Journal of Hainan Medical University 2017; 23(21): 130-134 130

Journal of Hainan Medical University

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Effect of Xingnaojing Injection on inflammatory cytokines and blood coagulation function in patients with acute cerebral hemorrhage Zhen-Bing Cai1, Ying-Hua Huang2, Ting-Kai Jiang1 1. Department of Neurology, Laibin People's Hospital, , Laibin 546100, 2. Department of Rehabilitation Medicine, Laibin People's Hospital, Sichuan, Laibin 546100, China

ARTICLE INFO ABSTRACT

Article history: Objective: To investigate the effect of Xingnaojing Injection on inflammatory cytokines and Received 25 Oct 2017 blood coagulation function in patients with acute cerebral hemorrhage. A total of 80 Received in revised form 28 Oct 2017 Method: Accepted 2 Nov 2017 patients with acute cerebral hemorrhage admitted to our hospital from October 2015 to May Available online 14 Nov 2017 2017 were randomly divided into the observation group and the control group, each group with 40 cases. Two groups both received conventional treatment; the observation group was given Keywords: Xingnaojing injection additionally. The two groups were treated for two weeks. Changes of Xingnaojing injection serum inflammatory factors TNF-α, hs-CRP, IL-10 and blood coagulation indexes of activated Acute cerebral hemorrhage partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (Fib), thrombin Inflammatory cytokines time (TT) and D-dimer (DD) of two groups were compared. Results: Before treatment, Coagulation function the differences of inflammatory factors TNF-α, hs-CRP, IL-10 and coagulation function indexes APTT, PT, Fib, TT and DD of the two groups were not statistically significant. After treatment, the levels of TNF-α, hs-CRP of the two groups were significantly decreased, and the IL-10 level of the two groups were significantly increased; the levels of TNF-α, hs-CRP in observation group were significantly lower than the control group, and the IL-10 level in observation group were significantly higher than the control group. After treatment, the levels of APTT, Fib and DD in the control group were significantly increased; the levels of PT and DD in the observation group were significantly decreased and the Fib level was significantly increased. After treatment, the levels of APTT, PT and DD in the observation group were significantly lower than those in the control group, and Fib level was significantly higher than that in the control group, these differences were statistically significant. There was no significant difference of TT levels between the two groups before and after the treatment. Conclusion: Xingnaojing injection treatment of acute cerebral hemorrhage can significantly reduce the level of serum inflammatory factors and promote the restoration of coagulation function. It is worth promoting.

local vascular circulation after cerebral hemorrhage, destruction 1. Introduction of blood-brain barrier, high inflammatory response are closely related to the pathological process of cerebral hemorrhage, thus Cerebral hemorrhage (ICH) refers to the bleeding caused by improving abnormal blood coagulation, reducing the release of angiorrhexis of non-traumatic brain parenchyma, which is mainly inflammatory factors, thereby reduced secondary brain injury, associated with cerebrovascular disease, and the death rate in which had important treatment value . Xingnaojing with effect of [3] acute stage is very high . Changes of hematoma around the promoting Qi, had a better effect on cerebral hemorrhage . This [1,2] [4] article discussed the effect of Xingnaojing injection on coagulation

 function and inflammatory factors in patients with acute cerebral Corresponding author: Huang Yinghua, Department of Rehabilitation Medicine, Laibin People's Hospital, Sichuan, Laibin 546100, China. hemorrhage. The report was as follows. E-mail: [email protected]. Fund Project: Scientific Research Project of Sichuan Provincial Science and Technology Department (No. 0152319). Zhen-Bing Cai et al./ Journal of Hainan Medical University 2017; 23(21): 130-134 131 2.3 Observe indicators 2. Data and methods Before and after treatment, collected with 6 mL of venous blood after 8 h of fasting, and centrifuged at 3 000 r/min for 5 min in 2.1 General data a high-speed centrifuge within 30 min. Then obtained serum to detect levels of TNF-α, hs-CRP and IL-10 by enzyme-linked All cases were obtained from patients with acute cerebral immunosorbent assay (ELISA). The kit was provided by hemorrhage who were admitted in the Laibin City People's Hospital Bangbian Biomedical Company. Obtained serum to detect blood from October 2015 to May 2017. 80 patients were randomly divided coagulation indexes by German BE coagulation test instrument, into observation group and control group, each group contained 40 including activated partial thromboplastin time (APTT), prothrombin cases. The observation group: 22 males, 18 females, aged from 44 time (PT), fibrinogen (Fib), thrombin time (TT) and D-dimerization to 76 years; control group: 19 males and 21 females, aged from 47 (DD), all the used reagents adopting original matching kits. to 78 years old. There was no significant difference in general data between the two groups (P>0.05). 2.4 Statistic analysis Inclusion criteria: (1) met the diagnostic criteria of acute cerebral The data were analyzed by SPSS 17.0 statistical software. In this hemorrhage , diagnosed through the head CT or magnetic [5] study, the levels of TNF-α, hs-CRP, IL-10 and coagulation function resonance imaging (MRI) examination; admitted in hospital within were all conformed to normal distribution, presented as (Mean ± 24 h after attacking; amount of brain or basal ganglia hemorrhage SD). Comparison of intergroup and intragroup was carried out t test. was less than 30 mL; amount of cerebellum or thalamus bleeding The difference was significant presented as P<0.05. was less than 10 mL; patients or their families agreed to participate in this study and signed informed consent. Exclusion criteria: did not meet the diagnostic criteria; condition 3. Results of disease aggregated severely within 48 h after admission, 3.1 Comparison of inflammatory cytokines accompanied by brain malignancies meanwhile; suffered from mental illness; accompanied by severe cardiovascular, liver, kidney, There was no significant difference in the levels of TNF-α, hs- blood system diseases; allergy to test drug. CRP and IL-10 between the two groups before treatment (P>0.05). After treatment, the levels of TNF-α and hs-CRP in the two groups 2.2 Treatment method were significantly lower than those before treatment (P<0.05), while the levels of IL-10 were significantly higher than before treatment ( <0.05). after treatment the level of TNF-α (30.77 ± 10.27) ng/ Patients in two groups were given symptomatic conventional P L in the observation group was significantly lower than that in the treatment, including hemostasis, appropriate control of blood control group (52.42 ± 11.95) ng/L, hs-CRP level (6.84 ± 2.27) ng/L pressure, reducing intracranial pressure, nourishing brain cells and was significantly lower than that in the control group (14.72 ±4.61) control of infection. Patients needed to surgery undergoing surgical ng/L, IL-10 level (66.19 ± 5.07) ng/L was significantly higher than removal of hematoma or decompression; patients with breathing that in the control group (63.19 ± 6.55) ng/L; Differences in each difficulties conducted tracheal intubation or tracheotomy, mechanical group were statistically significant (P <0.05). As shown in Table 1. ventilation. According to the specific condition, gave the two groups Table 1. of patients with mannitol or glycerol fructose to reduce intracranial Comparison of inflammatory cytokines in two groups before and after pressure; patients in observation group were given additionally treatment (n=40). Xingnaojing injection on this basis ( Shanhe Pharmaceutical Group Time TNF-α (ng/L) hs-CRP (mg/L) IL-10 (ng/L) Control group Before Co., Ltd., Approval number Z32020563): 20 mL of Xingnaojing treatment 88.54±26.34 31.61±8.41 52.85±23.71 After * * * injection liquid added in 250 mL, 0.9% of the saline intravenous for treatment 52.42±11.95 14.72±4.61 63.19±6.55 intravenous infusion, 1 time/d, during the treatment, forbade raw, Observation Before group treatment 89.21 ±28.51 33.21±8.63 51.17±22.95 cool, spicy food and smoking and drinking, and told the patient After *# *# *# treatment 30.77±10.27 6.84±2.27 66.18±5.07 to maintain emotional stability. 7 d for a course of treatment, two Note: Compared with before treatment, *P<0.05; compared with the control groups of patients were treated for two courses. group at the same time, # P<0.05. Zhen-Bing Cai et al./ Journal of Hainan Medical University 2017; 23(21): 130-134 132 Table 2. Comparison of coagulation function indexes in two groups before and after treatment (n=40). Group Time APTT (s) PT (s) TT (s) Fib (g/L) DD (µg/L) Control group Before treatment 27.09±5.31 14.51±2.27 15.27±3.84 3.24±1.32 3.29±2.26 After treatment 30.84±4.93* 14.27±3.02 15.22±3.67 4.64±1.23* 4.14±1.32* Observation group Before treatment 26.91±4.21 14.21±2.36 15.67±3.12 3.07±1.09 3.41±2.19 After treatment 27.31±5.44# 12.72±3.11*# 14.94±3.01 5.25±0.72*# 0.49±0.14*# Note: Compared with before treatment, *P<0.05; compared with the control group at the same time, # P<0.05.

prescription is from Angong Niuhuang pills, consists of musk, 3.2 Comparison of coagulation function indexes [13,14] radix curcumae, borneol, cape jasmine and other active ingredients. There was no significant difference in APTT, PT, TT, Fib and DD Among them, musk has effect of inducing resuscitation, removing levels between the two groups before treatment (P>0.05). After stasis and promoting circulation, which can increase the excitement treatment, the levels of APTT, Fib and DD in the control group of central nervous system, improve brain function; Radix curcumae were significantly increased (P<0.05). The levels of PT and DD can cool blood and clear away the heart-fire and relieve pain; borneol were significantly decreased and the level of Fib were significantly is able to remove stasis and promote the micro-circulation, which increased (P<0.05). Comparison of intergroup, the levels of APTT, can assist musk to enhance the awakening effect; cape jasmine can PT and DD in the observation group were significantly lower than remove heat and cool blood, purge triple energizer merdian fire; four those in the control group, Fib level in observation group was drugs combined, can play roles in refreshing resuscitation, purging obviously higher than control group, the difference was significant pathogenic fire and detoxification, reducing phlegm and promoting (P<0.05). There was no significant difference in TT level of blood circulation and others, suiting for acute fever syndrome. intragroup and intergroup before and after treatment (P>0.05). As Modern pharmacological studies showed that Xingnaojing [15] shown in Table 2. injection can protect nerves and vascular endothelial cells, improve blood microcirculation, dilate blood vessels, inhibit inflammation, with effect of reducing vascular resistance, decreasing the role 4. Discussions of nerve cell damage, which can thereby reduce the brain tissue edema and improve the metabolism level of hypoxia brain cells, and The incidence of cerebral hemorrhage is severe, the pathological enhance cell tolerance to hypoxia, thus reducing brain edema and mechanism is related to the ischemic edema around the lesion. The nerve cell damage, and promoting the recovery of brain function. direct oppression and the space occupying effect of the hematoma Studies showed that , brain hematoma after cerebral [16,17] can cause secondary brain injury, which is an important factor hemorrhage would press surrounding tissue and lead to local affecting the condition of disease . A large area of edema occurred ischemia and hypoxia, resulting in inflammatory response, [6,7] around the hematoma after 1-3 d of intracerebral hemorrhage and inflammatory factor generated in this process can injury brain triggered a series of inflammatory responses, which was one of the tissue, causing loss of neurological function in patients; at the major causes of secondary brain injury . Therefore, the prevention same time, The formation of hematoma was also closely related to [8,9] and treatment of brain edema after cerebral hemorrhage and relieving inflammation. TNF-α is a multifunctional inflammatory cytokine, the inflammatory response caused by the treatment of cerebral closely associating to cerebrovascular disease, mainly generated hemorrhage were one of the important measures. Studies have shown in brain tissue neurons, stellate cells and oligodendrocytes, will that abnormal blood coagulation after cerebral hemorrhage was also promote inflammatory cell infiltration, aggregation, triggering one of the critical factors leading to secondary brain injury, which inflammatory immune response, can induce sensitive cells to led to hypercoagulable state and appeared hypercholesterolemia, produce toxic effects, leading to the occurrence of cytotoxic brain extremely easily caused thrombosis, thereby resulting in secondary edema . hs-CRP is an inflammatory marker, which can indirectly [18] bleeding . At present, treatment of cerebral hemorrhage in reflect the degree of inflammatory response and tissue injury. IL- [10,11] clinic commonly used Xingnaojing injection, because of its effect 10 is mainly produced by monocyte macrophages, B lymphocytes of promoting blood circulation, inducing resuscitation, eased brain or keratinocytes. The inflammatory response mainly plays negative edema after cerebral hemorrhage through the blood-brain barrier, regulation effect, can inhibit the secretion of TNF-α, IL-6 and thereby improved injury on nerve caused by hematoma, promoted chemokines by macrophages, and assist T cells . This research [19] the recovery of neurological function in patients . Xingnaojing found that the levels of TNF-α and hs-CRP in the two groups [12] Zhen-Bing Cai et al./ Journal of Hainan Medical University 2017; 23(21): 130-134 133 were significantly decreased and IL-10 level dramatically increased to the improvement of blood circulation, reducing blood pressure (P<0.05); and the change in observation group was more obvious resistance, thereby relieved brain edema symptoms and inhibit than control group (P<0.05). The results showed that Xingnaojing formation of thrombus, thus regulated the balance of coagulation injection notably reduced the levels of TNF-α and hs-CRP in system, promoted coagulation function indexes to normal level. blood of patients with acute cerebral hemorrhage and promoted the In conclusion, Xingnaojing injection can significantly alleviate the secretion of anti-inflammatory cytokines IL-10, which was more inflammatory response caused by cerebral hemorrhage, promote significant than routine therapy. The reason may be Xingnaojing coagulation function indexes to normal level, thereby played a injection can improve cerebral edema and hypoxia symptoms role in reducing brain damage and brain edema, worthy of clinical after cerebral hemorrhage, reduce the degree of brain damage promotion. deterioration, reduce the inflammatory response. Coagulation dysfunction is one of the main factors that caused secondary brain injury after cerebral hemorrhage, seriously affect References the prognosis, how to correct the abnormal coagulation function, improve the prognosis, is the difficult problem to domestic and [1] Luo Fei. Effect of minimally invasive surgery assisting with sub-low foreign scholars . Coagulation function indicators, APTT can temperature on intracranial hematoma absorption, nervous injury degree [20,21] reflect the lack of prothrombin and fibrinogen, is the comprehensive in patients with hypertensive cerebral hemorrhage. J Hainan Med Coll test indicators of endogenous coagulation system; PT can reflect the 2017; 23(7): 950-953. abnormal coagulation factors, is the comprehensive test indicators [2] Li Zhong, Kaiming, Tan Shifeng. Significance of abnormal glucose of external coagulation system; Fib is a thrombin substrate that metabolism in acute stage of patients with cerebral hemorrhage and its can detect the formation of thrombus; DD is a specific fibrinolytic effect on short-term prognosis. J Hainan Med Coll 2010; 16(6): 726-728. process marker, produced by the hydrolysis of fibrinolytic enzymes, [3] Zhai Anlin, Yuan Miao, Gou Zhiyong. Clinical comparison of and is used to detect the dissolution of fibrinolytic enzymes. The different surgical approaches under microscopy in senile patients with dissolution of fibrin and the formation of activated thrombus hypertensive basal ganglia hemorrhage. Pract Geriatr 2014; 28(6): 484- in the vessels may lead to increase of DD levels . Studies 486. [22,23] demonstrated that , Xingnaojing injection through the blood-brain [4] Guo Wen, Zhuang Wei, Liu Jinwei. Investigation and analysis of the [24] barrier, inhibit the over-expression of inflammatory factors, thereby application of Xingnaojing injection in neurology. Beijing Tradit Chin reduced brain edema, intracranial pressure, promoted coagulation Med 2016; 35(8): 796-797. function to normal level. This study showed that APTT levels in [5] He Zhiyi. Diagnosis and differential diagnosis of cerebrovascular diseases: the control group were significantly increased (P<0.05). APTT clinical examples. Shenyang: Liaoning Science and Technology Press; level in observation group was significantly lower than control 2015. group (P<0.05). The PT level in the control group was significantly [6] Yuan Pu, Nie Wenchen. Risk factors analysis of edema around hematoma increased after treatment (P<0.05). PT level in the observation group inpatients with hypertensive cerebral hemorrhage. J Clin Neurosurg 2016; was significantly lower than that in the control group (P<0.05), 13(4): 307-309. moreover PT level in observation group was obviously lower than [7] Qureshi AI, Palesch YY, Barsan WG. Intensive blood-pressure lowering control group (P<0.05). After treatment, the levels of Fib in both in patients with acute cerebro hemorrhage. New Engl J Med 2017; groups were significantly higher than those before treatment, and 375(11): 1. the level of observation group was significantly higher than that [8] Wang Xian, Chen Gang, Ge Zhiqiang. Analysis of rebleeding reasons of the control group (P<0.05). After treatment, DD level in the after surgery hypertensive cerebral hemorrhage. J Clin Neurosurg 2015; control group was significantly higher than that before treatment, 43(1): 66-68. while the level of DD in the observation group was significantly [9] Lattanzi S, Cagnetti C, Provinciali L. Neutrophil-to-lymphocyte ratio decreased, and DD level after treatment in observation group was predicts the outcome of acute intracerebral hemorrhage. Stroke 2016; dramatically lower than that in the control group (P<0.05). There 47(6): 1654. was no significant difference in TT level between the two groups [10]Li Xingguang, Liu Jia, Cao Caipeng. Coagulation dynamic changes and before and after treatment (P>0.05). The results revealed that imaging change in patients with light and moderate cerebral hemorrhage. Xingnaojing injection significantly improved the level of abnormal J Pract Med 2015; 19(15): 23-25. blood coagulation in patients with cerebral hemorrhage may be due [11]Liu H, Li J, Yu J. Research into the predictive effect of TEG in the Zhen-Bing Cai et al./ Journal of Hainan Medical University 2017; 23(21): 130-134 134 changes of coagulation functions of the patients with traumatic brain [18]Charrad R, Berraïes A, Hamdi B. Anti-inflammatory activity of IL-37 in

hemorrhage. Open Med 2015; 10(1): 399 -404. asthmatic children: Correlation with inflammatory cytokines TNF-α, [12]Shuang Yuehua, Mao Zhenli, Yu Lin. Application observation of IL-β, IL-6 and IL-17A. Immunobiology 2016; 221(2): 182. Xingnaojing injection in patients with hypertensive intracerebral [19]Chen Hua, Liang Minghua, Yuan Rongjun. Changes and significance of

hemorrhage after minimally invasive hematoma evacuation. Shandong serum hs-CRP, TNF-α and IL-10 in patients with acute craniocerebral Med 2017; 57(12): 93 -95. injury. Modern Diagn Treatment 2016; 27(13): 2503-2504. [13]Xu Buxuan, Wang Dongyan, Jing Zhaode. Effect of acupuncture [20]Yu Yao, Wu Jun, Zhao Wei. Preliminary study of automatic correction of rehabilitation training combined with traditional Chinese medicine thrombin curve method to monitor the coagulation function in patients

Xingnaojing injection on functional recovery in patients with severe with cerebral hemorrhage. Chin J Geriatr Cardiol 2015; 17(1): 70-72. craniocerebral injury. Chin Emerg J Integr Tradit Western Med 2017; [21]Zhang Jian, Shi Chunmei, Zhou Chunyan. Clinical characteristics and 24(1): 24-27. risk factors of intracranial venous thrombosis combined with cerebral [14]Li Yongfeng, Li Wei. Effects of minimally invasive hematoma evacuation hemorrhage. Chin J Nervous Mental Dis 2015; 41(8): 455-459. combined with Xingnaojing on neurological impairment and cytokine [22]Zhu Minghui, Wang Hui, Xu Yan. The difference and significance of

content in patients with hypertensive intracerebral hemorrhage. J Hainan blood pressure, blood lipid and coagulation and fibrinolysis in patients Med Coll 2017; 23(6): 827-830. respectively with cerebral hemorrhage, cerebral infarction. J Shandong [15]Lu Zhigang, Liu Yun, Fang Jiahua. Effect of Xingnaojing injection on Med 2017; 57(4): 66-68. neurological deficits in patients with acute cerebral infarction and its [20]Yu Yao, Wu Jun, Zhao Wei. Preliminary study of automatic correction of

mechanism. Chin Emerg J Integr Tradit Western Med 2016; 23(4): 352- thrombin curve method to monitor the coagulation function in patients 355. with cerebral hemorrhage. Chin J Geriatr Cardiol 2015; 17(1): 70-72. [16]Yang Y, Zhang Y, Wang Z. Attenuation of acute phase injury in rat [24]Yao Dongmei, Li Zhenliang, Yaolan. Effect of Xingnaojing injection intracranial hemorrhage by cerebrolysin that inhibits brain edema and on plasma fibrinogen and D-dimer in patients with acute cerebral

inflammatory response. Neurochem Res 2016; 41(4): 1-10. hemorrhage. J Integr Chin Med Western Med Cardio-Cerebrovasc Dis [17]Chen S, Yang Q, Chen G. An Update on Inflammation in the Acute Phase 2016; 14 (16): 1923-1925. of Intracerebral Hemorrhage. Translation Stroke Res 2015; 6(1): 4-8.