The effect of Chinese herbal medicine on hemorrhagic shock: A systematic review and meta-analysis

Complementary Therapies in Medicine 29 (2016) 78–88

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Complementary Therapies in Medicine journal homepage: www.elsevierhealth.com/journals/ctim

The effect of Chinese herbal medicine on hemorrhagic shock: A systematic review and meta-analysis Da-long Wang b , Xiao-guang Lu a,∗ , Wen-xiu Guo b , Tuo Chen b , Yi Song a , Zhi-wei Fan a a b

Emergency Department, Affiliated Zhongshan Hospital of Dalian University, #6, Jiefang Street, ZhongShan district, Dalian, 116001, China Graduate School, Dalian Medical University, Dalian, Liaoning 116044, China

a r t i c l e

i n f o

Article history: Received 15 April 2015 Received in revised form 8 March 2016 Accepted 11 September 2016 Available online 12 September 2016 Keywords: Hemorrhagic shock Chinese herbal medicine Meta-analysis Systematic review

a b s t r a c t Background: Chinese herbal medicine (CHM) has been widely used in the treatment of hemorrhagic shock (HS) in China. Many controlled trials have been undertaken to investigate its efficacy. Objective: To evaluate the effectiveness and safety of CHM for Hemorrhagic Shock patients. Methods: We screening the Web of ScienceDirect database, PubMed, the Cochrane Library, EMBASE, China Biomedical Database web (CBM), China National Knowledge Infrastructure (CNKI) and WanFang database (WF), from inception to January 2015. All the randomized controlled trials (RCTs) that compared CHM plus conventional therapy with conventional therapy alone for HS patients were included. Meta-analysis on included studies was performed using fixed-effects model with RevMan 5.2. Risk ratio (RR) or mean difference (MD) with a 95% confidence interval (CI) was used as effect measure. STATA 12.0 was used for publication bias. Results: Fifteen RCTs involving 1076 participants were included in the meta-analysis. CHM combined with conventional therapy was tested to be more effective in reduce mortality (RR = 0.24, 95%CI:0.13–0.46, P < 0.0001), reduce the incidence of MODS (RR = 0.47, 95%CI: 0.34–0.66,P < 0.00001), symptomatic improvement: increase blood pressure (BP) (MD = 8.83, 95%CI:6.82–10.84,P < 0.00001), regulate heart rate (MD = −7.6,95%CI:−9.17 to −6.02,P < 0.00001), increase urine volume (MD = 7.26, 95%CI:5.00–9.53, P < 0.00001), compared with conventional therapy alone. No serious adverse events were reported. Conclusions: CHM combined with conventional therapy seems to be more effective on HS patients. However, the analysis results should be interpreted with caution due to the low methodological quality of the included trials. Future, the rigorously designed, high methodological quality, multicenter and large-scale trials are needed to confirm these conclusions. © 2016 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 2.2. Criteria for considering studies for this review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 2.2.1. Types of studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 2.2.2. Types of participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 2.2.3. Types of interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 2.2.4. Types of outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 2.3. Data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 2.4. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 3.1. Search result . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 3.2. Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

∗ Corresponding author. E-mail address: [email protected] (X.-g. Lu). http://dx.doi.org/10.1016/j.ctim.2016.09.014 0965-2299/© 2016 Elsevier Ltd. All rights reserved.

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3.3. 3.4.

Risk of bias in included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 The effectiveness of interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3.4.1. Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3.4.2. The incidence of MODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3.4.3. Mean arterial pressure (MAP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3.4.4. Heart rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3.4.5. Urine volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3.4.6. Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 3.4.7. Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 4.1. Limitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Author’s contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

1. Introduction Trauma is the leading cause of death among people aged 15–44 y, with more than 5 million injury-related deaths every year in the world. And the deaths caused by traumatic is still increasing year by year. By 2020, deaths from traumatic injury may increase to 8 million on a global scale, with one-third resulting from Hemorrhagic Shock (HS).1,2 Mortality is directly linked to massive blood loss or occurs indirectly due to secondary multiple organ failure(MOF).3 Immediately after injury, the volume of blood loss is a main determinant of outcome. If the blood loss greater than 25–30% of total blood volume within a short time, that exceeded the compensatory mechanisms of body, then the cardiac output and mean arterial pressure(MAP) decreased, and eventually led to shock. Once the blood loss greater than 45–50% of total blood volume, that could be rapidly lead to death.4 In later stages, posttraumatic hemorrhagic shock, initiated by massive tissue injury and ischemia/reperfusion, primes the innate immune system and trigger systemic inflammatory response syndrome (SIRS).5 When hemorrhagic shock occurs, the blood of intestinal was first discarded to supply center organs of human body, such as cerebrum, heart and lung. 6,7 Intestinal ischemia will lead to intestinal barrier damaged, then translocation of bacterial and endotoxin from the lumen into blood circulation caused intestinal endotoxemia (IETM), and trigger SIRS.8,9 This process ultimately results multiple organ dysfunction syndrome (MODS), which is the leading cause of death among those patients who die in the intensive care unit.10 Currently, therapy should be guided by the rate of bleeding and changes in hemodynamic parameters, such as blood pressure, heart rate, cardiac output, central venous pressure, pulmonary artery wedge pressure, mixed venous saturation, or metabolic markers (lactate, base deficit).11 Treatment strategy is to stop the source of hemorrhage first, then rapid and aggressive fluid resuscitation should be conducted to restore blood pressure and tissue perfusion prior to blood transfusion.12 However, after initial survival period, there is still great risk of death comes from multiorgan failure(MOF) in later hospital course.13 We have to consider prophylaxis and treatment intestinal endotoxemia (IETM) when therapy of HS patients, that is important for reduce the incidence of MODS and mortality. Hemorrhagic shock belongs to the category of “JueTuo syndrome” in traditional chinese medicine (TCM). “JueTuo syndrome” is mainly characterized pale complexion, cold limbs, profuse perspiration, decrease in urine output, dysphoria or lethargic, rapid and weak pulse, which is approximately consistent with the clinical manifestation of HS.14 TCM theory recognizes HS as deficiency pattern, which is mainly caused by massive hemorrhage, qi exhaus-

tion because of massive hemorrhage, disharmony of yin and yang, then Yin and yang movements not smoothly.15 In China, CHM has been wildly used as adjuvant therapy on HS. Recently years, a number of RCT studies have demonstrated that CHM has positive effects as complementary therapy for HS, such as improve the effect of fluid resuscitation, improving microcirculation, reducing mortality and the incidence of MODS.16–18 However, there has been no systematic review to assess the effectiveness and safety of CHM combine with conventional therapy on HS. Therefore, this review aims to systematically evaluate the effects and safety of CHM as an adjuvant treatment for treating HS. 2. Methods 2.1. Search strategy A comprehensive search was conducted in seven databases—PubMed, EMBASE, Cochrane Library, ScienceDirect, CBM, CNKI database, and Wan Fang database. The bibliographic databases were searched from respective inceptions to January 2015. We used the following keywords treated as title/abstract for the literature search: “hemorrhagic shock” or “hemorrhagic traumatic shock” and “traditional Chinese medicine” or “Chinese herbal injection” or “integrative medicine” or “herbal” or “herbs-botanical drugs” and examined the reference lists of the obtained articles. The search was restricted to studies in humans. No restrictions were imposed on publication language. We contacted authors of original studies for additional data when necessary. 2.2. Criteria for considering studies for this review 2.2.1. Types of studies Randomized controlled trials (RCTs) of CHM combined with conventional Western treatment versus conventional Western treatment only for HS patients. Case studies, case series, qualitative studies and uncontrolled trials were excluded. No language restrictions were imposed. 2.2.2. Types of participants All of the participants suffered from hemorrhagic shock caused by trauma, esophageal varices, hepatorrhexis and pepticulcer. Hemorrhagic shock cases diagnosed by generally accepted criteria (World Health Organization diagnostic guidelines4 or by the Chinese Ministry of Health’s guidelines were included).19 Hemorrhagic shock cases complicated with other illnesses such as severe cardiovascular disease or cancer were excluded. We did not intend to make any restrictions on age, gender and race.

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Fig. 1. Searching and screening process.

2.2.3. Types of interventions We included trials comparing CHM combined with conventional therapy versus conventional therapy alone for HS patients. The CHM included single herbs, Chinese patent medicines, or a compound of several herbs irrespective of preparation (for example decoction, oral liquid, or injection). The mode of delivery (such as oral, clyster or intravenous), dosage, and regimen of herbs were not restricted. 2.2.4. Types of outcome measures The primary outcome measures were mean arterial pressure (MAP), mortality and the incidence of MODS. The secondary outcome measures were: (1) Heart Rate (2) Urine volume. The adverse events were also measured. 2.3. Data extraction Two authors (D.-L.Wang and W.-X. Guo) conducted the data extraction independently. The following data were extracted: (1) citations (first author of study, year of publication), (2) participants (sample size, age), (3) detailed information of interventions and controls (drug, medication doses, therapeutic regimen), (4) treatment and observe time (5) outcome measures. Any disagreements were resolved by discussion. The methodological quality of trials was assessed using the criteria from the Cochrane Handbook for Systematic Review of Interventions, Version 5.1.0.20 The qualities of included trials were assessed according to seven specific domains: (1) random sequence generation (selection bias), (2) allocation concealment (selection bias), (3) blinding of participants and personnel (performance bias), (4) blinding of outcome data (detection bias), (5) incomplete outcome data (attrition bias), (6) selective reporting (reporting bias),

and (7) other bias. The quality of all the included trials was divided into low/unclear/high risk of bias. If needed, we contacted the authors of assessed trials for clarification. 2.4. Data analysis The meta-analysis was performed using RevMan5.2, provided by the Cochrane Collaboration. Dichotomous data were presented as risk ratio (RR), with 95% confidence interval (CI); continuous data were presented as mean difference (MD), with 95% confidence interval (CI). Fixed-effects models or random-effects models were used to calculate RR or MD. Statistical significance was assumed for P < 0.05. Heterogeneity of effect sizes was assessed with the I2 statistic. When I2 ≤ 50% or P ≥ 0.1, and each study did not show significant heterogeneity, we used the fixed effect model. When I2 > 50% or P < 0.1, and each study showed significant heterogeneity, we used the random effects models.20 Publication bias was explored applying a funnel plot analysis. 3. Results 3.1. Search result At first, a total of 1331 articles were retrieved from electronic databases. Majority of these studies were excluded after screening the titles and abstracts, mainly because they were case-reports, retrospective studies, or not relevant to our analysis. We conducted full-text evaluation on the remaining 62 articles, and 47 articles were excluded for not meeting our inclusion criteria. Finally, 15 studies involving a total of 1076 participants, met our inclusion criteria.16–18,21–32 Fig. 1 shows a flow chart of studies selection process.

Table 1 Characteristics of included studies. sample size

Sex (M/F)

Age

Intervention group

Control group

Treatment and observe time

Main outcomes

Yuan28 2009

50(25/25)

34/16

Not clear

MAP, Urine volume, Heart rate

30(15/15)

A:9/6 B:10/5

A:58.5 ± 10.8 B:57.5 ± 11.2

Monitoring of vital signs, Conventional anti-shock therapy,500 ml 5% glucose and sodium chloride injection intravenous infusion Monitoring of vital signs, Routine western medical therapy

2h

Cheng22 2008

24 h

MAP, Heart rate

Sun31 2011

36(18/18)

20/16

41 ± 12.3

Monitoring of vital signs, Conventional anti-shock therapy

2h

MAP

Wei16 2007

30(15/15)

22/8

18–45

Urine volume, Heart rate

60(30/30)

42/18

A:48 ± 13.2 B:48 ± 13.2

Monitoring of vitial signs, Conventional anti-shock therapy. 0.9% sodium chloride solution (1 ml/kg) intravenous infusion Monitoring of vitial signs, Conventional anti-shock therapy.

2h

Wang27 2006

Unclear

incidence of MODS

Guo26 2010

108(55/53)

A:33/22 B:32/21

A:38.83 B:37.8

MAP, Heart rate

52(26/26)

A:15/11 B:14/12

A:34.3 ± 2.1 B:33.7 ± 2.2

Monitoring of vital signs and Conventional therapy, 5% glucose 250 ml intravenous in 30 min,Polyglucose and sodium chloride injection intravenous,0.9% sodium chloride solution 500–1000 ml intravenous infusion Monitoring of vital signs, Conventional anti-shock therapy.

1.5 h

Liang17 2013

A:36.1 ± 5.9 h B:42.6 ± 10.7 h

MAP, Urine volume, Heart rate

Zheng18 2013

92(46/46)

58/34

36.6 ± 4.8

Monitoring of vital signs; Conventional anti-shock therapy; DA(>10 ug/(kg min)) + normal saline intravenous;

3h

MAP

Zhang30 2010

63(34/29)

A:20/14 B:17/12

A:36.9 ± 16.4 B:32.2 ± 16.6

Monitoring of vital signs, Conventional anti-shock therapy.

A:35.3 ± 5.7 h B:42.2 ± 10.5 h

MAP, Urine volume, Heart rate

Long32 2009

98(45/53)

81/17

41.7

Conventional therapy.

Lu21

87(45/42)

A:30/15 B:28/14

A: 42.12 ± 14.87 B: 39.68 ± 15.77

Monitoring of vital signs, Conventional anti-shock therapy, shen fu injection 100 ml + 5% glucose 500 ml intravenous infusion Monitoring of vitial signs, routine western medical therapy,shenmai injection 100–200 ml intravenous infusion (once every day) Monitoring of vital signs, Conventional anti-shock therapy. Shengmai injection 20 ml intravenous infusion(once every 15 min for 5 times) Monitoring of vitial signs, Conventional anti-shock therapy. Shenfu injection(1 ml/kg) + 5% glucose 100 ml intravenous infusion. Monitoring of vitial signs, Conventional anti-shock therapy, shenfu injection 50 ml intravenou for the first time, shenfu injection 200 ml/d intravenous infusion, 25 g Rhubarb Powder clyster or nasogastric twice a day. Monitoring of vital signs and Conventional therapy, shen mai injection 20–60ml(<1 ml/kg) + 5% glucose 250 ml intravenous in 30 min, Polyglucose and sodium chloride injection intravenous infusion,0.9% sodium chloride solution 500–1000 ml intravenous infusion Monitoring of vital signs, Conventional anti-shock therapy. shen fu injection 20 ml + 5% glucose 20 ml intravenous infusion (once every 30 min for 3times),shenfu injection 100 ml + 0.9% sodium chloride solution 400 ml intravenous infusion. Monitoring of vital signs; Conventional anti-shock therapy; dopamine(>10 ug/(kg min)) + normal saline intravenous; shenmai mixture 2.6–5.2 g + 5% glucose 250 ml intravenous infusion. Monitoring of vital signs, Conventional anti-shock therapy, shenfu injection 60 ml + 0.9% sodium chloride solution 250 ml intravenous infusion Conventional therapy; raw rhubarb 10 g through gastric tube injection, twice a day. Monitoring of vital signs; Mechanical ventilation, Conventional anti-shock therapy, hemostasis, DaHuang Fuzi Decoction 300 ml enemas everyday

A:1.5 ± 1.2 d B:5.8 ± 3.0 d A:13.85 ± 2.94 d B:10.57 ± 2.05 d

Mortality, Incidence of MODS Mortality

2013

Monitoring of vital signs; Mechanical ventilation, Conventional anti-shock therapy, hemostasis,

D.-l. Wang et al. / Complementary Therapies in Medicine 29 (2016) 78–88

Study ID

81

82

Study ID

sample size

Sex (M/F)

Age

Intervention group

Control group

Treatment and observe time

Main outcomes

Gao25 2002

137(71/66)

A:43/28 B:45/21

A:35.7 B:37.6

Mortality, incidence of MODS

92(46/46)

A:43/28 B:45/20

A:31.8 ± 3.5 B:33.1 ± 2.8

5d

Mortality

Yang29 2011

81(43/38)

41/40

A:31.9 ± 3.8 B:29.7 ± 5.8

Conventional anti-shock therapy, Vasoactive drugs, Treatment of the primary disease; Treated with primary disease, give the vasoactive agents therapy Monitoring of vital signs; Giving treatment of Domperidone or Cisapride; Giving parenteral nutrition supports before the gastrointestinal functional recovery General anesthesia before surgery, routine fluid therapy after the Surgery beginning.

5d

Dong23 2014

Conventional anti-shock therapy, Vasoactive drugs, Treatment of the primary disease; Rhubarb Powder 3 g nasogastric once every 8 h. Treated with primary disease, give the vasoactive agents therapy Monitoring of vital signs; Rhubarb Powder 3 g by nasogastric feeding once every 8 h. The subsequent treatment adjust the dosage of rhubarb until the bowel movement frequency 1–3 per day.

2h

Heart rate

Fang24 2006

60(30/30)

41/19

17–59

2h

MAP, Heart rate Urine volume

General anesthesia before surgery, routine fluid therapy, intravenous injection of pulse shengmai injection 20–40 ml after the Surgery beginning. Monitoring of vital signs, Conventional anti-shock therapy. shen mai injection 50 ml + 5% glucose 250 ml intravenous infusion in 30 min, then maintain with Ringer’s lactate.

Monitoring of vital signs, Conventional anti-shock therapy, 1000 ml Ringer’s lactate intravenous infusion in 30 min, then maintain with Ringer’s lactate.

Abbreviations: MAP: mean arterial pressure, MODS: multiple organ dysfunction syndrome, A: Intervention group, B: control group, M: male, F: female.

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Table 1 (Continued)

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3.2. Study characteristics Table 1 lists the primary characteristics of the 15 included prospective RCTs. These studies were conducted and published in China between 2002 and 2014, and only one performed in multicenter21 A total of 1076 participants were included in the 15 studies, 532 patients were in the control group, 544 patients were in the treatment group, and the ages ranged from 9 to 82 years old. All studies were two-group design study, which used conventional therapy plus CHM as the treatment group, and conventional therapy as control group. Shenfu injection preparation as one of the CHM preparations was used in five studies, shenmai injection used in three studies, shengmai injection used in three studies, rhubarb used in four studies, DaHuang Fuzi Decoction (a Chinese herbal preparation made of rhubarb, monkshood and asarum) used in one studies. Among the 15 studies, 4 studies reported mortality, 3 studies reported the incidence of MODS, 8 studies reported MAP, 7 studies reported heart rate, and 5 studies reported urine volume. None trials reported adverse events. 3.3. Risk of bias in included studies The result of assessment was represented in Figs. 2 and 3. All of the trials included indicated randomization, but appropriate random sequence generation was only reported in three trials where random number table was employed.18,21,23 No trial stated how allocation concealment performed, and none of the 15 studies described blinding of participants and personnel. However, we can infer from the studies, that the patients of shocks couldn’t know the therapy methods in the period of resuscitation. Hence, six trials16–18,24,28,30 we assessed using the single-blind. None of the trials described blinding of outcome assessment. In most studies, data collection was clearly described and reported, so they were judged as complete data and as non-selective reporting results (drop out). We could not assess selective reporting and other important risk of bias existed due to insufficient information in all included studies. We tried to contact any of the authors of the included studies, however, we have received only one response.21 3.4. The effectiveness of interventions 3.4.1. Mortality Four studies reported on hospital mortality, giving an overall sample of 414 patients (207 in the treatment group and 207 in the control group). It showed homogeneity in the results (Fig. 4) (P = 0.96, I2 = 0%). Therefore, we use fixed-effects model did a quantitative data synthesis. The overall Risk Ratio (RR) shows a statistically significant difference in favor of the combination group of CHM and conventional therapy (RR = 0.24, 95%CI:0.13–0.46, P < 0.0001). It is suggested that CHM combination conventional therapy had a better effect on reduce mortality.

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The results of the MAP showed a slight statistical heterogeneity (P = 0.24, I2 = 24%), three Chinese Herbal Injections (shenfu, shenmai and shengmai injection) used in intervention groups, so we performed subgroup analysis according to the different injection. The results are as follow Fig. 6. It is indicated that combination therapy group had a better effect on stabilizing and raising blood pressure compared with the conventional therapy, shenfu injection (MD = 7.25, 95% CI:4.21–10.29, P < 0.00001), shenmai injection (MD = 10.78, 95%CI:7.75–13.82, P < 0.00001), shengmai injection (MD = 7.50, 95%CI: 1.78–13.23, P = 0.01), and overall effect (MD = 8.83, 95%CI:6.82–10.84, P < 0.00001). 3.4.4. Heart rate Seven studies reported the heart rate, giving an overall sample of 366 patients (188 in the treatment group and 178 in the control group). It showed homogeneity in Fig. 7 (P = 0.84, I2 = 0%), three Chinese Herbal Injections (shenfu, shenmai and shengmai injection) used in intervention groups, so we performed subgroup analysis according to the different injection. The results indicate that combination therapy group had a significant effects on slowed heart rate compared with the conventional therapy group, shenfu injection (MD = −7.74, 95% CI:−9.98 to −5.50, P < 0.00001), shenmai injection (MD = −6.24, 95%CI:−9.51 to −2.97, P = 0.0002), shengmai injection(MD = −8.84, 95% CI: −11.48 to −5.48, P < 0.00001), and overall effect (MD = −7.6,95%CI:−9.17 to −6.02, P < 0.00001). 3.4.5. Urine volume Five studies reported the urine volume, giving an overall sample of 303 patients (155 in the treatment group and 148 in the control group). There was no significant heterogeneity in the results (Fig. 8) (P = 0.12, I2 = 45%), three Chinese Herbal Injections (shenfu, shenmai and shengmai injection) used in intervention groups, so we performed subgroup analysis according to the different injection. The results indicate that combination therapy group had a significant effects on increase urine output compared with the conventional therapy group, shenfu injection (MD = 10.48,95% CI:6.80–14.15, P < 0.00001), shenmai injection (MD = 4.54, 95%CI: 1.19–7.89, P < 0.008), shengmai injection(MD = 7.40,95% CI: 1.84–12.96, P = 0.009), and overall effect (MD = 7.26, 95%CI:5.00–9.53, P < 0.00001). 3.4.6. Publication bias As is shown in the figures, the funnel plot is almost symmetrical (Fig. 9), and the result of Egger’s test was presented in Fig. 10 [P = 0.724, 95%CI (−6.60, 4.87)]. It indicated that there is no potential publication bias among the included studies. 3.4.7. Adverse effects None of the included trials report the adverse effects. 4. Discussion

3.4.2. The incidence of MODS Three studies reported the incidence of MODS, giving an overall sample of 295 patients (146 in the treatment group and 149 in the control group). It showed homogeneity in the results (Fig. 5) (P = 0.48, I2 = 0%).Therefore, we use fixed-effects model did a quantitative data synthesis. The overall Risk Ratio(RR)shows a statistically difference in favor of the combination group of CHM and routine therapy (RR = 0.47,95%CI: 0.34–0.66, P < 0.00001). It is suggested that CHM combination conventional therapy had a better effect on reduce the incidence of MODS. 3.4.3. Mean arterial pressure (MAP) Eight studies reported the MAP, giving an overall sample of 491 patients (249 in the treatment group and 242 in the control group).

This is the first systematic analysis to explore the efficacy and safety of CHM for hemorrhagic shock. The pooled analyses showed that CHM combined with routine western therapy was more effective in terms of in reducing mortality (RR = 0.24, 95%CI:0.13–0.46, P < 0.0001), reduce incidence of MODS (RR = 0.47, 95%CI:0.34–0.66, P < 0.00001);improve blood pressure (MD = 8.83, 95%CI:6.82–10.84, P< 0.00001), regulate heart rate (MD = −7.6, 95%CI:−9.17 to −6.02, P < 0.00001), and increase urine output (MD = 7.26, 95%CI:5.00–9.53, P < 0.00001), compared to routine western therapy alone. However, there were no reported serious adverse events. Modern research showed that Chinese patent medicines (shenmai, shenfu and shengmai injection) could enhance myocardial

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Fig. 2. Risk of bias summary: review authors’ judgments about each risk of bias item for each included study. “+”: low risk of bias; “?”: unclear risk of bias; or “−”: high risk of bias.

Fig. 3. Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.

Fig. 4. Forest plot shows mortality.

Fig. 5. Forest plot shows rate of MODS.

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Fig. 6. Forest plot shows blood pressure.

Fig. 7. Forest plot shows heart rate.

systole, increased cardiac output, improve microcirculation, antiarrhythmic and inflammation.33–37 Ginsenoside is the main active ingredient in shenmai, shenfu and shengmai injection, which had a bidirectional regulation of blood pressure. Previous studies have

found that ginseng cures patients with low blood pressure, restoring it to normal levels. In addition, ginseng also reduces blood pressure in patients with high blood pressure.38,39 It is beneficial to increase and stable blood pressure for the patients of

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Fig. 8. Forest plot shows urine volume.

Fig. 9. Funnel plots of Mean Arterial Pressure (MAP).

HS. Besides, ginsenosides has protective effect on acute organ ischemia-reperfusion injury. As a potent antioxidant, ginsenosideRe may play an important role in antioxidant actions to increase cardiomyocyte survival and contractile function during ischemia and reperfusion.40 Moreover, pharmacological researches demonstrated that ginsenoside-Rd could significantly improve a variety of antioxidant enzyme activity, then significantly reduced the levels

of Malondialdehyde (MDA) in Serum and kidney tissue.41 Animal studies have shown that ginsenosides-Re could alleviate the damage of renal tubular epithelial cell in the rat model of kidney ischemia-reperfusion injury.42 Therefore, the renal dysfunction caused by ischemia-reperfusion could be improved. According to the theory of TCM, qi being the chief of blood, blood being the mother of qi, qi dominate blood circulation, blood could

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Fig. 10. Egger’s Test of Mean Arterial Pressure (MAP).

carry qi. And the yang qi could promote blood circulation, yin qi makes the blood circulation more smoothly. When HS happen, the body lost a large quantity of blood, and qi exhausted due to blood depletion. Therefore, hemorrhagic shock patients presenting the symptom of deficiency qi and blood, exhausted of yin and yang. TCM holds that the tangible of blood can’t fast-growing, invisible of qi should be recover first.43 Ginseng is the major components of shenfu, shengmai and shenmai injection, which could greatly tonifying YuanQi. Moreover, the Chinese patent medicines (shenfu shenmai and shengmai injection) were also applied to nourish yin, recuperate the exhausted yang. Chinese rhubarb has the effect of heat-clearing and detoxifying, purgative and activating blood circulation to dissipate blood stasis.44 Secondly, rhubarb could promote peristalsis, promotes bacteria and endotoxin excretion, inhibits bacterial and endotoxin translocation, and then play a role in protecting intestinal barrier. Moreover, modern pharmacological studies have shown that rhubarb has the functions in antagonistic proinflammatory cytokines (TNF-␣, IL-1, IL-6) and bacterial,45,46 scavenging oxygen free radicals and increase gastrointestinal mucosa blood flow perfusion. All these functions could enhance the overall effectiveness of the treatment of hemorrhagic shock, thus reduce the incidence of MODS and overall mortality.

4.1. Limitation We should pay attention to several limitations before accepting the findings of this systematic review. The main problem was the low quality of methodological. (1) Randomization: all the included trials stated that random assignment was used, however, random sequence generation were not reported in details in most of the trials. Moreover, no trials described how implemented allocation concealment. It has been demonstrated that trials with inadequate concealment of allocation or unclear reporting of the technique used were on average 18% more ‘beneficial’ than effect estimated from trials with adequate concealment (95%CI: 5% to 29%).47 (2) No studies state whether they performed blinding or not, non-doubleblinding may lead to performance bias. (3) Placebo controlled: all

trials included used the “A + B versus B” design, which patients were randomized to receive combined therapy versus conventional therapy. The main reason not using placebo maybe it’s difficultly to prepare a liquid form (decoction or injection liquid) to have the same appearance, smell, or taste as the placebo. (4) publication bias: Even though we try our best to conducted comprehensive searches, we only got the trials which were conducted and published in Chinese. Therefore, we still hold that publication bias would exist in this review though both Funnel plots and Egger’s Test did not suggest. Heterogeneity was another problem that we need to consider. First, there are three Chinese patent medicines, one single herb and one practitioner-prescribed herbal formulae used in the intervention group. Hence, different medicines used in the trials may lead to heterogeneity. Secondly, different resuscitation fluids were used in each of study, which could led to inconsistencies in the comparison. Besides, the different dosages of medicine used in each trial also could cause heterogeneity.

5. Conclusion This meta-analysis shows that CHM combined with conventional therapy appeared to have benefits in regulating heart rate, improvement blood pressure and microcirculation, reduce mortality and incidence of MODS. Therefore, CHM combined with conventional therapy was capable of enhancing the efficacy for hemorrhagic shock patients. However, the results should be interpreted with caution due to the poor methodological quality of included studies. Future, the more rigorously designed, high methodological quality, multicenter and large-scale trials are needed to confirm these conclusions.

Funding The study was supported by two funds from National Natural Science Foundation of China (NSFC) (No. 81173397, No. 81473512).

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