a b s t r a c t

Background: The potential benefits and possible risks associated with Xuebijing when combined with ulinastatin for Sepsis treatment are not fully understood.

Methods: Databases, such as PubMed, Web of Science, CNKI, WanFang and VIP, were searched to collect random- ized, controlled trials. Studies were screened, data were extracted, and the methodological quality was assessed by two reviewers independently. A meta-analysis was carried out with Stata 11.0 software.

Results: A total of 16 studies involving 1192 participants were enrolled for meta-analysis based on the inclusion and exclusion criteria. The results showed that compared with the group using routine therapies and the group using a single administration of either ulinastatin or Xuebijing, the trial group using Xuebijing combined with ulinastatin was significantly superior in the following aspects: mortality (RR = 0. 54,95% CI (0. 41, 0. 70, P = .000), 7 d APACHE II (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), duration of mechanical

ventilation (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), average length of time in the intensive care unit (SMD = -1.21, 95%CI (-1.62, -0.80), P = .000), incidence of Multiple organ dysfunction syndromes (RR = 0. 54, 95% CI (0.41, 0. 70, P = .000), interleukin-6 (SMD = -1.36,95%CI (-2.46, -0.27), P = .000),

lipopolysaccharide (SMD = -9.92, 95%CI (-11.7, -7.90), P = .006), and procalcitonin (SMD = -0.30, 95%CI (-0.34, -0.26), P = .012).

Conclusions: Our results found that Xuebijing when combined with ulinastatin was superior to both routine ther- apies and the single administration of either ulinastatin or Xuebijing. This finding provides a new therapeutic op- tion for the treatment of sepsis.

(C) 2017

Introduction

Sepsis refers to systemic inflammation caused by infection re- sponse syndrome, and it is a common complication of severe trau- ma, burn, shock, major surgical operation in critically ill patients and is also one of the major causes of shock, multiple organ dys- functions and organ failure in patients [1]. Septic shock refers to sepsis with tissue hypoperfusion, which occurs after fluid

? Disclosure of conflict of interest: None.

* Corresponding author at: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Emergency Medicine and Difficult Diseases Institute, Central South University, No.139, Renmin Middle Road, Changsha, Hunan Province 410011, China.

E-mail address: [email protected] (X. Xiang).

resuscitation is still difficult to reverse, and it typically occurs after the initial fluid resuscitation of sustained hypotension or to maintain a high level of blood lactate concentration [2]. Septic shock is a major threat to human health. Even with optimal treat- ment, mortality due to septic shock is approximately 40%, and it can exceed 50% in very sick patients [3]. Hemodynamic disorders exist in most patients with septic shock, which is an important fac- tor to determine the prognosis and cardiac function; vessel endo- thelial function is another important factor in hemodynamics [4]. Sepsis-induced myocardial dysfunction is one of the most serious complications of sepsis, and it leads directly to increased mortality rates [5]. Until now, no treatment has shown efficacy for sepsis. It is of great importance to determine drugs that would be effective in the improvement of sepsis-induced myocardial dysfunction, as well as to explore the underlying mechanism; Chinese medicine shows superiority in this respect. In 2002, a phase III trial with

https://doi.org/10.1016/j.ajem.2017.12.007 0735-6757/(C) 2017

N500 patients found that patients with sepsis could greatly benefit from Xuebijing treatment. From 2005 to 2008, a multi-center ran- domized controlled trial, consisting of 78 hospitals and 2590 pa- tients with sepsis, reported that the complete response rates of sepsis, severe sepsis and multiple organ dysfunction syndromes were 78.8%, 73.2% and 57.4%, respectively. The incidence of side ef- fects was only 0.12% [6]. This trial shows the efficacy and safety of Xuebijing. In parallel with the study above, another randomized, controlled trial with 731 sepsis patients reported that Xuebijing promotes the restoration of organs, corrects the abnormality in co- agulation function, and improves prognosis [7]. Ulinastatin is a protease inhibitor that can improve immune function and protein metabolism in patients after operations and protect the cells of internal organs from being damaged by surgical stimulation [8]. It has been widely used in clinical practice. The use of Xuebijing or ulinastatin still has some limitations. Some researchers suggested a comprehensive treatment plan with two or more agents for sep- sis. It was reported that Xuebijing combined with ulinastatin was superior to a single drug, and this provided new insights for sepsis treatment; however, the results remained inconsistent. We sys- tematically searched online databases and evaluated the Clinical effectiveness of Xuebijing combined with ulinastatin for treating sepsis.

Methods

We performed this meta-analysis by following the recommenda- tions of the Cochrane Handbook for Systematic Reviews and reported the results in accordance with The Preferred Reporting Items for Sys- tematic Reviews and Meta-analysis statement guidelines [9]. The ethical guidelines were not applicable for this second study based on published articles.

Literature search

We conducted a systematic online search in PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases from their inception to May 31, 2017. The following medical subject headings, terms and relevant keywords were used: Xuebijing, ulinastatin, and sepsis. We placed no language restrictions on electronic searches. We also manually checked the reference lists of previous reviews and other potentially eligible trials to ensure study saturation.

Selection criteria

Two authors independently conducted literature searches by ex- cluding duplicates, screening titles and abstracts, and then identify- ing studies as eligible for inclusion or not. We went through the full text of studies and confirmed whether the studies could be included in the analyses. Those studies included had to meet the following criteria: (1) Randomized, controlled trials or cohort studies. (2) Study population included patients with sepsis who received Xuebijing and routine treatment, or Xuebijing combined with ulinastatin. (3) One or more of the index of outcomes, such as mor- tality, APACHE II, duration of mechanical ventilation, average length of time in intensive care unit, incidence of MODS, interleukin-6, lipo- polysaccharide, and procalcitonin, were shown, which can be used for pooling. Studies with larger sample sizes were selected when du- plicate publications were found.

Data extraction

The standard data extraction sheet was used. The two authors reviewed and extracted the data independently in accordance with the inclusion criteria. Discrepancies were resolved by discussion. From each study, the following information was extracted: author’s surname,

Publication year, average age of the control group and the trial group, sample size of trials and controls, intervention, treatment cycle, and index of outcomes. Authors were contacted to provide supplemental data if data were not available in the eligible studies. When studies in- cluded subjects of more than one ethnicity, data were extracted separately.

Assessment of quality

For the randomized, controlled study, we used the bias tool recom- mended by the Cochrane handbook to assess the quality of included studies [10]. This assessment tool consisted of the following seven items: random sequence generation; allocation concealment; blinding, including study design and outcome assessment; selected reported data; incomplete data; and other potential biases. We identified each item as low risk, high risk or unclear risk according to the reported re- sults of each study.

Statistical analysis

All statistical analyses were performed using the Stata 11.0 software (StataCorp, College Station, TX, USA). For qualitative data, pooled risk ratios (RRs) with corresponding 95% CIs were calculated to evaluate the efficacy of Xuebijing combined with ulinastatin in benefiting pa- tients with sepsis. For quantitative data, standardized mean differences were used to evaluate the efficacy. Stratification analyses were carried out by follow-up durations. A P b .05 was considered as statistically significant. Taking possible between-study heterogeneity into account, we considered the presence of significant heterogeneity at the 10% level of significance and values of I² exceeding 50% as an indicator of sig- nificant heterogeneity. When no heterogeneity was found with P N

.10 or I² b 50%, a fixed-effect model was used. Otherwise, a random ef-

fects model was applied [11]. Sensitivity analysis was conducted to de- termine the effect on the test of heterogeneity and evaluate the stability of the results by omitting each study in turn. Publication bias was eval- uated by visual inspection of symmetry of Begg’s funnel plot and assess- ment of Egger’s test [12, 13]; P b .05 was regarded as statistically significant.

Results

Study selection

Fig. 1 presents the process of literature screening, study selection, and reasons for exclusion. Our initial search returned 315 records. After 89 duplicates were removed, 226 records were screened by scanning titles and abstracts. 44 articles were thought to be potentially eligible for inclusion. After reviewing the full texts, we confirmed 16 studies for use in the final Qualitative and quantitative analyses [14-29].

General characteristics of included studies

The general characteristics of the included studies are summarized in Table 1. These studies were published from 2008 to 2015. The sample sizes ranged from 36 to 184, with a total of 1192 patients. Of these stud- ies, 11 of 16 studies reported the mortality; 4 studies reported 28-day mortality, and 7 studies reported 7-day mortality. Ten studies reported the Acute Physiology and Chronic Health Evaluation (APACHE II), five studies gave the duration of mechanical ventilation, and five studies gave the average length of intensive care unit time. Three studies re- ported the incidences of multiple organ dysfunction syndromes, nine studies compared interleukin-6, three compared lipopolysaccharide, and nine compared procalcitonin. Fourteen of the 16 studies compared the efficacy over 7 days, and 2 studies compared the efficacy over

14 days. The control group received the Xuebijing and routine, and the trial group received Xuebijing combined with ulinastatin (Table 2).

Quality of assessment

The Supplementary material 1 (S1 and S2) gives the details of the quality assessment. Overall, eight studies were randomized, controlled studies and used the double-blinding method with a low risk bias, and the other half did not use blinding methods and were categorized as being of unclear risk. The blinding application of patients and clinicians in the current study was quite difficult and generally unfeasible in these studies, and we judged that the primary outcome was less prone to be influenced by the lack of blinding.

Pooled results

Eleven studies provided data on mortality. Compared with the use of solely Xuebijing, the combination of Xuebijing with ulinastatin signifi- cantly reduced mortality (RR = 0.54, 95%CI: 0.41-0.70, P = .000) without heterogeneity (I² = 0.0%, P = .956). We conducted subgroup analyses according to follow-up duration. Seven studies reported a 7-days mortality, and four studies reported a 28-days mortality. The same reduced risks were found (RR = 0.46, 95%CI: 0.32-0.66, P = .026; RR = 0.64, 95%CI: 0.43-0.96, P = .000, Fig. 2) with no

heterogeneity (I² = 0.0%).

For the ten studies compared with APACHE II, a random-effect model was used because the heterogeneity was high (I² = 83.6%). Significantly reduced scores were observed for patients who received Xuebijing combined with ulinastatin (SMD = - 1.21, 95%CI (-1.62-0.80), P = .000, Fig. 3). The duration of

Fig. 1. Flow char of study selection.

Table 1

General characteristics of included studies in the meta-analysis

Author Year Mean age Sample size Intervention Treatment cycle (d) Outcomes Score of quality

	Control	Trial		Control	Trial		Control	Trial
Zhang et al. 2015	44.6 +- 14.7	46.3 +- 16.5		36	36		Xuebijing and routine	Combined with Ulinastation	7	(1)(2)(6) 5
Chen et al. 2014	-	-		40	40		Xuebijing and routine	Combined with Ulinastation	7	(1)(2)(4)(6) 4
Wang et al. 2014	-	65.0 +- 17.0		32	32		Xuebijing and routine	Combined with Ulinastation	7	(6) 4
Wang et al. 2014	-	57.3 +- 9.6		16	20		Xuebijing and routine	Combined with Ulinastation	14	(6) 5
Yi et al. 2014	53.2 +- 8.7	58.6 +- 9.6		30	30		Xuebijing and routine	Combined with Ulinastation	7	(1)(2)(6) 3
Zeng et al. 2013	49.2 +- 9.8	45.3 +- 13.1		27	27		Xuebijing and routine	Combined with Ulinastation	7	(2)(6) 4
Zhou et al. 2013	-	43.6 +- 1.3		57	56		Xuebijing and routine	Combined with Ulinastation	14	(6) 3
Zhao et al. 2013	-	62.8 +- 10.5		44	44		Xuebijing and routine	Combined with Ulinastation	7	(1)(2)(3)(4) 4
Jiang et al. 2013	49.3 +- 11.5	49.5 +- 11.2		43	43		Xuebijing and routine	Combined with Ulinastation	7	(1)(2)(3)(4)(5) 5
Zhou et al. 2012	35.5 +- 11.2	39.3 +- 12.0		32	36		Xuebijing and routine	Combined with Ulinastation	7	(1)(5) 4
Wu et al. 2012	36-60	-		20	20		Xuebijing and routine	Combined with Ulinastation	7	(1)(2) 4
An et al. 2011	54.2 +- 11.6	53.5 +- 10.7		20	20		Xuebijing and routine	Combined with Ulinastation	7	(2) 3
Yang et al. 2010	47.2 +- 12.1	-		85	99		Xuebijing and routine	Combined with Ulinastation	7	(2) 4
Zhang et al. 2010	58.5 +- 12.1	-		23	20		Xuebijing and routine	Combined with Ulinastation	7	(1)(2)(3) 5
Ye et al. 2010	40.0 +- 5.0	-		23	27		Xuebijing and routine	Combined with Ulinastation	7	(2)(4)(5) 3
Mao et al. 2008	51.5 +- 11.5	50.1 +- 9.6		57	57		Xuebijing and routine	Combined with Ulinastation	7	(1)(3)(4) 4

(1) Mortality, (2) APACHE II, (3) Duration of mechanical ventilation, (4) average length of intensive care unit, (5) multiple organs dysfunction syndromes, and (6) Interleukin-6.

mechanical ventilation in the trial group was significantly less than that in the control group with medium heterogeneity (I² = 69.1%, Fig. 4). Five articles reported data on the average length of time in the intensive care unit. No heterogeneity was found, and a fixed-effect model was used. The trial tended to have a less-than-aver- age length of Intensive care unit stay (SMD = -0.83, 95%CI (-1.03- 0.64), P = .000, Fig. 5).

Nine studies reported data on interleukin-6, and a random-effect model with I² of 84.3% found decreased levels of interleukin-6 (SMD = -1.36, 95%CI (-2.46-0.27), P = .000) compared to that of the control group. Three studies reported the incidence of MODS. The results from the fixed-effect model indicated there was a reduced risk of MODS in the trial group compared to that in the control group (RR = 0.56, 95%CI: 0.38-0.83, P = .003). Three studies reported results of lipopolysaccharides with no heterogeneity (I² = 0.0%). The lipopoly- saccharide level in the trial group was lower than that in the control (SMD = -9.92, 95%CI: -11.7-7.91, P = .006). Nine studies reported the procalcitonin level. A random-effect model was used, and the heterogeneity was high (I² = 80.8%). The reduced procalcitonin level was significantly observed in the trial group (SMD = -0.30, 95%CI: -0.34-0.26, P = .012).

Sensitivity analyses and publication bias

We conducted sensitivity analyses through excluding individual studies. The results did not change significantly (data shown).

The Egger and Begg tests reported no publication bias (Z = 1.710, P = .087; t = -2.220, P = .054). The funnel plot gave a slight asymmetry (Fig. 6).

Discussion

Sepsis has a high incidence and mortality rate, and it is one of the major causes of death in patients in the intensive care unit, as well as one of the ten major causes of death. A multi-center ep- idemiological investigation showed that the incidence rate of sep- tic shock in the intensive care unit was 8.68%, the mortality rate was as high as 44.7%, and the high Medical costs brings great phys- ical, psychological and Economic burdens to the patients [30]. In the USA, 215,000 people died annually of sepsis and its follow-up complications. The mortality of sepsis in the intensive care unit was approximately 30-40%, while the mortality in elderly patients or in patients with basic diseases is higher than 70% [31]. There- fore, any progress in treating the disease is greatly needed. The present study found that Xuebijing combined with ulinastatin could reduce the mortality of sepsis patients, shorten the duration of mechanical ventilation, shorten the average length of time in the intensive care unit, and decrease the incidence of multiple organ dysfunction syndromes. The combined method was also su- perior to the single administration of either ulinastatin or Xuebijing in reducing the levels of interleukin-6, lipopolysaccha- rides, and procalcitonin.

Table 2

Pooled results of different outcomes.

Outcomes	Number of study	I2 (%)	P	Effect size (95%CI)	Model
Mortality	11	0.0	0.956	0.54(0.41-0.70)	Fixed
7 days	7	0.0	0.847	0.46(0.32-0.66)	Fixed
28 days	4	0.0	0.987	0.64(0.43-0.96)	Fixed
APACH IIa	10	83.6	0.000	-1.21(-1.62-0.80)	Random
Duration of mechanical ventilation	5	69.1	0.012	-1.04(-1.40-0.67)	Random
Average length of intensive care unit	5	0.0	0.753	-0.83(-1.03-0.64)	Fixed
Incidence of MODSa	3	0.0	0.561	0.56(0.38-0.83)	Fixed
Interleukin-6	9	84.3	0.000	-1.36(-2.46-0.27)	Random
Lipopolysaccharide	3	0.0	0.837	-9.82(-11.7-7.91)	Fixed
Procalcitonin	9	80.8	0.000	-0.30(-0.34-0.26)	Random

^a APACH II, Acute Physiology and Chronic Health Evaluation MODS, multiple organs dysfunction syndromes.

Fig. 2. Comparison of mortality between trail group and control group.

Ulinastatin is a broad-spectrum protease inhibitor of glycoprotein, extracted from human urine, and it belongs to the endogenous inhibito- ry inflammatory substances of the human body [32]. On the one hand, it can inhibit enzyme activity and promote the degradation of enzymes [23]. In addition, it can inhibit the release of a variety of Inflammatory mediators such as interleukins-1, 6, 8, and tumor necrosis factors. It also clears oxygen free radicals, decreases blood viscosity, improves cir- culation during shock, reduces Ischemia-reperfusion injury and Organ function damage, and improves the body’s immune function [33]. The previous meta-analysis found that tumor necrosis factor-? in the ulinastatin group had significant differences with the control group, as well as the interleukin-6, white blood count, C-reactive protein and APACHE II grade. In general, beneficial changes were observed. There was no difference found among individual experiments. No adverse events were found. This study was based on an observational design. The high-quality research was still limited [34]. This study only included four studies with limited sample sizes. There was no reliable, sufficient evidence to indicate the safety of ulinastatin in treating sepsis. Previous studies reported that either the single medication or the combination of the drugs was suggested to be effective for sepsis. Our results suggested that the use of Xuebijing combined with ulinastatin was superior to the use of single medication. The reasons could be as follows. Ulinastatin promoted the production of lipopolysaccharides and blocked the Toll-

like receptor, both of which could inhibit the nuclear factor-?b and anti-inflammatory cytokine release and reduce the level of inflammato- ry factors [35]. The incidences of multiple organ dysfunction syndromes decreased. This may be associated with an improvement of immune function. The combination of the medications promoted the recovery of patients.

The main strength of our meta-analysis was that it was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. There are still some limita- tions of the present study. First, we did not obtain unpublished data based on current conditions. This may have some effects on the pooled results. The included studies were conducted in different populations and clinical settings. The risk of introducing potential heterogeneity was imminent. Only half of the included studies used blinding methods during their implementations. This could result in performance and de- tection biases. Some outcome evaluations included several studies, and studies with larger sample sizes are required in the future.

Conclusions

This analysis suggests that Xuebijing, when combined with ulinastatin, for treating sepsis, is superior to both the routine therapies and the single administration of either ulinastatin or Xuebijing. It provides a new and

Fig. 3. Comparison of APACHE II score between trail group and control group.

Fig. 4. Comparison of duration of mechanical ventilation between trail group and control group.

Fig. 5. Comparison of Average length of intensive care unit between trail group and control group.

prospective therapeutic method for sepsis. However, this conclusion must be further verified by large-scale randomized, controlled studies.

Supplementary data to this article can be found online at https://doi.

org/10.1016/j.ajem.2017.12.007.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Fig. 6. Funnel plot to evaluate the publication bias.

Acknowledgments

No acknowledgments.

References

1. Lam SM, Lau AC, Lam RP, Yan WW. Clinical management of sepsis. Hong Kong Med J

   2017;23(3):296-305.

   Kuhn SO, Meissner K, Rehberg S. Fluid resuscitation in sepsis: “get the balance right”. Crit Care Med 2017;45(3):555-6.

2. Carrillo-Esper R, Carrillo-Cordova JR, Carrillo-Cordova LD. Epidemiological study of sepsis in Mexican intensive care units. Cir Cir 2009;77(4):301-8 [279-285].
3. Plotkin LL. Use of vasopressin to correct hemodynamic disorders in patients with ab- dominal sepsis. Anesteziol Reanimatol 2007;2:47-9.
4. Matter ML, Shvetsov YB, Dugay C, Haiman CA, Le Marchand L, Wilkens LR, et al. High mortality due to sepsis in Native Hawaiians and African Americans: the multiethnic cohort. PLoS One 2017;12(5):e178374.
5. Gao J, Kong L, Liu S, Feng Z, Shen H, Liu Q. A prospective multicenter clinical study of Xuebijing injection in the treatment of sepsis and multiple organ dysfunction syn- drome. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2015;27(6):465-70.
6. Y C, S LC. The effectiveness of XueBiJing injection in therapy of sepsis: a multicenter clinical study. Chin J Emer Med 2013;22(2):130-5.
7. Li J, Li NP, Gu YF, Yang X, Lu XB, Cong JN, et al. Dynamic activity of NF-kappaB in mul- tiple trauma patients and protective effects of ulinastain. Chin J Traumatol 2011; 14(6):354-8.
8. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097.
9. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343:d5928.
10. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta- analyses. BMJ 2003;327(7414):557-60.
11. Song F, Gilbody S. Bias in meta-analysis detected by a simple, graphical test. Increase in studies of publication bias coincided with increasing use of meta-analysis. BMJ 1998;316(7129):471.
12. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publi- cation bias. Biometrics 1994;50(4):1088-101.
13. Mao XS, Lv T, Meng DL, Zhou L, Ying LJ, Jin LZ. Clinical and mechnism study of Xuebijing injection and ulinastatin in the treatment of patients with severe sepsis. Chin J Crit Care Med 2008;12:1077-80.
14. Ye DW, Wu JG. Clinical study of Xuebijing injection and ulinastatin in the treatment of patients with sepsis. Chin J Primary Med & Pharm 2010;17(4):514-5.
15. Zhang C, Luo H, Zhang S, Zhang WX. Effects of Xuebijing and ulinastatin on coagula- tion function in patients with sepsis. J Inter Intensive Med 2010;16(3):145-7.
16. Yang M. Effects of Ulinastatin Combined With Xuebijing on Immune Function in Pa- tients With Sepsis. Zhengjiang; 2011; 2010209-11.
17. An N, He JY, Wang YX, Honh QQ. Study of ulinastatin combined with Xuebijing in treatment of severe sepsis. Prog Mod Biomed 2011;11(15):2898-900.
18. Wu XM, Dai JW, Wu JM. Clinical study of Xuebijing injection and ulinastatin in the treatment of patients with sepsis. J Clin Res 2012;10:1980-1.
19. Zhou YP, Chen XW, Zhang CX, Wan L, Shen QX, Wang B. Effects of using both Ulinastain and Xuebijing on the sepsis of burn. Chin J Injury Repair Wound Healing 2012;7(1):72-5.
20. Jiang L, Mao XS. clinical efficacy assessment of Chinese traditional medicine prepa- ration in the treatment of severe sepsis. Chin J Hosp 2013;33(13):1078-80.
21. Zhao GK, Liu YH. Clinical efficacy assessment of Xuebijing and ulinastatin prepara- tion in the treatment of severe sepsis. Lab Med Clin 2013;20:2718-20.
22. Zhou CW, Fang ZC. Clinical study of Xuebijing injection and ulinastatin in the treat- ment of patients with sepsis. Clin Pulm Med 2013;18(4):647-8.
23. Zeng FJ, Chen FL, Chen SM, Peng N, Xu XW. Protective effects of Xuebijing and ulinastatin on myocardial injury in patients with sepsis. Guangdong Med J 2013; 34(4):616-8.
24. Wang ZB. Clinical study of Xuebijing injection and ulinastatin in treatment of 36 pa- tients with sepsis. J Hainan Med University 2014;20(3):362-5.
25. Wang H, Liu KJ, Hu M. Protective effect of ulinastatin combined with Xuebijing on multiple organ function in patients with sepsis. Chin J Integr Med 2014;S1:113-6.
26. Chen YJ, Gao YQ, Peng YW. The clinical study of ulinastatin and Xuebijing on elderly patients with severe pneumonia. J Emerg Med 2014;19(4):269-70 [273].
27. Yi CF, Fang YH. Effects of ulinastatin combined with Xuebijing on Pyemia. Pract Clin Med 2014;15(1):19-20 [26].
28. Zhang J, Qiu Y. Clinical study of ulinastatin combined with Xuebijing on sepsis with septic shock. Chin Foreign Med Res 2015;21:37-8 [39].
29. Cheng B, Xie G, Yao S, Wu X, Guo Q, Gu M, et al. Epidemiology of severe sepsis in crit- ically ill surgical patients in ten university hospitals in China. Crit Care Med 2007; 35(11):2538-46.
30. Kleinpell R. Advances in treating patients with severe sepsis. Role of drotrecogin alfa

    (activated). Crit Care Nurse 2003;23(3):16-29 [67-68].

    Han D, Shang W, Wang G, Sun L, Zhang Y, Wen H, et al. Ulinastatin- and thymosin alpha1-based immunomodulatory strategy for sepsis: a meta-analysis. Int Immunopharmacol 2015;29(2):377-82.

31. Atal SS, Atal S. Ulinastatin - a newer potential therapeutic option for multiple organ dysfunction syndrome. J Basic Clin Physiol Pharmacol 2016;27(2):91-9.
32. Liu G, Li Q. Meta-analysis of Xuebijing joint ulinastatin treating sepsis. Value Health 2014;17(7):A807.
33. Khakpour S, Wilhelmsen K, Hellman J. Vascular endothelial cell Toll-like receptor pathways in sepsis. Innate Immun 2015;21(8):827-46.