Scientific Evidence of Xuebijing Injection in the Treatment of Sepsis

Objectives To systematically collate, appraise, and synthesize the current evidence on the Xuebijing injection (XBJI) for sepsis. Methods Eight databases were searched for systematic reviews (SRs) or meta-analyses (MAs) on XBJI for sepsis. Assessing the Methodological Quality of Systematic Reviews-2 (AMSTAR-2), Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA), and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methods were used to assess the methodological quality, reporting quality, and evidence quality of the enrolled studies, respectively. Results Out of the 13 studies that were included, all studies were rated critically low quality based on AMSTAR-2 results. Based on the results obtained from PRISMA, all studies were reported to be over 80%, while the GRADE system yielded three outcome measures rated high-quality, 16 were of moderate quality, and the rest were of low or critically low quality. Conclusions The combination of XBJI and Western medicine (WM) showed significant synergy for the treatment of sepsis compared to WM alone. However, this conclusion should be treated with caution since the quality of the SRs/MAs providing the evidence was relatively low.


Introduction
Sepsis is a severe complication resulting from severe infection, severe trauma, burns, surgery, and shock. is complication is quite perilous, leading to septic shock and multiple organ dysfunction syndromes [1]. Sepsis is a common cause of death in the intensive care unit [2], where it accounts for one-third to one-half of hospital deaths [3], as more than six million people die from this disease worldwide each year [4]. Despite the major advances in antibiotics and supportive therapies over the last few decades, mortality from sepsis still maintains an increasing trend [5]. At present, there is still no effective treatment for sepsis. Conventional anti-infection and supportive therapies have also shown no significant improvement in the survival rate of patients with sepsis [6,7]. Under these circumstances, complementary and alternative therapies have drawn attention.
is study aims to systematically collate, appraise, and synthesize scientific evidence through the presentation of an overview of these SRs/MAs.

Methods
is study was registered in the PROSPERO registry (CRD42021264569). e methods of the Cochrane handbook and some high-quality reviews were followed [12,13].

Strategy for Search.
A systematic search was conducted utilizing PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, Chongqing VIP, SinoMed, and Wanfang databases from inception to June 2021. e following medical subject headings, terms, and relevant keywords were used in this search: Xuebijing, sepsis, and systematic review. e search strategies can be found in additional file 1.

Criteria of Inclusion and Exclusion.
e studies that met the following criteria would be included for further evaluation. (1) Study type: participants enrolled in randomized controlled trials. (2) Subjects: patients diagnosed with sepsis according to internationally recognized diagnostic criteria.
(3) Interventions: the experimental intervention was a combination of XBJI plus WM and the control intervention was WM alone. (4) Outcomes: one or more of the index of outcomes was present, such as 28-day mortality, acute physiology and chronic health evaluation (APACHE) II score, white blood cell, and procalcitonin (PCT). A study was excluded if it had the following factors: (1) it was a duplicate publication, (2) it was an expert comment or a conference report, (3) it did not undergo peer review, (4) the control group included XBJI, and (5) the lack of further data.

Literature Selection and Data Extraction.
Two independent authors strictly followed the inclusion and exclusion criteria to conduct the study selection. Titles and abstracts of the literature were screened first, followed by the full text of all the initial qualified literature. e following data were extracted from each study: general information (first authors, country, and publication year), characteristics of the study (sample size and interventions), and results (outcomes and relative effect). A third author resolved any discrepancies between the two authors.

Quality Assessment.
For the eligible studies that were included, two independent authors assessed the methodological quality, reporting quality, and evidence quality using the appraisal tool for systematic reviews of randomized and observational studies, Assessing the Methodological Quality of Systematic Reviews-2 (AMSTAR-2) [14], Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) [15], and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [16], respectively. A third author resolved any discrepancies between the two authors. e items obtained from AMSTAR-2 and the checklists of PRISMA can be found in the additional file 2 and additional file 3.

3.1.
Results of the Literature Search. From the databases utilized, 132 articles were identified from the initial search. After 63 duplicate articles were removed, 69 were eliminated based on the title and abstract following the criteria. en, the eligibility of the remaining 22 articles was evaluated by scanning the full text of each article. Finally, examining full text resulted in the exclusion of eight studies (Appendix file 4), and the remaining 14 studies [17][18][19][20][21][22][23][24][25][26][27][28][29][30] met the inclusion criteria. Flow diagram of the literature selection process is shown in Figure 1.

Basic Characteristics.
e studies included were published between 2010 and 2021. Five of these reviews were published in English, while the remaining were in Chinese.
e number of trials of the included reviews ranged from 11 to 49 studies, and the total number of subjects ranged from 399 to 1970. As for the intervention, all reviews compared XBJI plus WM as a treatment intervention, while the control group only utilized WM. Six reviews out of 13 applied the Jadad scale for methodological quality assessment of included trials, while the remaining seven reviews used the Cochrane criteria tool. Further details of the assessment are given in Table 1.
e key factors affecting the methodological quality were item 2 (no review established protocol), item 4 (11 reviews did not provide the search strategy), item 7 (no review provided a list of excluded trials), item 10 (6 reviews did not report the sources of funding), and item 16 (5 reviews did not report any potential sources of conflict of interest). Further details of this assessment are given in Table 2.

Quality of Reporting Appraisal.
e quality of reporting was evaluated using the PRISMA guidelines, which included 7 sections and 27 items. e sections of the studies, including project title, abstract, introductions, and discussion, were comprehensively reported (100%). In the Methods section, the protocol and registration numbers were not reported in any of the reviews (0%), while the searches were completely reported in three reviews (21.4%), and the additional analyses conducted in the studies were reported in 10 reviews (78.6%). In the results section, the additional analyses were reported in 8 reviews (57.1%). Furthermore, funding was only reported in 8 reviews (57.1%). Further details are given in Table 3.

GRADE Evidence Quality Classification.
e 13 reviews included 43 outcome indicators that were related to the effectiveness of XBJI for sepsis. ree outcomes were identified as high quality, 16 were identified to be of moderate quality, 19 were identified to be of low quality, and the remaining 3 were identified to be with critically low quality. e risk of bias, inconsistency, imprecision, and publication bias were the main reasons for the decrease in quality. Further details are given in Table 4.

Effect of the Interventions.
e effects of the outcome indicators related to the effectiveness of XBJI for sepsis are given in Table 4. Twelve reviews [17,24,26,27,29,30] reported the meta-analysis results of the 28-day mortality.
e results revealed that the 28-day mortality rate of the XBJI group was lower when compared to the control group. Night reviews [17,21,23,25,27,30] reported the outcomes for the APACHE II score revealed that XBJI combined with WM was superior to a single WM in improving the APACHE II score. ree reviews [17,19,20] then reported the outcomes for the duration of mechanical ventilation. ese results showed that the time of mechanical ventilation of XBJI combined with the WM group was shorter than the control group, while three reviews [17,19,20] reported that the outcomes for the length of ICU stay showed that the XBJI plus WM group had an advantage over the WM only group in reducing the length of ICU stay. Two reviews [18,20] reported the outcomes for body temperature changes, where their results revealed that XBJI accompanied with WM could lower body temperature better than the treatment with WM alone. Five reviews [17,19,21,22,25] then reported the serum levels of PCT for XBJI in combination with WM and the control group. e results showed that the XBJI plus WM group had a lower PCT level than the control group. Furthermore, four reviews [18,25,27,28,30] reported that the white blood cell count of the XBJI plus WM group was lower than the control group.

Safety of the Interventions.
A total of five reviews [18,19,24,25,29] mentioned the adverse effects of XBJI for sepsis. Wherein, no adverse effects were reported in 3 reviews [18,24,25]. Two reviews [19,29] identified the following side effects, including pruritus and mild diarrhea, but no significant difference was found compared with the control group.

Discussion
e treatment of sepsis remains unsatisfactory despite the use of combined antibiotics and therapy [18]. erefore, it is essential to identify a more effective, innovative, and    Evidence-Based Complementary and Alternative Medicine is overview summarized the scientific evidence on the effectiveness and safety of XBJI for sepsis by evaluating the methodological quality, reporting quality, and evidence quality of SRs/MAs. e current evidence indicated that subjects treated using the combination of XBJI and WM showed a significant reduction in the 28-day mortality, APACHE II score, duration of mechanical ventilation, length of ICU stays, body temperature, serum levels of PCT, and white blood cell count as compared to those treated with WM alone. However, this conclusion must be considered with caution, given the limitations of the study. According to the results of AMSTAR-2, all reviews failed to meet the key item of I2 (established protocol) and I7 (provided the list of excluded trials), which may contribute to the possibility of risk of bias and undermine the reliability of the conclusions. en, according to the results of PRISMA, I5 (protocol and registration protocol and registration), I8 (search), I16 (additional analyses), I23 (additional analyses), and I27 (funding) were not reported adequately. is reasoning may increase the risk of bias and affect the rigor of SRs/MAs.  I1  I2  I3  I4  I5  I6  I7  I8  I9  I10  I11  I12  I13  I14  I15 I16 Chen et al. [17]  Wu, 2020 Evidence-Based Complementary and Alternative Medicine Based on the results of GRADE, only three outcome indicators provided high-quality evidence, 16 provided moderate-quality evidence, and the remaining 24 provided low or critical low-quality evidence. ese results indicate that the conclusions of the reviews may differ from the true results and therefore cannot be used as an evidence-based basis. Furthermore, it is worth noting that almost all the included SRs/MAs indicated that XBJI plus WM seems to have significant clinical efficacy in the therapy of patients with sepsis. However, most authors did not wish to draw definitive conclusions due to low methodological quality or the small size of the enrolled studies. e pathogenesis of sepsis includes inflammation, immune dysregulation, and coagulopathy, with uncontrolled inflammation being the most critical for patients [31]. According to traditional Chinese medicine, the basic pathogenesis of sepsis involves the accumulation of toxins in the interior and extremities, leading to siltation, stagnation, and weakened body resistance [10]. XBJI was then created according to this theory as a possible treatment for sepsis [32]. XBJI was composed of five herbs containing approximately 30 bioactive compounds, including hydroxysafflor yellow A, danshenol, ferulic acid, paeoniflorin, and senna lactone I, among others [17]. erefore, XBJI has the effects of "multiingredient, multitarget, and multipathway," including detoxifying and toning, elimination of bacteria and viruses, supplementing vital energy, and invigorating blood circulation [19]. Modern pharmacological studies have uncovered the potential therapeutic mechanisms of XBJI for sepsis. It was reported that XBJI could regulate the immune status of the body by inhibiting the release of inflammatory mediators, reducing the total accumulation of endotoxins, bacterial toxin detoxification, and reducing the total amount of oxygen free radicals in the circulatory system. ese effects help regulate the overall microcirculatory status of the body, protect and restore vascular endothelial function, and increase the total blood perfusion of the organs [19]. Moreover, XBJI also reduces the release of mast cells, which reduces the synthetic activity of fibroblasts. ese effects lead to the avoidance of inflammatory exudation and increase the permeability of blood vessels [11]. Furthermore, XBJI helps the body absorb necrotic material and hematoma, promoting rehabilitation [33]. us, the use of XBJI is considered a promising approach for the treatment of sepsis.
To our knowledge, this is the first study to systematically collate, appraise, and synthesize the scientific evidence on XBJI for sepsis. However, we found that most of the included reviews were of poor quality, which could result in these studies having low credibility. Furthermore, the AMSTAR-2 tool, PRISMA checklist, and the GRADE system are highly subjective as different reviewers have their independent judgment. e subjectivity of the authors may then lead to varying results as subjective factors or errors cannot be eliminated.

Conclusion
e combination of XBJI and WM showed significant synergy for the treatment of sepsis compared to the use of WM alone. It provided a new and prospective therapeutic method for sepsis. However, this conclusion should be treated with caution as the quality of SRs/MAs providing evidence was generally low.

XBJI:
Xuebijing injection WM: Western medicines SR: Systematic review MA: Meta-analysis AMSTAR-2: Assessing the Methodological Quality of Systematic Reviews-2 GRADE: Grading of Recommendations, Assessment, Development, and Evaluation PRISMA: Preferred Reporting Item for Systematic Reviews and Meta-Analyses ICU: Intensive care unit APACHE: Acute physiology and chronic health evaluation PCT: Procalcitonin RCT: Randomized controlled trials WMD: Weighted mean difference SMD: Standard mean difference MD: Mean difference OR: Odds ratio RR: Relative risk.
Data Availability e data generated or analyzed during this study are included within this article.