Evidence-Based Complementary and Alternative Medicine

Evidence-Based Complementary and Alternative Medicine / 2021 / Article
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Complementary and Alternative Therapies for Immune-Inflammation Interactions in the Digestive System

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Review Article | Open Access

Volume 2021 |Article ID 6621368 | https://doi.org/10.1155/2021/6621368

Hongxin Chen, Zhaohui Bai, Hongyu Li, Yanyan Wu, Haijuan Yao, Le Wang, Hanyang Lin, Zhenhua Tong, Rolf Teschke, Xingshun Qi, "Efficacy of Xuebijing Injection for Acute Pancreatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials", Evidence-Based Complementary and Alternative Medicine, vol. 2021, Article ID 6621368, 14 pages, 2021. https://doi.org/10.1155/2021/6621368

Efficacy of Xuebijing Injection for Acute Pancreatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Academic Editor: Guang Chen
Received09 Jan 2021
Revised22 Mar 2021
Accepted07 Apr 2021
Published26 Apr 2021

Abstract

Background and Aim. Xuebijing injection is a traditional Chinese medicine compound for the improvement of systemic inflammation response. This meta-analysis of randomized controlled trials (RCTs) aimed to explore the clinical efficacy and safety of Xuebijing injection for the treatment of acute pancreatitis (AP). Methods. PubMed Medline, Embase, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, VIP, and Wanfang databases were searched. The primary outcome was treatment response. The secondary outcomes included changes in clinical and laboratory indicators and incidence of AP-related complications. Meta-analyses were performed by using a random-effect model. Risk ratios (RRs) with 95% confidence intervals (CIs) or weighted mean differences (WMDs) with 95% CIs were calculated. Results. Overall, 23 RCTs were included. The rates of overall (RR = 1.16; 95% CI = 1.12 to 1.20; ) and complete (RR = 1.40; 95% CI = 1.30 to 1.50; ) responses were significantly higher in the Xuebijing injection group. After treatment, the levels of interleukin-6 (WMD = −18.22; 95% CI = −23.36 to −13.08; ), tumor necrosis factor-α (WMD = −16.44; 95% CI = −20.49 to −12.40; ), serum amylase (WMD = −105.61; 95% CI = −173.77 to −37.46; ), white blood cell (WMD = −1.51; 95% CI = −1.66 to −1.36; ), and C-reactive protein (WMD = −11.05; 95% CI = −14.32 to −7.78; ) were significantly lower in the Xuebijing injection group. Abdominal pain (WMD = −1.74; 95% CI = −1.96 to −1.52; ), abdominal distension (WMD = −1.56; 95% CI = −2.07 to −1.04; ), gastrointestinal function (WMD = −2.60; 95% CI = −3.07 to −2.13; ), body temperature (WMD = −2.16; 95% CI = −2.83 to −1.49; ), serum amylase level (WMD = −1.81; 95% CI = −2.66 to −0.96; ), and white blood cell (WMD = −2.16; 95% CI = −2.99 to −1.32; ) recovered more rapidly in the Xuebijing injection group. The incidence of multiple organ dysfunction syndrome (RR = 0.18; 95% CI = 0.05 to 0.62; ), pancreatic pseudocyst (RR = 0.17; 95% CI = 0.04 to 0.77; ), and renal failure (RR = 0.16; 95% CI = 0.05 to 0.60; ) was significantly lower in the Xuebijing injection group. Conclusions. Xuebijing injection added on the basis of conventional treatment has a potential benefit for improving the outcomes of AP.

1. Introduction

Acute pancreatitis (AP) is one of the most common gastrointestinal diseases that require urgent hospitalization [1, 2]. Its global incidence is 34 cases per 100,000 general population per year [3]. About 20% of AP cases are moderately severe or severe [4]. At present, the overall mortality of AP is about 5% [5], and the mortality of severe AP is up to 30% [6], despite the fact that fluid resuscitation, nutritional support, enzyme suppression, antibiotics, analgesia, and treatment of local and systemic complications have been widely employed [710].

Xuebijing injection is a traditional Chinese medicine compound developed by Professor Jinda Wang on the basis of the ancient blood regulating formula and the theory of “simultaneous treatment of bacteria, toxin, and inflammation” [11]. It consists of five Chinese herbs, as follows: Carthami Flos (hong hua), Paeoniae Radix Rubra (chi shao), Chuanxiong Rhizoma (chuan xiong), Salviae Miltiorrhizae Radix et Rhizoma (dan shen), and Angelicae Sinensis Radix (dang gui), which can promote blood circulation, strengthen and consolidate body resistance, clear heat, and remove toxicity [12]. Xuebijing injection has been widely employed for the clinical treatment of AP in China, but its effectiveness still needs to be further confirmed. Additionally, it should be noted that published studies are of poor quality, thereby influencing the reliability of previous findings. Herein, we selected relatively high-quality randomized controlled trials (RCTs) and performed a meta-analysis to clarify the role of Xuebijing injection for the treatment of AP.

2. Methods

This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The PRIMSA checklist is shown in Supplementary Table 1.

2.1. Registration

The meta-analysis was registered in the PROSPERO with a registration number of CRD42020219118.

2.2. Search Strategy

PubMed Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine disc (CBMdisc), VIP, and Wanfang databases were searched. The search items are as follows: “Xuebijing” AND “pancreatitis” (Supplementary Material 1 (available here)). The last search was conducted on November 07, 2020.

2.3. Study Selection

There was neither publication language nor publication status restriction. All RCTs regarding Xuebijing injection for the treatment of AP were included. The Xuebijing injection group should include patients, who received Xuebijing injection combined with conventional treatment. The control group should be patients, who received conventional treatment alone.

Exclusion criteria were as follows: (1) duplicates; (2) catalogue, indexes, guidelines, and conferences; (3) reviews or meta-analyses; (4) animal experiments; (5) non-RCTs; (6) irrelevant papers; (7) low-quality RCTs; and (8) absence of efficacy data.

2.4. Outcomes of Interest

The primary outcome should be treatment response. The secondary outcomes include laboratory indicators after treatment; recovery time of clinical symptoms and signs and laboratory indicators after treatment; and incidence of AP-related complications.

2.5. Data Extraction

The following data were extracted from the included studies: first author; journal; publication year; region; study design; usage and dosage of Xuebijing injection; study population; follow-up duration; classification of AP; laboratory indicators after treatment; recovery time of clinical symptoms and signs and laboratory indicators after treatment; incidence of AP-related complications; and outcomes.

2.6. Definitions

The conventional treatment of AP was mainly in accordance with the treatment strategy employed in each included study. Briefly, major treatment strategy included fasting for solids and liquids, fluid resuscitation, gastrointestinal decompression, nutritional support, inhibition of acid and pancreatic secretion, improvement of pancreatic microcirculation, and prophylaxis of infection.

Assessment of response was mainly in accordance with the definitions made by every individual study. In detail, overall response included complete response and partial response; complete response was defined as significant remission or disappearance of clinical symptoms and signs and significant improvement or normalization of laboratory indicators after treatment; partial response was defined as improvement of clinical symptoms and signs and laboratory indicators after treatment; no response was defined as no improvement or even deterioration of clinical symptoms and signs and laboratory indicators after treatment.

2.7. Risk of Bias Assessment

The quality of RCTs was assessed using the Cochrane Collaboration’s Risk of Bias tool [13], which includes random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias.

2.8. Statistical Analysis

We performed the meta-analysis by the Review Manager 5.2 (Cochrane collaboration, the Nordic Cochrane Centre, Copenhagen, Denmark) and STATA 12.0 (Stata Corp, College Station, Texas, USA). A random-effect model was employed. value < 0.05 was considered statistically significant. Dichotomous outcomes were expressed as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes were expressed as weighted mean differences (WMDs) with 95% CI. The Cochran’s Q test and I2 statistics were employed to assess the heterogeneity. and/or I2 > 50% was considered as a statistically significant heterogeneity. Subgroup analyses were conducted in patients diagnosed with severe AP. Publication bias was performed with Egger test. was considered as a statistically significant publication bias. The meta-regression analyses and sensitivity analyses were used to explore the sources of heterogeneity. Covariates used for meta-regression analyses included the year of publication, region, and dosage of Xuebijing injection every time. Sensitivity analyses were performed by omitting a single study in turn.

3. Results

3.1. Study Selection

Overall, 3051 publications were identified via the 7 databases. Finally, 23 RCTs [1436] were included in this meta-analysis (Figure 1).

3.2. Study Characteristics

The characteristics of these studies are shown in Tables 1 and 2. All of them were conducted in China and published from 2012 to 2020 as full texts. A total of 1882 AP patients were included with a sample size ranging from 39 to 146 among studies.


First author (year)RegionJournalStudy designClassification of APGroupsInterventionsDuration of treatment (days)

Li (2020)ShanxiGuangming Journal of Chinese MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 time/day14
Control groupConventional treatment
Zhan (2019)BeijingChinese Archives of Traditional Chinese MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day10
Control groupConventional treatment
Yuan (2019)HubeiChinese and Foreign Medical ResearchRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Hu (2019)ZhejiangChinese Journal of Surgery of Integrated Traditional and Western MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 1 time/day10
Control groupConventional treatment
Zhang (2018)HenanChinese Journal of New Clinical MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Zhang (a) (2018)ShaanxiModern Journal of Integrated Traditional Chinese and Western MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Zhang (b) (2018)ShaanxiMedical Journal of West ChinaRCTSAPXBJ groupConventional treatment; Xuebijing injection 50 ml, 2 times/day7
Control groupConventional treatment
Fan (2018)ChongqingJournal of Clinical MedicalRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Zha (2018)HenanChongqing MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Ji (2017)QinghaiShaanxi Journal of Traditional Chinese MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 50 ml, 2–3 times/day7
Control groupConventional treatment
Chen (2017)HenanModern Diagnosis and TreatmentRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Liu (2017)HubeiWorld Chinese Journal of DigestologyRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Gao (2016)LiaoningChinese Traditional Patent MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Chen (2015)HubeiWorld Chinese Journal of DigestologyRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Chen (2015)HebeiInternational Journal of Traditional Chinese MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 50 ml, 2 times/day7
Control groupConventional treatment
Zhang (2015)LiaoningMedical InformationRCTAPXBJ groupConventional treatment; Xuebijing injection 50 ml, 2 times/dayNA
Control groupConventional treatment
Zhu (2015)JiangsuThe World Clinical MedicineRCTAPXBJ groupConventional treatment; Xuebijing injection 50 ml, 2 times/dayNA
Control groupConventional treatment
Liu (2015)ZhejiangJournal of Emergency in Traditional Chinese MedicineRCTAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Bai (2015)Nei MongolChina Foreign Medical TreatmentRCTAPXBJ groupConventional treatment; Xuebijing injection 50 ml, 2 times/day7
Control groupConventional treatment
Yang (2014)FujianFujian Journal of Traditional Chinese MedicineRCTAPXBJ groupConventional treatment; Xuebijing injection 50 ml, 2 times/day5–7
Control groupConventional treatment
Liu (2014)HenanModern Journal of Integrated Traditional Chinese and Western MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 50 ml, 2 times/day7
Control groupConventional treatment
Lin (2012)XinjiangNei Mongol Journal of Traditional Chinese MedicineRCTSAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment
Hong (2012)ZhejiangJournal of Emergency in Traditional Chinese MedicineRCTAPXBJ groupConventional treatment; Xuebijing injection 100 ml, 2 times/day7
Control groupConventional treatment

Abbreviations: RCT: randomized controlled trial; AP: acute pancreatitis; SAP: severe acute pancreatitis; XBJ: Xuebijing injection.

First author (year)No. ptsEtiology of acute pancreatitisSex (male/female) (n)Age (mean)GroupsFollow-up (days)Overall response (n)Complete response (n)No response (n)

Li (2020)32NA16/1643.1XBJ group1428154
32NA17/1543.6Control group1420812
Zhan (2019)39Biliary diseases 14; alcohol 11; surgery 4; overeating 1028/1146.6XBJ group1039320
39Biliary diseases 15; alcohol 11; surgery 5; overeating 7; other 124/1545.9Control group1037232
Yuan (2019)35Biliary diseases 13; alcohol 15; hyperlipidemia 719/1650.7XBJ group734281
35Biliary diseases 13; alcohol 13; hyperlipidemia 921/1449.8Control group728157
Hu (2019)67NA40/2741.5XBJ group1064533
67NA39/2841.4Control group10564111
Zhang (2018)35NA19/1642.8XBJ group733292
35NA20/1543.1Control group727228
Zhang (a) (2018)37NA18/1939.3XBJ group731206
37NA17/2038.0Control group7231314
Zhang (b) (2018)40Biliary diseases 14; alcohol 11; surgery 4; overeating 1023/1742.1XBJ group739341
40Biliary diseases 20; alcohol 10; overeating 9; other 125/1540.5Control group732258
Fan (2018)20NA11/938.6XBJ group71793
20NA12/838.9Control group71268
Zha (2018)49NANANAXBJ group746283
49NANANAControl group7391810
Ji (2017)61NA48/1348.0XBJ group759502
61NA46/1548.2Control group7513910
Chen (2017)43NA24/1943.1XBJ group740293
43NA25/1843.3Control group7332110
Liu (2017)52NA29/2342.5XBJ group749353
42NA24/1840.5Control group7311911
Gao (2016)44NA23/2141.9XBJ group741313
44NA24/2042.6Control group7322112
Chen (2015)73Biliary diseases 43; alcohol or overeating 3045/2842.7XBJ group772511
73Biliary diseases 42; alcohol or overeating 3146/2742.8Control group765348
Chen (2015)52Biliary diseases 25; alcohol 109; overeating 8; hyperlipidemia 6; other 330/2253.6XBJ group748434
52Biliary diseases 24; alcohol 9; overeating 9; hyperlipidemia 8; other 231/2153.7Control group7383114
Zhang (2015)21NANANAXBJ groupNA19142
18NANANAControl groupNA1593
Zhu (2015)25NA17/836.5XBJ groupNA23152
25NA18/736.7Control groupNA1877
Liu (2015)40NA28/1232.6XBJ group738302
40NA26/1430.4Control group734226
Bai (2015)50NA33/1746.7XBJ group748292
48NA30/1849.0Control group7372011
Yang (2014)31NA22/940.3XBJ group5–729262
31NA20/1141.2Control group5–723188
Liu (2014)25Biliary diseases 2; alcohol 12; overeating 9; other 216/948.2XBJ group723162
20Biliary diseases 4; alcohol 9; overeating 5; other 213/749.1Control group714106
Lin (2012)43NA26/1738.8XBJ group741242
43NA28/1539.2Control group734189
Hong (2012)62NA40/2244.5XBJ group760502
62NA40/2244.9Control group756376

Abbreviations: Pts: patients; XBJ: Xuebijing injection.
3.3. Risk of Bias

We used the Cochrane Collaboration’s Risk of Bias tool to evaluate a total of 69 potentially eligible papers. Among them, 23 RCTs, which had 3 items at a low risk, were included; the remaining 46 papers, which had 2 or even fewer items at a low risk, were excluded (Supplementary Figure 1).

In the 23 included RCTs, regarding random sequence generation, all studies had a low risk of bias, of which 20 employed a random number table, 1 employed a computer random number generator, and 2 employed a drawing of lots. Regarding incomplete outcome data and selective reporting, all studies had a low risk of bias. Regarding allocation concealment, blinding of participants and personnel, blinding of outcome assessment, and other bias, all studies had an unclear risk of bias (Figure 2).

3.4. Outcomes
3.4.1. Overall Response

Twenty-three studies reported the data regarding overall response. The overall response rate was 94.4% (921/976) in the Xuebijing injection group, and 79.0% (755/956) in the control group. Meta-analysis showed that the Xuebijing injection group had a significantly higher overall response rate than the control group (RR = 1.16; 95% CI = 1.12 to 1.20; ) (Figure 3). There was no significant heterogeneity among studies (I2 = 7%; ).

In the subgroup analysis of severe AP, the Xuebijing injection group also had a significantly higher overall response rate than the control group (RR = 1.17; 95% CI = 1.12 to 1.22; ) (Supplementary Figure 2). There was no significant heterogeneity among studies (I2 = 11%; ).

3.4.2. Complete Response

Twenty-three studies reported the data regarding complete response. The complete response rate was 70.8% (691/976) in the Xuebijing injection group and 49.9% (477/956) in the control group. Meta-analysis showed that the Xuebijing injection group had a significantly higher complete response rate than the control group (RR = 1.40; 95% CI = 1.30 to 1.50; ) (Figure 4). There was no significant heterogeneity among studies (I2 = 0%; ).

In the subgroup analysis of severe AP, the Xuebijing injection group also had a significantly higher complete response rate than the control group (RR = 1.40; 95% CI = 1.29 to 1.51; ) (Supplementary Figure 3). There was no significant heterogeneity among studies (I2 = 0%; ).

3.4.3. No Response

Twenty-three studies reported the data regarding no response. The non-response rate was 5.6% (55/976) in the Xuebijing injection group and 21.0% (201/956) in the control group. Meta-analysis showed that the Xuebijing injection group had a significantly lower rate of non-response than the control group (RR = 0.28; 95% CI = 0.21 to 0.37; ) (Figure 5). There was no significant heterogeneity among studies (I2 = 0%; ).

In the subgroup analysis of severe AP, the Xuebijing injection group also had a significantly lower rate of non-response than the control group (RR = 0.28; 95% CI = 0.20 to 0.38; ) (Supplementary Figure 4). There was no significant heterogeneity among studies (I2 = 0%; ).

3.5. Laboratory Indicators after Treatment
3.5.1. Interleukin-6 Level

Ten studies including 984 patients reported the data regarding interleukin- (IL-) 6 level after treatment. Meta-analysis showed that the Xuebijing injection group had a significantly lower IL-6 level than the control group (WMD = −18.22; 95% CI = −23.36 to −13.08; ) (Table 3). There was a significant heterogeneity among studies (I2 = 97%; ). Meta-regression analysis and sensitivity analysis did not find any source of heterogeneity (Supplementary Tables 2 and 3).


EndpointsNo. studiesPooled proportion using random-effects modelHeterogeneity
WMDI2 (%)

IL-6 level10−18.22 (95% CI = −23.36 to −13.08)<0.0000197<0.00001
TNF-α level12−16.44 (95% CI = −20.49 to −12.40)<0.0000197<0.00001
AMS level5−105.61 (95% CI = −173.77 to −37.46)0.00295<0.00001
WBC6−1.51 (95% CI = −1.66 to −1.36)<0.0000188<0.00001
CRP level5−11.05 (95% CI = −14.32 to −7.78)<0.0000195<0.00001
hs-CRP level4−12.39 (95% CI = −19.34 to −5.44)0.000596<0.00001

Abbreviations: WMD: weighted mean difference; CI: confidence Interval; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α; AMS: serum amylase; WBC: white blood cell; CRP: C-reactive protein; hs-CRP: hypersensitive C-reactive protein.
3.5.2. Tumor Necrosis Factor-α Level

Twelve studies including 1152 patients reported the data regarding tumor necrosis factor-α (TNF-α) level after treatment. Meta-analysis showed that the Xuebijing injection group had a significantly lower level of TNF-α than the control group (WMD = −16.44; 95% CI = −20.49 to −12.40; ) (Table 3). There was a significant heterogeneity among studies (I2 = 97%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.5.3. Serum Amylase Level

Five studies including 508 patients reported the data regarding serum amylase level after treatment. Meta-analysis showed that the Xuebijing injection group had a significantly lower level of serum amylase than the control group (WMD = −105.61; 95% CI = −173.77 to −37.46; ) (Table 3). There was a significant heterogeneity among studies (I2 = 95%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.5.4. White Blood Cell

Six studies including 586 patients reported the data regarding white blood cell (WBC) after treatment. Meta-analysis showed that the Xuebijing injection group had a significantly lower WBC than the control group (WMD = −1.51; 95% CI = −1.66 to −1.36; ) (Table 3). There was a significant heterogeneity among studies (I2 = 88%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.5.5. C-Reactive Protein Level

Five studies including 560 patients reported the data regarding C-reactive protein level after treatment. Meta-analysis showed that the Xuebijing injection group had a significantly lower level of C-reactive protein value than the control group (WMD = −11.05; 95% CI = −14.32 to −7.78; ) (Table 3). There was a significant heterogeneity among studies (I2 = 95%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.5.6. Hypersensitive C-Reactive Protein Level

Four studies including 380 patients reported the data regarding hypersensitive C-reactive protein level after treatment. Meta-analysis showed that the Xuebijing injection group had a significantly lower level of hypersensitive C-reactive protein than the control group (WMD = −12.39; 95% CI = −19.34 to −5.44; ) (Table 3). There was a significant heterogeneity among studies (I2 = 96%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.6. Recovery Time of Clinical Symptoms and Signs and Laboratory Indicators after Treatment
3.6.1. Abdominal Pain

Twelve studies including 1093 patients reported the recovery time of abdominal pain. Meta-analysis showed that the Xuebijing injection group had a significantly shorter recovery time of abdominal pain than the control group (WMD = −1.74; 95% CI = −1.96 to −1.52; ) (Table 4). There was a significant heterogeneity among studies (I2 = 41%; ). Meta-regression analysis did not find the source of heterogeneity (Supplementary Table 2). Sensitivity analysis found that the heterogeneity became not significant after excluding the study by Lin et al. (I2 = 37%; ) and Zhang et al. (I2 = 19%; ) (Supplementary Table 3).


EndpointsNo. of studiesPooled proportion using random-effects modelHeterogeneity
WMDI2 (%)

Abdominal pain12−1.74 (95% CI = −1.96 to −1.52)<0.00001410.07
Abdominal distension7−1.56 (95% CI = −2.07 to −1.04)<0.0000179<0.0001
Gastrointestinal function6−2.60 (95% CI = −3.07 to −2.13)<0.0000189<0.00001
Body temperature6−2.16 (95% CI = −2.83 to −1.49)<0.0000185<0.00001
AMS level5−1.81 (95% CI = −2.66 to −0.96)<0.000184<0.0001
WBC8−2.16 (95% CI = −2.99 to −1.32)<0.0000186<0.00001

Abbreviations: WMD: weighted mean difference; CI: confidence Interval; AMS: serum amylase; WBC: white blood cell.
3.6.2. Abdominal Distension

Seven studies including 637 patients reported the recovery time of abdominal distension. Meta-analysis showed that the Xuebijing injection group had a significantly shorter recovery time of abdominal distension than the control group (WMD = −1.56; 95% CI = −2.07 to −1.04; ) (Table 4). There was a significant heterogeneity among studies (I2 = 79%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.6.3. Gastrointestinal Function

Six studies including 536 patients reported the recovery time of gastrointestinal function. Meta-analysis showed that the Xuebijing injection group had a significantly shorter recovery time of gastrointestinal function than the control group (WMD = −2.60; 95% CI = −3.07 to −2.13; ) (Table 4). There was a significant heterogeneity among studies (I2 = 89%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.6.4. Body Temperature

Six studies including 551 patients reported the recovery time of body temperature. Meta-analysis showed that the Xuebijing injection group had a significantly shorter recovery time of body temperature than the control group (WMD = −2.16; 95% CI = −2.83 to −1.49; ) (Table 4). There was a significant heterogeneity among studies (I2 = 85%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.6.5. Serum Amylase Level

Five studies including 385 patients reported the recovery time of serum amylase level. Meta-analysis showed that the Xuebijing injection group had a significantly shorter recovery time of serum amylase level than the control group (WMD = −1.81; 95% CI = −2.66 to −0.96; ) (Table 4). There was a significant heterogeneity among studies (I2 = 84%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.6.6. WBC

Eight studies including 631 patients reported the recovery time of WBC. Meta-analysis showed that the Xuebijing injection group had a significantly shorter recovery time of WBC than the control group (WMD = −2.16; 95% CI = −2.99 to −1.32; ) (Table 4). There was a significant heterogeneity among studies (I2 = 86%; ). Meta-regression analysis and sensitivity analysis did not find the source of heterogeneity (Supplementary Tables 2 and 3).

3.7. AP-Related Complications
3.7.1. Multiple Organ Dysfunction Syndrome

Four studies including 368 patients reported the incidence of multiple organ dysfunction syndrome. Meta-analysis showed that the Xuebijing injection group had a significantly lower incidence of multiple organ dysfunction syndrome than the control group (RR = 0.18; 95% CI = 0.05 to 0.62; ) (Table 5). There was no significant heterogeneity among studies (I2 = 0%; ).


EndpointsNo. of studiesPooled proportion using random-effects modelHeterogeneity
RRI2 (%)

MODS40.18 (95% CI = 0.05 to 0.62)0.00600.94
ARDS30.38 (95% CI = 0.14 to 1.04)0.0600.55
Septicemia30.67 (95% CI = 0.19 to 2.36)0.5400.54
Pancreatic pseudocyst30.17 (95% CI = 0.04 to 0.77)0.0200.80
Shock20.30 (95% CI = 0.08 to 1.12)0.07230.25
Renal failure20.16 (95% CI = 0.05 to 0.60)0.00600.55
Pleural effusion or ascites20.35 (95% CI = 0.12 to 1.01)0.0560.30

Abbreviations: AP: acute pancreatitis; RR: risk ratio; CI: confidence Interval; MODS: multiple organ dysfunction syndrome; ARDS: acute respiratory distress syndrome.
3.7.2. Acute Respiratory Distress Syndrome

Three studies including 193 patients reported the incidence of acute respiratory distress syndrome. Meta-analysis showed that the Xuebijing injection group had a lower incidence of acute respiratory distress syndrome than the control group, but there was no significant difference between the two groups (RR = 0.38; 95% CI = 0.14 to 1.04; ) (Table 5). There was no significant heterogeneity among studies (I2 = 0%; ).

3.7.3. Septicemia

Three studies including 294 patients reported the incidence of septicemia. Meta-analysis showed that the Xuebijing injection group had a lower incidence of septicemia than the control group, but there was no significant difference between the two groups (RR = 0.67; 95% CI = 0.19 to 2.36; ) (Table 5). There was no significant heterogeneity among studies (I2 = 0%; ).

3.7.4. Pancreatic Pseudocyst

Three studies including 265 patients reported the incidence of pancreatic pseudocyst. Meta-analysis showed that the Xuebijing injection group had a significantly lower incidence of pancreatic pseudocyst than the control group (RR = 0.17; 95% CI = 0.04 to 0.77; ) (Table 5). There was no significant heterogeneity among studies (I2 = 0%; ).

3.7.5. Shock

Two studies including 123 patients reported the incidence of shock. Meta-analysis showed that the Xuebijing injection group had a lower incidence of shock than the control group, but there was no significant difference between the two groups (RR = 0.30; 95% CI = 0.08 to1.12; ) (Table 5). There was no significant heterogeneity among studies (I2 = 23%; ).

3.7.6. Renal Failure

Two studies including 152 patients reported the incidence of renal failure. Meta-analysis showed that the Xuebijing injection group had a significantly lower incidence of renal failure than the control group (RR = 0.16; 95% CI = 0.05 to 0.60; ) (Table 5). There was no significant heterogeneity among studies (I2 = 0%; ).

3.7.7. Pleural Effusion or Ascites

Two studies including 119 patients reported the incidence of pleural effusion or ascites. Meta-analysis showed that the Xuebijing injection group had a lower incidence of pleural effusion or ascites than the control group, but there was no significant difference between the two groups (RR = 0.35; 95% CI = 0.12 to 1.01; ) (Table 5). There was no significant heterogeneity among studies (I2 = 6%; ).

3.8. Safety

In our included studies, none reported the data regarding adverse events related to Xuebijing injection.

3.9. Publication Bias

Publication bias is reported in Supplementary Table 4.

4. Discussion

Our systematic review suggests that Xuebijing injection combined with conventional treatment is more effective for AP than conventional treatment alone. Similar findings could be observed in the subgroup analysis of severe AP. Our study has several major features in study design and statistical analysis. First, we conducted more extensive literature search and included a larger number of publications. Second, we excluded low-quality RCTs. Third, we explored the efficacy outcomes in more details, including overall response, complete response, and no response. Fourth, we explored the laboratory indicators after treatment between Xuebijing injection and control groups. Fifth, we analyzed the incidence of various complications of AP between the two groups. Sixth, we conducted the meta-regression analyses to explore the source of heterogeneity.

In AP, the initial mediator that induces inflammatory cell response is TNF-α, which is the earliest promoter of inflammatory mediator chain reaction [37]. TNF-α induces the expression of many inflammatory factors, such as IL-6 [38], which react on macrophages, thereby producing more TNF-α [39]. This vicious cycle triggers the inflammatory cascade reaction, causing toxic damage to pancreas and other organs [40, 41].

It has been confirmed that Xuebijing injection can improve microcirculation, increase blood flow, reduce inflammation and capillary permeability, decrease inflammatory exudation, promote inflammation absorption, and inhibit the formation of inflammatory granulomas, which can alleviate the pathological damage during the infection [42]. Xuebijing injection is the only patented Chinese medicine officially authorized for the treatment of systemic inflammatory response syndrome and multiple organ dysfunction syndrome [43]. In the current clinical practice, Xuebijing injection has been widely used to treat critical diseases, such as sepsis [12], acute respiratory distress syndrome [44], severe pneumonia [45], and spontaneous bacterial peritonitis [46]. Xuebijing injection has a strong ability to antagonize endotoxin, which can effectively block the uncontrolled release of endogenous inflammatory mediators produced by endotoxin-induced monocytes/macrophages, thereby preventing from inflammation reaction [42, 46]. In addition, it can effectively reduce the levels of TNF-α, hypersensitive C-reactive protein, and IL-6, which are pro-inflammatory factors, upregulate the IL-10 level, which is an anti-inflammatory factor, block the cascade reaction mediated by inflammatory factors, and finally reduce the inflammatory reaction [11]. Our meta-analysis showed that Xuebijing injection can significantly reduce the levels of inflammatory mediators.

The incidence of adverse reactions of Xuebijing injection is about 0.3%, which often develops within 30 minutes of medication [47]. Most of them are mild. Adverse reactions are mainly located at the respiratory system, skin, and accessories. Main manifestations are skin pruritus, erythema, and chest tightness [48]. Based on the findings of the present systematic review, no adverse reactions related to Xuebijing injection have been reported.

Our meta-analysis has several major limitations. First, the treatment strategy of the control group was not completely equal. Second, the follow-up duration was too short. The average duration is always 7 days, and the longest duration is only 14 days. Third, blinding and allocation concealment were not reported in all included studies. Fourth, most of the included studies had a small sample size and were conducted at a single center. Fifth, all of included studies were conducted in China.

In conclusion, the application of Xuebijing injection on the basis of conventional treatment can improve the outcomes of AP. However, Xuebijing injection is currently used in China alone. In the future, more high-quality, well-designed, multi-center, and large-scale RCTs are still needed to validate the clinical efficacy and safety of Xuebijing injection for the treatment of AP.

Abbreviations

AP:Acute pancreatitis
CBMdisc:China Biology Medicine disc
CNKI:China National Knowledge Infrastructure
CIs:Confidence intervals
IL:Interleukin
RRs:Risk ratios
RCTs:Randomized controlled trials
TNF-α:Tumor necrosis factor-α
WBC:White blood cell
WMDs:Weighted mean differences.

Disclosure

Hongxin Chen, Zhaohui Bai, and Hongyu Li are the co-first authors.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Supplementary Materials

Supplementary Material 1: search strategy. Supplementary Material 2: Supplementary Figure 1: risk of bias assessment of potentially eligible papers. Supplementary Material 3: Supplementary Figure 2: comparison of overall response between Xuebijing injection and control groups in subgroup analyses of severe acute pancreatitis. Supplementary Material 4: Supplementary Figure 3: comparison of complete response between Xuebijing injection and control groups in subgroup analyses of severe acute pancreatitis. Supplementary Material 5: Supplementary Figure 4: comparison of no response between Xuebijing injection and control groups in subgroup analyses of severe acute pancreatitis. Supplementary Material 6: Supplementary Table 1: the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Supplementary Material 7: Supplementary Table 2: meta-regression analyses. Supplementary Material 8: Supplementary Table 3: sensitivity analyses. Supplementary Material 9: Supplementary Table 4: publication bias. (Supplementary Materials)

References

  1. S. Tenner, J. Baillie, J. DeWitt, and S. S. Vege, “American college of gastroenterology guideline: management of acute pancreatitis,” American Journal of Gastroenterology, vol. 108, no. 9, pp. 1400–1415, 2013. View at: Publisher Site | Google Scholar
  2. A. F. Peery, E. S. Dellon, J. Lund et al., “Burden of gastrointestinal disease in the United States: 2012 update,” Gastroenterology, vol. 143, no. 5, pp. 1179–1187, 2012. View at: Publisher Site | Google Scholar
  3. M. S. Petrov and D. Yadav, “Global epidemiology and holistic prevention of pancreatitis,” Nature Reviews Gastroenterology and Hepatology, vol. 16, no. 3, pp. 175–184, 2019. View at: Publisher Site | Google Scholar
  4. S. M. van Dijk, N. D. L. Hallensleben, H. C. van Santvoort et al., “Acute pancreatitis: recent advances through randomised trials,” Gut, vol. 66, no. 11, pp. 2024–2032, 2017. View at: Publisher Site | Google Scholar
  5. Y. Du, Q. Chen, H. Yu et al., “Chinese guidelines for the management of acute pancreatitis (Shenyang, 2019),” Journal of Clinical Hepatology, vol. 35, no. 12, pp. 2706–2711, 2019. View at: Google Scholar
  6. A. Waller, B. Long, A. Koyfman, and M. Gottlieb, “Acute pancreatitis: updates for emergency clinicians,” The Journal of Emergency Medicine, vol. 55, no. 6, pp. 769–779, 2018. View at: Publisher Site | Google Scholar
  7. P. G. Lankisch, M. Apte, and P. A. Banks, “Acute pancreatitis,” The Lancet, vol. 386, no. 9988, pp. 85–96, 2015. View at: Publisher Site | Google Scholar
  8. P. J. Lee and G. I. Papachristou, “New insights into acute pancreatitis,” Nature Reviews Gastroenterology and Hepatology, vol. 16, no. 8, pp. 479–496, 2019. View at: Publisher Site | Google Scholar
  9. S. Majidi, A. Golembioski, S. L. Wilson, and E. C. Thompson, “Acute pancreatitis: etiology, pathology, diagnosis, and treatment,” Southern Medical Journal, vol. 110, no. 11, pp. 727–732, 2017. View at: Publisher Site | Google Scholar
  10. J. A. Greenberg, J. Hsu, M. Bawazeer et al., “Clinical practice guideline: management of acute pancreatitis,” Canadian Journal of Surgery, vol. 59, no. 2, pp. 128–140, 2016. View at: Publisher Site | Google Scholar
  11. Y. Teng, F. Sun, W. Zhang et al., “Research Progress on the mechanism of Xuebijing injection in the treatment of acute pancreatitis,” Chinese Journal of Integrated Traditional and Western Medicine in Intensive and Critical Care, vol. 22, no. 6, pp. 663–665, 2015. View at: Google Scholar
  12. C. Li, P. Wang, L. Zhang et al., “Efficacy and safety of Xuebijing injection (a Chinese patent) for sepsis: a meta-analysis of randomized controlled trials,” Journal of Ethnopharmacology, vol. 224, pp. 512–521, 2018. View at: Publisher Site | Google Scholar
  13. J. P. T. Higgins, D. G. Altman, P. C. Gotzsche et al., “The cochrane collaboration’s tool for assessing risk of bias in randomised trials,” BMJ, vol. 343, Article ID d5928, 2011. View at: Publisher Site | Google Scholar
  14. B. Yuan, “Clinical value of Xuebijing injection in adjuvant treatment of severe acute pancreatitis,” Chinese and Foreign Medical Research, vol. 17, no. 5, pp. 33-34, 2019. View at: Google Scholar
  15. Y. Bai and Y. Liang, “Clinical analysis of Xuebijing in the treatment of acute pancreatitis,” China Foreign Medical Treatment, vol. 34, no. 10, pp. 114–116, 2015. View at: Google Scholar
  16. C. Chen and P. Xie, “Clinical study on Xuebijing injection combined with conventional western medicine therapy in the treatment of severe acute pancreatitis,” International Journal of Traditional Chinese Medicine, vol. 37, no. 5, pp. 405–408, 2015. View at: Google Scholar
  17. L. Chen and Y. Zhang, “Clinical observation of Xuebijing combined with somatostatin in the treatment of severe acute pancreatitis,” Modern Diagnosis and Treatment, vol. 28, no. 14, pp. 2595-2596, 2017. View at: Google Scholar
  18. Q. Chen and H. Yin, “Clinical effects of anisodamine combined with Xuebijing in treatment of severe pancreatitis,” World Chinese Journal of Digestology, vol. 23, no. 21, pp. 3464–3468, 2015. View at: Publisher Site | Google Scholar
  19. P. Gao and Z. Hu, “Clinical efficacy of Xuebijing combined with somatostatin in treatment of severe acute pancreatitis,” Chinese Traditional Patent Medicine, vol. 38, no. 3, pp. 714–716, 2016. View at: Google Scholar
  20. L. Hong, Y. Zhan, and X. Pan, “Clinical observation of Xuebijing injection in the treatment of acute pancreatitis and its effect on serum high sensitivity C-reactive protein,” Journal of Emergency in Traditional Chinese Medicine, vol. 21, no. 6, pp. 973-974, 2012. View at: Google Scholar
  21. Y. Hu, Y. Shan, and P. Huang, “Effect of ulinastatin combined with xuebijing on severe acute pancreatitis,” Chinese Journal of Surgery of Integrated Traditional and Western Medicine, vol. 25, no. 5, pp. 674–678, 2019. View at: Google Scholar
  22. J. Zhang, “Effect of Xuebijing combined with ulinastatin in the treatment of severe acute pancreatitis and its influence on serum inflammatory factors,” Chinese Journal of New Clinical Medicine, vol. 11, no. 6, pp. 599–602, 2018. View at: Google Scholar
  23. H. Ji and P. Yang, “Effect of Xuebijing injection combined with ulinastatin on serum inflammatory factors and clinical efficacy in patients with severe acute pancreatitis,” Shaanxi Journal of Traditional Chinese Medicine, vol. 38, no. 7, pp. 909-910, 2017. View at: Google Scholar
  24. L. Zhang, “Analysis of Xuebijing in the treatment of acute pancreatitis,” Medical Information, vol. 23, p. 232, 2015. View at: Google Scholar
  25. L. Zhu, “Clinical effect of somatostatin and pantoprazole combined with Xuebijing in the treatment of acute pancreatitis,” The World Clinical Medicine, vol. 9, no. 10, pp. 161–163, 2015. View at: Google Scholar
  26. G. Li and Y. Lv, “Effect of Xuebijing Injection on Hemorheology and TNF-α and IL-6 levels in patients with severe acute pancreatitis,” Guangming Journal of Chinese Medicine, vol. 35, no. 8, pp. 1161–1163, 2020. View at: Google Scholar
  27. F. Lin, Y. Lin, and J. Hong, “Clinical observation of Xuebijing injection combined with ulinastatin in the treatment of severe acute pancreatitis,” Nei Mongol Journal of Traditional Chinese Medicine, vol. 31, no. 15, pp. 8-9, 2012. View at: Google Scholar
  28. S. Liu and Z. Li, “Clinical observation of Xuebijing injection combined with western medicine in the treatment of acute pancreatitis,” Journal of Emergency in Traditional Chinese Medicine, vol. 24, no. 4, pp. 733–735, 2015. View at: Google Scholar
  29. W. Liu, “Effect of Xuebijing Injection on plasma endothelin and ammonia monoxide levels in patients with severe pancreatitis,” Modern Journal of Integrated Traditional Chinese and Western Medicine, vol. 23, no. 7, pp. 726–728, 2014. View at: Google Scholar
  30. X. Dong, “Xuebijing Injection for treatment of severe acute pancreatitis: curative effect and influence on inflammatory factors,” World Chinese Journal of Digestology, vol. 25, no. 10, pp. 929–933, 2017. View at: Google Scholar
  31. Y. Fan, “Clinical observation of Xuebijing combined with esomeprazole in the treatment of severe acute pancreatitis,” Journal of Clinical Medical, vol. 5, no. 39, p. 22, 2018. View at: Google Scholar
  32. J. Yang, R. Zhang, and H. Chen, “Xuebijing injection treated 31 cases of acute pancreatitis,” Fujian Journal of Traditional Chinese Medicine, vol. 45, no. 4, p. 30, 2014. View at: Google Scholar
  33. L. Zha, Y. Gu, and M. Zhao, “Clinical observation of ulinastatin combined with Xuebijing in the treatment of severe acute pancreatitis,” Chongqing Medicine, vol. 47, no. 08, pp. 1124-1125, 2018. View at: Google Scholar
  34. Y. Zhan, F. Xu, and Z. Fang, “Effect of Xuebijing injection combined with octreotide and ulinastatin in treatment of severe acute pancreatitis and its influence on immune function,” Chinese Archives of Traditional Chinese Medicine, vol. 37, no. 5, pp. 1262–1266, 2019. View at: Google Scholar
  35. H. Zhang, C. Wang, Y. Zhang et al., “Clinical effecacy of stilamin combined with Xuebijing in the treatment of severe acute pancreatitis and its effect on serum IL-10, IL-18 and TNF-α,” Medical Journal of West China, vol. 30, no. 12, pp. 1778–1782, 2018. View at: Google Scholar
  36. H. Zhang, N. Zhang, D. Niu et al., “Clinical observation of Xuebijing combined with esomeprazole in the treatment of severe acute pancreatitis,” Modern Journal of Integrated Traditional Chinese and Western Medicine, vol. 27, no. 4, pp. 387–389, 2018. View at: Google Scholar
  37. J. Guo and Y. Wang, “The effection of Xuebijing injection on serum TNF-α IL-6 and IL-10 in severe acute pancreatitis,” China Modern Doctor, vol. 51, no. 19, pp. 52-53, 2013. View at: Google Scholar
  38. J. Sandoval, J. Pereda, J. L. Rodriguez et al., “Ordered transcriptional factor recruitment and epigenetic regulation of tnf-α in necrotizing acute pancreatitis,” Cellular and Molecular Life Sciences, vol. 67, no. 10, pp. 1687–1697, 2010. View at: Publisher Site | Google Scholar
  39. J. Pereda, L. Sabater, L. Aparisi et al., “Interaction between cytokines and oxidative stress in acute pancreatitis,” Current Medicinal Chemistry, vol. 13, no. 23, pp. 2775–2787, 2006. View at: Publisher Site | Google Scholar
  40. J. Zeng and N. Chen, “The regulation of immune cytokines by Xuebijing combined with ulinastatin in treatment of severe acute pancreatitis,” Practical Journal of Clinical Medicine, vol. 10, no. 05, pp. 119–122, 2013. View at: Google Scholar
  41. H. Xiao and K. Tang, “Effects of Xuebijing injection combined with ulinastain on endotoxin and inflammatory factors in patients with severe acute pancreatitis,” Journal of Hainan Medical University, vol. 22, no. 14, pp. 1506–1508, 2016. View at: Google Scholar
  42. W. Zhang, Z. Li, and J. Wang, “Clinical observation of Xubijing injection in treating 42 cases of severe acute pancreatitis,” Chinese Journal of Critical Care Medicine, vol. 26, no. 8, pp. 635-636, 2006. View at: Google Scholar
  43. C. Li, P. Wang, M. Li et al., “The current evidence for the treatment of sepsis with Xuebijing injection: bioactive constituents, findings of clinical studies and potential mechanisms,” Journal of Ethnopharmacology, vol. 265, Article ID 113301, 2020. View at: Google Scholar
  44. L. Dai, M. Chen, Y. Zhuang et al., “Meta-analysis of the clinical efficacy of xuebijing injection in the treatment of acute respiratory distress syndrome,” World Latest Medicine Information, vol. 19, no. 92, pp. 32–34, 2019. View at: Google Scholar
  45. D. Han, R. Wang, Y. Yu et al., “Xuebijing injection combined with antibiotics for the treatment of spontaneous bacterial peritonitis in liver cirrhosis: a meta-analysis,” Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 2989846, 2018. View at: Publisher Site | Google Scholar
  46. Y. Song, C. Yao, Y. Yao et al., “Xuebijing injection versus placebo for critically ill patients with severe community-acquired pneumonia,” Critical Care Medicine, vol. 47, no. 9, pp. e735–e743, 2019. View at: Publisher Site | Google Scholar
  47. A. Nie, Z. Guo, Y. Zhang et al., “Literature analysis of 211 cases of adverse reactions of Xuebijing injection,” Strait Pharmaceutical Journal, vol. 31, no. 11, pp. 246–249, 2019. View at: Google Scholar
  48. R. Zheng, H. Wang, Z. Liu et al., “A real-world study on adverse drug reactions to Xuebijing injection: hospital intensive monitoring based on 93 hospitals (31,913 cases),” Annals of Translational Medicine, vol. 7, no. 6, p. 117, 2019. View at: Publisher Site | Google Scholar

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