Effectiveness of Xuebijing injection for sepsis: an overview of systematic reviews and meta-analyses

Sepsis is a devastating condition caused by dysregulated host response to infection which leads to organ failure and death (1). In 2017, an estimated 49 million incident cases of sepsis were recorded worldwide among which more than 40% were children younger than 5 years, and 11 million sepsis-related deaths were reported, representing about 1/5 of all global deaths (2). Sepsis not only imposes a high burden on hospitalized patients (3), but also affects their quality of life, because half of the discharged patients are still not completely recovered (4,5). It has become a global public health concern due to its high mortality and morbidity and substantial economic burden (6). Moreover, with aging of the population, the presence of more people suffering from chronic diseases or on immunosuppressive medications, and the increase in invasive procedures, the incidence of sepsis will continue to increase (7,8).

Sepsis is a medical emergency and should be treated as quickly and efficiently as possible once it has been identified. Each hour of delay in treatment over the ensuing 6 hours was associated with an average decrease in survival of 7.6% (9). Current managements for the treatment of sepsis are fluid resuscitation, source control, antibiotic therapy and organ support therapy (7). Despite modern advances in critical care, most of the managements for sepsis are largely supportive but not specific. In other words, sepsis is a common illness associated with substantial lethality but has no specific treatment. Sepsis thus still remains a scientific and clinical challenge. There is an urgent need to find new drugs and therapies for sepsis. Recently, Xuebijing injection (XBJ) originating from complementary and alternative medicines has been developed to treat sepsis.

XBJ consists of the following five Chinese herbs: Hong Hua (Carthamus tinctorius L.), Chi Shao (Paeonia lactiflora Pall.), Chuan Xiong (Ligusticum chuanxiong Hort.), Dan Shen (Salvia miltiorrhiza Bge.) and Dang Gui [Angelica sinensis (Oliv.) Diels] (10). Its main components are hydroxysafflor yellow A, paeoniflorin oxide, Ligusticum chuanxiong lactone I and paeoniflorin, etc. (11). And it has been approved for the treatment of sepsis in China since 2004 and has been widely used as an add-on treatment for sepsis or septic shock with few side effects (10). XBJ has many pharmacological mechanisms including anti-inflammatory, anti-coagulation, immune regulation, vascular endothelial protection, anti-oxidative stress and others (12).

Currently, a number of randomized controlled trials (RCTs) have been conducted (13-15), and subsequently increasing numbers of systematic reviews (SRs) and meta-analyses (MAs) (10,16-18), have arisen to evaluate the effectiveness of XBJ for sepsis. However, most of the SRs/MAs reported that the evidence supporting the effectiveness of XBJ is insufficient, and those SRs/MAs reported varied and heterogeneous results and low methodological quality, making it difficult to draw a comprehensive conclusion on the effectiveness of XBJ on sepsis. Furthermore, no critically designed overview has been performed to assess the reporting and methodological quality of the published SRs/MAs so far.

Therefore, this overview aims to evaluate the methodological quality and evidence quality of extant SRs/MAs and to provide comprehensive evidence to identify whether XBJ is an effective treatment for sepsis. We present the following article in accordance with the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/lcm-21-13).

Methods

This overview of SRs/MAs has been conducted according to the methodological recommendations by the Cochrane Collaboration (19), and has been registered with INPLASY (20) (registration no. INPLASY2020120126).

Search strategy

The four international electronic databases of PubMed, Embase, Cochrane Library, and Web of Science and four Chinese electronic databases of the China National Knowledge Infrastructure Database (CNKI), WANFANG DATA, Chongqing VIP (CQVIP) and Chinese Biomedical Literature Database (CBM) were searched from their inception to September 30, 2020 without language restriction. The basic search strategies were as follows: (“sepsis” OR “severe sepsis” OR “septic shock”) AND (“xuebijing” OR “xue bi jing” OR “XBJ”) AND (“systematic review” OR “meta-analysis”). Meanwhile, we also searched conference abstracts and the reference lists of all retrieved articles to avoid missing relevant SRs/MAs. Details of the literature search strategy are shown in Appendix 1.

Literature screening

The database in Endnote software (version X9) were created. Duplicates were eliminated first, then titles and abstracts were read for the preliminary screening. Whenever we could not definitively exclude articles based on the titles and abstracts, full texts were downloaded and filtered again until all SRs/MAs were confirmed. Literatures were screened by two investigators (YL Shi and CT Chen), and any inconsistencies were discussed with the other two investigators (YD Xu and YJ Chen).

The inclusion criteria were: (I) patients were diagnosed with sepsis; (II) the intervention groups were XBJ plus routine treatment (RT); (III) the control groups were RT alone, and RT comprises fluid resuscitation, source control, antibiotic therapy and organ support therapy (7); (IV) at least one outcome followed was measured: 28-day mortality, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (the higher the score, the more frequent the need for monitoring and treatment), infection [measured by white blood cells (WBC) or procalcitonin (PCT) or C-reactive protein (CRP)], or coagulation function [measured by platelet (PLT) or activated partial thromboplastin time (APTT) or prothrombin time (PT)]; 5) SRs/MAs of RCTs.

The exclusion criteria were: (I) interventions which combined XBJ with other drugs that affect the efficacy judgment (e.g., ulinastatin); (II) protocols of SRs/MAs, commentaries; (III) studies that published in abstracts forms for which full texts were unavailable; (IV) duplicate reports of the same study.

Data extraction

One researcher (YL Shi) extracted the following basic information: first author, publication date, number of included trials and participants, interventions, outcomes reported, quality assessment tools, and overall conclusions. Another researcher (CT Chen) checked it against the original, and if there was any discrepancy, the original text was referred and the data will be revised accordingly.

Methodological quality

The methodological quality of the included reviews was assessed by researchers (YL Shi and CT Chen) according to the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool (21), which contains 16 items with 7 items (2,4,7,9,11,13,15) were considered crucial domains that critically affect the validity of a review and its conclusions. Any inconsistencies were resolved via discussion with the other two authors (YD Xu and YJ Chen).

Each item was evaluated as “methodological requirements met”, “methodological requirements partly met” or “methodological requirements not met”. Overall confidence in the results of the reviews was rated “high” (none or one non-critical weakness), “moderate” (>1 non-critical weakness but no critical flaws), “low” (1 critical ± non-critical weakness), and “critically low” (>1 critical flaw ± non-critically weakness).

Evidence quality

The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system (22) was applied to evaluate the evidence quality of the concerned outcomes (28-day mortality, APACHE II scores, WBC, PCT, CRP, PLT, APTT, PT). For each outcome, we awarded a high grade to begin with as these were RCTs and downgraded if there were problems relating to risk of bias, inconsistency, indirectness, imprecision, or publication bias. We classified evidence quality as high, moderate, low, or very low. The two researchers (YL Shi and CT Chen) independently assessed the quality of evidences and resolved disputes through discussions with the other two researchers (YD Xu and YJ Chen).

Results

Literature selection

A total of 125 articles were identified from the database. Through strict screening, 12 reviews (10,16-18,23-30) were finally included in this overview. The flow diagram of literature screening is shown in Figure 1. The characteristics of excluded studies are shown in Appendix 2.

Figure 1 Study selection process for the overview.

Study characteristics

Twelve SRs/MAs were included for the overview, with number of RCTs from 8 to 49 and of participants from 399 to 3,884. All of the 12 reviews conducted MAs. Two tools of quality assessment were employed in MAs, including Cochrane Handbook for Systematic Reviews of Interventions (10,18,26-28,30) and Jadad scale (10,16,17,23-25,29). The characteristics of the included 12 reviews are demonstrated in Table 1.

Methodological quality evaluation of included MAs

According to the AMSTAR 2 results, all included MAs were rated as critically low quality. The main causes influencing the methodological quality of reviews are item 2 (none of the included reviews contain an explicit statement that the review methods were established prior to the conduct of the review), item 3 (none of the included reviews explain their selection of the study designs for inclusion in the review), item 7 (none of the included reviews provide a list of excluded studies) and item 10 (none of the included reviews report on the sources of funding for the studies included in the review). The methodological quality evaluations of included reviews are presented in Figure 2.

Figure 2 Methodological quality evaluation of meta-analyses (Mas) with Assessment of Multiple Systematic Reviews 2 (AMSTAR 2). Q1: did the research questions and inclusion criteria for the review include the components of population, intervention, comparison, outcome (PICO)? Q2: did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol? Q3: did the review authors explain their selection of the study designs for inclusion in the review? Q4: did the review authors use a comprehensive literature search strategy? Q5: did the review authors perform study selection in duplicate? Q6: did the review authors perform data extraction in duplicate? Q7: did the review authors provide a list of excluded studies and justify the exclusions? Q8: did the review authors describe the included studies in adequate detail? Q9: did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? Q10: did the review authors report on the sources of funding for the studies included in the review? Q11: if meta-analysis was performed did the review authors use appropriate methods for statistical combination of results? Q12: if meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis? Q13: did the review authors account for RoB in individual studies when interpreting/discussing the results of the review? Q14: did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review? Q15: if they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? Q16: did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?

Evidence quality evaluation of outcomes

We evaluated the evidence quality for the 45 outcomes according to the GRADE system. Only 1 (2.2%) outcome was rated as high-quality evidence, 10 (22.2%) were rated as moderate quality, 28 (62.2%) were rated as low quality, and 6 (13.3%) were rated as very low quality.

The main factor for downgrading was the risk of bias (the included studies of all outcomes designed with a bias in random sequence generation, allocation concealment, blinding, or incomplete outcome data) and only 2 (4.4%) outcomes did not present this issue. Of 45 outcomes, evidence quality was downgraded for 17 (37.8%) due to imprecision, and for 24 (53.3%) due to inconsistency. There was no publication bias and indirectness in all outcomes. The details of the evidence quality are shown in Table 2.

Effectiveness of XBJ for sepsis

Twenty-eight-day mortality

A total of ten reviews (10,17,18,24-30) analyzed the 28-day mortality of XBJ for sepsis, with RCTs from 1 to 32 and participants from 21 to 2,315. Nine reviews suggested that upon comparison of the effects of XBJ plus RT vs. RT alone, the combined treatment had a significantly greater effect. However, one review (25) pointed out that XBJ could effectively reduce 28-day mortality at a dose of 100 mL/d, but not necessarily at 200 mL/d. According to the GRADE system, the quality of evidences for 28-day mortality was low to moderate.

APACHE II scores

Eight reviews (10,17,18,24,26-28,30), with number of RCTs from 4 to 34 and of participants from 177 to 2,838 compared the effects of XBJ plus RT treatment vs. RT treatment alone using the APACHE II scores, and the results revealed that the combined treatment had a better effect than RT alone. Only one (30) of them was rated high-quality evidence and the others were very low to low.

WBC

Six reviews (10,17,18,23,24,27) reported the effectiveness of XBJ for sepsis on WBC, among which 1–27 RCTs and 40–1,678 participants were included. One review (10) reported that XBJ combined with RT at doses of 400 and 100 mL/d worked better in improving WBC count than RT alone, but not at a dose of 200 mL/d group. The quality of evidence for WBC was very low to low.

CRP

Four MAs (17,18,24,27) reported the pooled results of XBJ plus RT vs. RT alone, and the number of RCTs included in the MAs ranged from 2 to 23 with participants from 306 to 1,643. Three MAs (17,18,27) with low-grade evidence indicated that combined treatment was superior to RT alone, and the reduction of the CRP was significantly higher in the XBJ plus RT group. However, one review (24) which was rated very low grade found no significant difference in CRP between two groups.

PCT

Three reviews (17,24,27) used the PCT level to compare the effects of XBJ plus RT vs. RT alone, and two reviews (17,27) showed that the combined treatment could significantly reduce the PCT more than RT alone, which had low quality of evidence. One MA (24), rated very low-grade evidence, analyzed 2 RCTs with 126 participants and came to the conclusion that there was no significant difference in PCT between the two groups.

PLT

Five reviews (16,23,24,26,30) used the PLT to access the effectiveness of XBJ for sepsis, and 5–12 RCTs and 332–737 participants were included. All of them indicated that compared with the control group, PLT counts markedly increased in the treatment group. The quality of evidence for PLT was low to moderate.

APTT and PT

The APTT and PT were reported in three MAs (16,24,26) which encompassed 8–14 RCTs (519–867 participants). The pooled results demonstrated that XBJ plus RT could considerably shorten the APTT and PT when compared with RT alone. The quality of evidence for APTT was low to moderate and for PT was low.

Discussion

Main findings

In this overview, XBJ has exhibited potential effectiveness in reducing or improving the relevant outcomes, reflecting its possible clinical effectiveness on sepsis. It may be manifested in the improvement of non-endpoint outcomes: inflammation (WBC, PCT and CRP) and coagulopathy (PLT, shorting APTT and PT); the clinical endpoint: 28-day mortality, and a long-term prognosis indicator: APACHE II scores.

AMSTAR 2 and the GRADE system were used to assess the methodological quality and evidence quality of 12 MAs of XBJ for sepsis. The results for methodological quality using AMSTAR 2 showed that all of the reviews were rated as “critically low”. Consistent drawbacks of methodology included the following: (I) lack of a prior protocol. Advanced registration can help to promote processing transparency and avoid post-decision bias (31). (II) Lack of explanation for the selection of the type of study for inclusion. This may lead to selection bias and lower credibility of the results. (III) Lack of a list of excluded studies. The availability of exclusion lists reduces selectivity bias and ensures research transparency. (IV) Lack of reports on sources of research funding. It is important to avoid other biases as the results of researches that receive corporate funding are more beneficial to the funder (32). Therefore, the absence of any of the above factors will reduce the credibility of the research results. We should avoid the occurrence of these problems in the future.

According to the GRADE system, this overview of 12 reviews and 45 outcomes showed that only 1 (2.2%) outcome was rated as high quality, 10 (22.2%) were rated as moderate quality, 28 (62.2%) were rated as low quality, and 6 (13.3%) were rated as very low quality. The main factors for downgrading evidence quality are as follows: (I) risk of bias, almost all the outcomes related to RCTs designed with a large bias in random sequence generation, allocation concealment, blinding, or incomplete outcome data. Due to the particularity of XBJ (a brown color liquid), blinding participants is difficult, which would require covering the bottles and transmission pipes during transfusion. (II) Imprecision, 17 (37.8%) outcomes were downgraded for small sample size and wide confidence interval, so large sample size RCTs are needed. (III) Inconsistency, 24 (53.3%) outcomes were downgraded due to inconsistency. Therefore, it is essential to perform the subgroup analysis to consider possible factors such as XBJ dose, diagnostic criteria, etc., in order to reduce inconsistencies. Despite the potential efficacy of XBJ, the strength of evidence for all outcomes is still unsatisfactory.

Interpretation to efficacy of XBJ

In this overview, the potential effectiveness of XBJ on sepsis may be manifested in the improvement of non-endpoint outcomes: inflammation (WBC, PCT and CRP) and coagulopathy (PLT, shorting APTT and PT); the clinical endpoint: 28-day mortality, and a long-term prognosis indicator: APACHE II scores.

Although the quality of evidence for most of the results was low, the efficacy of XBJ in treating sepsis was worthy of recognition. Twenty-eight-day mortality is the most appropriate endpoint in sepsis (33). In our results, only one review (25) showed that XBJ could not effectively reduce 28-day mortality at a dose of 200 mL/d. However, due to the low quality of evidence, the reliability of this result was reduced. Meanwhile, such a result suggested that it may be necessary to explore the effects of different doses of XBJ on the prognosis of patients with sepsis in future studies.

APACHE II scores were used to predict hospital mortality in septic patients (34), which consist of three parts: 12 acute physiological variables, age and chronic health status (35). Our results revealed that RT combined with XBJ could reduce the APACHE II scores and improve the prognosis of patients. But the credibility of the results is undermined by the fact that only one of the outcomes is high grade in quality and the rest are all very low to low grade. It is suggested that more rigorous experimental design is needed to evaluate this index in the future.

WBC, PCT and CRP are all indicators of inflammation, PCT can reflect the active degree of systemic inflammation, and WBC and CRP are commonly used clinical indicators of inflammatory response. Of the 15 inflammatory outcomes, the positive outcomes were rated low, and the negative outcomes were rated very low. This suggested that positive outcomes may be more reliable, meaning that RT plus XBJ is more effective at reducing inflammation than RT alone. In addition, one review (10) also found that the dose of XBJ had an impact on the above-mentioned WBC, suggesting that subgroup analysis of XBJ dose is particularly necessary. Moreover, many reviews have indicated that XBJ could inhibit the release of pro-inflammatory cytokines such as TNF-α (23,30) and IL-6 (36) in patients with sepsis. There are some studies that have shown that XBJ could also promote the release of anti-inflammatory cytokine IL-10 in the early stage of sepsis (37,38). Further studies suggested that XBJ might play its anti-inflammatory role by down-regulating the expression of NF-κB, MAPK, and PI3K/Akt signaling pathway (39,40). More precise and comprehensive researches into the mechanism are needed.

PLT, APTT and PT are all effective indicators to reflect the coagulation function of the body, and all have strong sensitivity (41). Not only did this overview demonstrated that XBJ could improve coagulation function in patients with sepsis, but other MAs (42,43) had demonstrated this as well. XBJ reduced the release of tissue factor (44,45), increases the levels of plasma activated protein C (46) and inhibits the expression of plasminogen activator inhibitor-1 (47), thereby improving the coagulation dysfunction (12).

Inflammation (48), immunosuppression (49) and coagulation dysfunction (50) are key features in the pathogenesis of sepsis. In addition to the improvement of inflammatory response and coagulation dysfunction mentioned above, XBJ has also been reported to improve the immune function (28,51,52) of patients with sepsis. Therefore, XBJ has the effect of a multi-target treatment and a comprehensive regulation on sepsis. Over the last three decades, most of the therapeutics strategies successful in experimental sepsis failed in the clinical trials (53,54) and sepsis also remains a scientific and clinical challenge. The multi-target therapeutic advantage of XBJ is well-suited to address the critical points of the current sepsis clinical trial failure. Despite the low methodological quality and low evidence quality, it is still a good choice in the situation in which no treatment approved by the FDA is available for sepsis treatment. Moreover, the protection mechanism of XBJ is being further investigated (12,39).

In addition, it is worth nothing that XBJ is not only effective in treating sepsis, but also widely used in severe pneumonia (11), severe heat stroke (55), acute organophosphorus pesticide poisoning (56), rheumatoid arthritis (57) and other diseases. In particular, XBJ has been widely used in the treatment of COVID-19, which is the most pertinent application in the world at this moment, and its effect is remarkable (58-60). Researches on the application of XBJ to different diseases are ongoing.

Strengths and limitations

This overview is the first attempt to assess the methodological quality of SRs and MAs using the AMSTAR 2 tool and GRADE system to evaluate the quality of evidence for the efficacy of XBJ for sepsis. We conducted systematic and comprehensive searches and a reasonable literature screening, which may greatly reduce possible selection bias. Furthermore, this overview included SRs of randomized trials using strict inclusion standards, and excluded reviews with non-RCTs or observational studies in order to reduce the risk of mixed bias.

This overview still has limitations. Firstly, the evaluation process of AMSTAR 2 and GRADE is inevitably subjective and may result in bias. Secondly, the methodological quality and evidence quality of the included MAs were generally low; thus, results should be interpreted with caution. Third, we did not conduct the subgroup analysis and comparison of XBJ dose, so the effect of dose on XBJ efficacy needs further study.

Suggestions for future research

Since the methodological quality and evidence quality of MAs were generally low, the credibility of the results has been reduced, indicating that the efficacy of XBJ on sepsis is limited. We recommend that rigorous RCTs be designed, with attention to specific blinding and allocation concealment. For SRs and MAs, we suggest that subgroup analysis should be performed strictly according to consistent diagnosis and intervention, consistent treatment dose, and outcome measurement so as to reduce bias. In addition, safety evaluation of XBJ is rarely seen in RCTs, and only 2 (14,15) of the RCTs included in the 12 MRs reported adverse reactions such as skin itching and rash after the use of XBJ. The RCTs should give more attention to reporting safety aspects.

Conclusions

In this paper, the inclusion results of MAs were extracted and analyzed systematically, suggesting that XBJ is clinically effective in the treatment of sepsis, especially in reducing inflammation, reducing mortality, improving coagulation dysfunction and prognosis. But this conclusion should be interpreted prudently, given the generally low methodological quality and low quality of evidence of the included MAs. In the future, rigorous MAs are needed following methodological requirements to provide robust evidence for definitive conclusions.

Acknowledgments

Funding: This work was supported by the National Natural Science Foundation of China (NSFC) (grant numbers 81774429, 81973952 and 81973951), Natural Science Foundation of Shanghai (grant number 19ZR1451500), Scientific Research Project of Shanghai Municipal Health Commission (grant number 20194Y0164), Shanghai Sailing Program (grant number 20YF1445300), National Key R&D Program of China (grant number 2018YFC1704600).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/lcm-21-13

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/lcm-21-13). The authors have no conflicts of interest to declare.

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

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

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