubMed  Google Scholar 

  50. Wada R, Aviv RI, Fox AJ, Sahlas DJ, Gladstone DJ, Tomlinson G, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 2007; 38: 1257–62.

    Article  PubMed  Google Scholar 

  51. Nie YX, Wang D, Zhang X . Effect of panax notoginseng saponins injection on brain edema in intracerebral hemorrhage rats. Chin J Integr Tradit West Med 2006; 26: 922–5. Chinese

    CAS  Google Scholar 

  52. Xue M, Hollenberg MD, Demchuk A, Yong VW . Relative importance of proteinase-activated receptor-1 versus matrix metalloproteinases in intracerebral hemorrhage-mediated neurotoxicity in mice. Stroke 2009; 40: 2199–204.

    Article  CAS  PubMed  Google Scholar 

  53. Guangzhou University of Traditional Chinese Medicine. Clinical re-evaluation of removing blood stasis therapy in treating acute cerebral hemorrhage safety and efficacy [database on the Internet]. Bethesda: National Library of Medicine (US). c2013 - [cited 2014 Jun 18]. Available from: http://clinicaltrials.gov/show/NCT01918722

  54. Wang J, **ong X . Current situation and perspectives of clinical study in integrative medicine in china. Evid Based Complement Alternat Med 2012; 2012: 268542.

    PubMed  PubMed Central  Google Scholar 

  55. Jiang M, Lu C, Zhang C, Yang J, Tan Y, Lu A, et al. Syndrome differentiation in modern research of traditional Chinese medicine. J Ethnopharmacol 2012; 140: 634–42.

    Article  PubMed  Google Scholar 

  56. Bensoussan A, Talley NJ, Hing M, Menzies R, Guo A, Ngu M . Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial. JAMA 1998; 280: 1585–9.

    Article  CAS  PubMed  Google Scholar 

  57. Li SM, Xu H, Chen KJ . The diagnostic criteria of blood-stasis syndrome: considerations for standardization of pattern identification. Chin J Integr Med 2014; 20: 483–9.

    Article  CAS  PubMed  Google Scholar 

  58. Lu A, Jiang M, Zhang C, Chan K . An integrative approach of linking traditional Chinese medicine pattern classification and biomedicine diagnosis. J Ethnopharmacol 2012; 141: 549–56.

    Article  PubMed  Google Scholar 

  59. Wang L, Yuan Q, Marshall G, Cui X, Cheng L, Li Y, et al. Adverse drug reactions and adverse events of 33 varieties of traditional Chinese medicine injections on national essential medicines List (2004 edition) of China: an overview on published literatures. J Evid Based Med 2010; 3: 95–104.

    Article  PubMed  Google Scholar 

  60. Bian ZX, Tian HY, Gao L, Shang HC, Wu TX, Li YP, et al. Improving reporting of adverse events and adverse drug reactions following injections of Chinese materia medica. J Evid Based Med 2010; 3: 5–10.

    Article  PubMed  Google Scholar 

  61. Schulz KF, Altman DG . Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 2010; 63: 834–40.

    Article  PubMed  Google Scholar 

  62. Flower A, Witt C, Liu JP, Ulrich-Merzenich G, Yu H, Lewith G . Guidelines for randomised controlled trials investigating Chinese herbal medicine. J Ethnopharmacol 2012; 140: 550–4.

    Article  PubMed  Google Scholar 

  63. Bian Z, Liu B, Moher D, Wu T, Li Y, Shang H, et al. Consolidated standards of reporting trials (CONSORT) for traditional Chinese medicine: current situation and future development. Front Med 2011; 5: 171–7.

    Article  PubMed  Google Scholar 

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Acknowledgements

This project was supported by the National Natural Science Foundation of China (81173395/H2902); the young and middle-aged university discipline leaders of Zhejiang province, China (2013277); the Project of Wenzhou Municipal Science and Technology Bureau in Zhejiang province (Y20110031); and the Administration of Traditional Chinese Medicine of Zhejiang Province (2011ZB094).

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  1. Hui-qin Li and **g-**g Wei: The first two authors contributed equally to this work.

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  1. Department of Neurology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China

    Hui-qin Li, **g-**g Wei, Wan ** Fan

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Li, Hq., Wei, Jj., **a, W. et al. Promoting blood circulation for removing blood stasis therapy for acute intracerebral hemorrhage: a systematic review and meta-analysis. Acta Pharmacol Sin 36, 659–675 (2015). https://doi.org/10.1038/aps.2014.139

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