Effect of ulinastatin injection on left ventricular diastolic function in patients with sepsis / 中华急诊医学杂志

Objective:To investigate the effect of ulinastatin injection on left ventricular diastolic function and prognosis in patients with sepsis.Methods:A total of 100 patients with sepsis admitted to the Intensive Care Unit from January 2021 to March 2022 were selected. According to the random number table, they were randomly (random number) divided into the control group (conventional treatment) and experimental group (conventional treatment + ulinastatin injection). The baseline data on admission were compared between the two groups. The echocardiographic indexes [mitral peak velocity of early filling/early diastolic mitral annular velocity (E/e'), early diastolic mitral annular velocity (e'), mitral peak velocity of early filling/ mitral peak velocity of late filling (E/A), and tricuspid regurgitation rate (TRV)], myocardial damage-related and cardiac function-related indicators [troponin I (cTnI), N terminal pro B type natriuretic peptide (NTproBNP)] and inflammation-related indicators [C-reaction protein (CRP), procalcitonin (PCT), erythrocyte sedimentation rate (ESR)], length of ICU stay, duration of infection control, duration of vasoactive drug use and 28-day mortality were observed and compared between the two groups on admission and 7 days after treatment.Results:On the 7th day after treatment, the levels of e 'and E/A in the experimental group were significantly higher than those in the control group, and the levels of E/e', TRV, cTnI, NTproBNP, CRP and PCT were significantly decreased ( P<0.05). There were no significant differences in duration of infection control and duration of vasoactive drug use between the experimental group and the control group ( P<0.05), but the length of ICU stay was shorter and 28-day mortality was significantly lower in the experimental group than in the control group ( P<0.05). Conclusions:Ulinastatin can reduce the degree of inflammatory response, relieve myocardial injury, improve left ventricular diastolic function, and reduce the length of ICU stay and 28-day mortality in patients with sepsis.

Efficacy and safety of ulinastatin for treatment of upper gastrointestinal ulcer complicated with hemorrhage in children / 中华全科医师杂志

From January 2018 to August 2019, 87 children aged 2 to 8 years with upper gastrointestinal ulcer bleeding were admitted to the Department of Pediatrics of Shangqiu First People′s Hospital. Patients were randomly assigned in two groups, 45 cases received omeprazole for treatment (group A) and 42 cases received ulinastatin and omeprazole for treatment (group B). The omeprazole 10 mg/d was administrated orally for 2 to 4 weeks in two groups, while in group B additional ulinastatin injection (10 000-50 000 IU·kg -1·d -1 was given for 1 week. The effective rate in group B was 95.2% (40/42), which was significantly higher than that in group A (80.0%, 36/45) (χ2=4.567, P=0.03). After treatment, gastroscopy showed that the time of hemostasis, the time of stopping hematemesis, the time of fecal occult blood turning negative, and the length of hospital stay in group B were significantly shorter than those in group A ( P<0.05). The results of flow cytometry showed that the percentages of CD3 + and CD4 + increased and the percentages of CD8 + decreased significantly after treatment in the two groups, while the changes in group B were more marked than those in group A ( P<0.05). Serum inflammatory factors (serum procalcitonin, high-sensitivity C-reactive protein and tumor necrosis α) were significantly reduced after treatment in the two groups, while the above indicators in group A were significantly lower than those in group A (all P<0.05). In group A, there was 1 case of nausea and vomiting, 1 case of abdominal pain and diarrhea, and 1 case of lethargy; in group B, there was 1 case of nausea and vomiting and 1 case of abdominal pain and diarrhea. The study suggests that ulinastatin combined with omeprazole has a better effect than omeprasole alone in treatment of children with upper gastrointestinal ulcer bleeding without increasing adverse effects.

Study on the therapeutic effect and related mechanism of ulinastatin on sepsis-related acute lung injury / 中国医师进修杂志

Objective:To explore the protective effect of ulinastatin on sepsis-related acute lung injury (ALI) in mice and its related mechanism analysis.Methods:A total of 50 male mice aged 6-8 weeks were selected and randomly divided into 5 groups, with 10 mice in each group. Group A was the sham operation group, group B was the sham operation and ulinastatin (30 000 U/kg) intervention group, group C was the simple cecal ligation and perforation (CLP) group, group D was the CLP+low-dose ulinastatin (15 000 U/kg) treatment group, and group E was the CLP+high-dose ulinastatin (30 000 U/kg) treatment group. Ulinastatin in groups B, D and E was injected intraperitoneally at the corresponding dose 1 h before CLP operation. The hematological characteristics, lung edema and inflammatory changes of lung tissue in mice of each group were evaluated and the expression levels of interleukin(IL)-6, tumor necrosis factor(TNF)-ɑ, IL-1β and nuclear factor(NF)-κB p65 mRNA and protein expression in blood and lung tissue were compared among the five groups.Results:Compared with that in group A, the lung water content in group C was significantly increased: (78.68 ± 1.85)% vs. (51.98 ± 0.77)%, P<0.01. Compared with that in group C, pulmonary edema of the mice treated with ulinastatin was significantly reduced, with a certain dose-effect relationship. The wet weight/dry weight ratio of the lung tissue in group C was significantly higher than that of group A, B, D, E: 4.74 ± 0.28 vs. 2.23 ± 0.16, 2.25 ± 0.22, 2.89 ± 0.31, 2.09 ± 0.12, P<0.01, and group E had the lowest ratio. After ulinastatin intervention, the inflammatory manifestations of the lungs were reversed in a dose-dependent manner. The degree of structural destruction was improved, and edema and polymorphonuclear neutrophil infiltration were reduced. Ulinastatin could significantly reduce the neutrophil and lymphocyte counts of mice after CLP treatment, reduce the expression of IL-6, TNF-α, IL-1β inflammatory cytokines and MPO activity. The reverse transcription-polymerase chain reaction (RT-PCR) results and Western blot analysis showed that the mRNA and protein expressions of NF-κB p65 in group C of lung tissue was significantly increased. However, after treatment with ulinastatin, it was significantly reduced, and it had a certain dose-effect relationship. Conclusions:Ulinastatin pretreatment can significantly reduce the expression levels of IL-6, IL-1β and TNF-α in sepsis-related acute lung injury, and can alleviate the inflammatory response in the lung. The protective effect of ulinastatin may be related to the inhibition of NF-κB pathway activation.

Different doses of ulinastatin combined with glutamine in treatment of acute severe pancreatitis / 中华内分泌外科杂志

Objective:To study the clinical effect of different doses of ulinastatin combined with glutamine in treatment of acute severe pancreatitis.Methods:70 patients with acute severe pancreatitis patients admitted in our hospital from Jan. 2017 to Oct. 2019 were enrolled. According to the different dosage of ulinastatin, these patients were divided into 200 000 IU ulinastatin combined with glutamine group (200 000 IU combination group) , 400 000 IU ulinastatin combined with glutamine group (400000 IU combination group) , and 600 000 IU ulinastatin combined with glutamine group (600 000 IU combination group) . The study compared the 1-week mortality rate, abdominal pain relief time, respiratory frequency and heart rate back to normal time, blood amylase, glucose, C-reactive protein, procalcitonin levels, and white blood cell (WBC) count among the different groups.Results:The mortality of 400 000 IU combined group and 600 000 IU combined group were 4.35% and 5.56% respectively, which were significantly lower than 31.58% and 35% of the control group and 200 000 IU combined group ( P< 0.05) . The time of abdominal pain relief, respiratory rate and heart rate returning to normal in the 400 000 IU combined group were (7.21±1.25) d, (8.54±1.83) d and (9.54±2.23) d respectively, and (7.52±1.83) d, (8.13±1.75) d and (9.37±2.31) d in the 600 000 IU combined group, which were significantly lower than (9.12±2.78) d, (9.85± 3.16) d and (10.86±2.68) d in the control group and (8.76±1.96) d, (8.76±1.96) d and (10.62±1.43) d in the 200 000 IU combined group ( P<0.05) , There was no significant difference between the control group and the 200 000 IU combination group ( P>0.05) . Compared with the control group, there were significant differences in blood glucose, CRP and leukocyte count in different doses of ulinastatin+ glutamine treatment group ( P<0.05) ; However, there was no significant difference in blood glucose and CRP levels between different doses of ulinastatin+ glutamine treatment group ( P>0.05) , but compared with 200 000 IU combination group and 400 000 IU combination group, the leukocyte level of 600 000 combination group was significantly higher ( P<0.05) . Conclusion:ulinastatin combined with glutamine can significantly improve the clinical prognosis of patients with severe acute pancreatitis, but the clinical effect varies with the dose of ulinastatin. Conclusion Ulinastatin combined with glutamine can significantly improve the clinical prognosis of patients with acute severe pancreatitis, but the clinical effect varies with the dose of ulinastatin.

The severe COVID-19: A sepsis induced by viral infection? And its immunomodulatory therapy / 中华创伤杂志(英文版)

COVID-19 is known for its magical infectivity, fast transmission and high death toll based on the large number of infected people. From the perspective of the clinical manifestation, autopsy examination and pathophysiology, the essence of COVID-19 should be viewed as a sepsis induced by viral infection, and has the essential characteristics as sepsis induced by other pathogens. Therefore, in addition to etiological and supportive treatment, immunomodulatory therapy is also appropriate to severe COVID-19. Although there is still a lack of consensus on immunotherapy for sepsis so far, relatively rich experiences have been accumulated in the past decades, which will help us in the treatment of severe COVID-19. This article will elaborate immunotherapy of sepsis, though it may not be consistent.

Effects of ulinastatin combined with glutamine on early hemodynamics in patients with severe burns / 中华烧伤杂志

Objective@#To observe the effect of ulinastatin combined with glutamine on early hemodynamics in patients with severe burns.@*Methods@#Thirty-two patients with severe burns who met the inclusion criteria and hospitalized in the Affiliated Huaihai Hospital of Xuzhou Medical University from January 2016 to December 2018 were selected for conducting a prospective randomized controlled trial. According to the random number table, the patients were divided into conventional treatment group (4 males and 4 females), ulinastatin group (5 males and 3 females), glutamine group (5 males and 3 females), and ulinastatin+ glutamine group (4 males and 4 females), with ages of (36±8), (34±8), (35±9), and (38±13) years in turn. From post injury day 2, patients in the 4 groups were given nutritional support of equal nitrogen and equal calories, of which protein was 2.0 g/kg daily. In addition, patients in the ulinastatin group received intravenous injection of 100 kU ulinastatin every 8 hours for 7 consecutive days; 0.3 g/kg of protein given to patients in the glutamine group was provided by alanine glutamine for 7 consecutive days; patients in the ulinastatin+ glutamine group received corresponding treatments of both ulinastatin group and glutamine group. With the help of pulse contour cardiac output (PiCCO) monitoring technology, the cardiac index, stroke volume index (SVI), global end-diastolic volume index (GEDI), systemic vascular resistance index (SVRI), extravascular lung water index (EVLWI), pulmonary vascular permeability index (PVPI) of patients in each group were measured on treatment day (TD) 1, 3, and 7. Data were processed with Fisher′s exact probability method, one-way analysis of variance, analysis of variance for repeated measurement, and Bonferroni method.@*Results@#The cardiac index was low and the SVI value was lower than the normal value on TD 1 in patients of the 4 groups, without statistically significant differences between any two groups (P>0.05), and then they were all gradually increased. On TD 3 and 7, compared with those of the conventional treatment group, the cardiac index and SVI of patients in the other three groups were all increased, and the cardiac index and SVI of patients in the ulinastatin+ glutamine group were significantly increased (P<0.05 or P<0.01). On TD 1, the GEDI of patients in the conventional treatment group, ulinastatin group, glutamine group, and ulinastatin+ glutamine group were at normal low levels, which were (659±58), (661±79), (659±88), and (653±71) mL/m2 respectively, without statistically significant differences between any two groups (P>0.05), and then they all gradually increased. On TD 3 and 7, compared with (684±82) and (742±46) mL/m2 of the conventional treatment group, the GEDI of patients in the ulinastatin group, glutamine group, and ulinastatin+ glutamine group were all elevated, which were (732±53) and (777±33), (725±58) and (783±49), (813±65) and (849±27) mL/m2 respectively, and the GEDI of patients in the ulinastatin+ glutamine group was significantly increased (P<0.05). The SVRI of patients in the four groups were all at high levels on TD 1, without statistically significant differences between any two groups (P>0.05), and then they all gradually decreased. On TD 3 and 7, compared with those of the conventional treatment group, the SVRI of patients in the other three groups were all increased, and the SVRI in the ulinastatin+ glutamine group was significantly increased (P<0.05). On TD 1, the EVLWI of patients in the conventional treatment group, ulinastatin group, glutamine group, and ulinastatin+ glutamine group were all in the normal range, which were (6.6±0.6), (6.3±0.4), (6.5±0.4), and (6.6±0.6) mL/kg respectively, without statistically significant differences between any two groups (P>0.05), and then they all showed the increasing trend. On TD 3 and 7, compared with (7.1±0.9) and (7.9±0.5) mL/kg of the conventional treatment group, the EVLWI of patients in the ulinastatin group, glutamine group, and ulinastatin+ glutamine group were all decreased, which were (6.2±0.6) and (7.1±0.4), (6.3±1.0) and (7.2±0.9), (5.8±0.7) and (6.7±0.6) mL/kg respectively, and the EVLWI of patients in the ulinastatin+ glutamine group was significantly decreased (P<0.05). On TD 1, the PVPI of patients in the four groups were all in the normal range, without statistically significant differences between any two groups (P>0.05), and then they all gradually decreased. On TD 3 and 7, compared with those of the conventional treatment group, the PVPI of patients in the other three groups were all decreased, and the PVPI in the ulinastatin+ glutamine group was significantly decreased (P<0.05).@*Conclusions@#Ulinastatin combined with glutamine can increase the cardiac index, SVI, GEDI, and SVRI and reduce the EVLWI and PVPI in treating patients with severe burns, thereby increasing early cardiac output after injury, promoting tissue and organ perfusion, and reducing pulmonary edema, resulting in significant improvement in early hemodynamics of patients with severe burns.

Clinical Observation of Different Doses of Xuebijing Injection Combined with Ulinastatin Injection in the Treat- ment of Sepsis Complicated with Acute Lung Injury / 中国药房

OBJECTIVE：To compare cli nical effect and safety of different doses of Xuebijing injection combined with Ulinastatin injection in the treatment of sepsis complicated with acute lung injury （ALI）. METHODS ：Totally 115 patients diagnosed as sepsis complicated with ALI were collected from Jul. 2015 to Nov. 2019 in intensive care unit of our hospital. According to therapy method ，the patients were divided into control group （26 cases），low-dose group （29 cases），medium-dose group（30 cases），high-dose group （30 cases）. The control group received Ulinastatin injection 300 thousands u intravenously ，q8 h， for consecutive 5 days，on the basis of routine treatment. On the basis of control group ，low-dose group additionally received intravenous drip of Xuebijing injection 50 mL，bid，for consecutive 7 days；medium-dose group additionally received intravenous drip of Xuebijing injection 100 mL，bid，for consecutive 7 days；high-dose group additionally received intravenous drip of Xuebijing injection 100 mL，qid，for consecutive 7 days. The serum inflammatory factors （IL-6，TNF-α，CRP），respiratory function indexes （PaO2，PaO2/FiO2，ELWI）and related scores （APACEⅡ score and SOFA score ）were compared among 4 groups before and after treatment ，and mechanical ventilation time ，ICU hospitalization time ，28-day mortality rate and adverse reactions during the treatment were recorded. RESULTS ：Before treatment ，there was no statistical significance in serum inflammatory factors，respiratory function indexes or related scores among 4 groups（P＞0.05）. After treatment ，serum inflammatory factors ， ELWI and related scores of 4 groups were decreased significantly ；the low-dose ，medium-dose and high-dose groups were significantly lower than the control group ；the high-dose group was significantly lower than the low-dose and medium-dose groups （P＜0.05）. PaO 2 and PaO 2/FiO2 of 4 groups were increased significantly ，compared with before treatment ；the low-dose ， medium-dose and high-dose groups were significantly higher than the control group ；the high-dose group was significantly higher than the low-dose and medium-dose groups （P＜0.05）. The mechanical ventilation time and ICU hospitalization time in the low-dose，medium-dose and high-dose groups were significantly shorter than control group （P＜0.05），but there was no statistical significance in above indexes among different doses groups （P＞0.05）. There was no statistical significance in 28-day mortality among 4 groups（P＞0.05），and no serious adverse reactions were found. CONCLUSIONS ：Different doses of Xuebijing injection combined with Ulinastatin injection could effectively decrease the level of serum inflammatory factors in patients with sepsis complicated with ALI ，improve lung function and relieve the degree of organ failure ；after combined with high-dose Xuebijing injection，the therapeutic effect is more obvious and does not affect the treatment safety.

Changes of inflammatory factors after hepatic cystic echinococcosis surgery and intervention of ulinastatin in Qinghai area / 中国血吸虫病防治杂志

Objective To observe the changes of inflammatory factors after the hepatic cystic echinococcosis surgery and explore the intervention effect of ulinastatin on postoperative inflammatory factors. Methods Sixty patients with hepatic cystic echinococcosis were selected and randomly divided into a control group and ulinastatin intervention group according to whether or not use ulinastatin. The peripheral venous blood was extracted in all the patients and the levels of IL-6, IL-8, IL-9, and IL-10 were detected by the ELISA method on the day before operation, 1 day, 3 days, 5 days and 7 days after operation, respectively. The data was statistical analyzed to detect the relationships between/among the inflammatory factors mentioned above and ulina-statin and time. Results The variation of the levels of IL-6, IL-8, IL-9, and IL-10 were changed by the intervention of ulina-statin at different time. The differences of the levels of IL-6, IL-8, IL-9, and IL-10 between the ulinastatin intervention group and the control group were not significant on the day before operation, 1 day and 3 days after operation (t = -1.15 to 1.82, all P > 0.05), but the levels of IL-6, IL-8, IL-9, and IL-10 of the ulinastatin intervention group were significantly lower than those of the control group and there were statistically significant differences 5 days and 7 days after the operation (t = 3.22 and 23.51, both P<0.05) . Conclusion Ulinastatin has a good effect in inhibiting the inflammatory factors and can protect and repair the postoperative hepatic injury as well in patients with hepatic cystic echinococcosis.

Influence of SPINK1 Gene Polymorphism on Efficacy of Ulinastatin in Treatment of Acute Pancreatitis / 胃肠病学

Background: Ulinastatin is an important drug for the treatment of acute pancreatitis (AP). However, there are some differences in the efficacy of ulinastatin among different patients. Aims: To explore influence of SPINK1 gene polymorphism on the efficacy of ulinastatin in treatment of AP. Methods: A total of 572 patients with AP from January 2005 to December 2015 at Baoji Hospital of Traditional Chinese Medicine were enrolled. Ulinastatin 100 000 U was given intravenously. Mutation of SPINK1 gene was detected by PCR. The levels of TNF-α, IL-2, IL-8, IL-10 and blood, urine amylase were determined by ELISA. The efficacy of ulinastatin was evaluated. Results: Rate of c.101A>G mutation in AP patients was significantly higher than that in the control group (PA mutation resulted in a significant decrease of SPINK1 mRNA expression (PC and c.200G>A mutations than in wild type (PA mutation were significantly decreased than those in wild type (PA mutation (PC and c.200G>A mutations was significantly lower than that in wild type (PG mutation in patients with AP is higher than that in general population. Mutations of c. 36G>C and c.200G>A could influence the efficacy of ulinastatin for the treatment of AP.

Protective effects of ulinastatin combined with lung-protective ventilation on lungs in patients undergoing laparoscopic colorectal carcinoma surgery / 中国基层医药

Objective@#To evaluate the protective effects of ulinastatin combined with lung-protective ventilation on lungs in patients undergoing laparoscopic colorectal carcinoma surgery.@*Methods@#A total of 120 patients undergoing laparoscopic radical resection of colorectal cancer in Yuncheng Central Hospital were selected in this study.According to thedigital table, they were randomly divided into conventional mechanical ventilation group(G0 group), lung protection mechanical ventilation group(G1 group), conventional mechanical ventilation combined with ulinastatin group(G2 group)and lung protection mechanical ventilation combined with ulinastatin group(G3 group), with 30 cases in each group.Ulinastatin 2 500IU was intravenously infused 10min before induction of anesthesia in G2 group and G3 group.Ventilator parameters were set as tidal volume(VT)10mL/kg, respiratory frequency 12 times/min, inspiration-expiration ratio(I∶E)1∶2 in G0 group and G2 group.VT 6mL/kg in G1 group and G3 group , positive end-expiratory pressure ventilation(PEEP)5-10cmH2O, respiratory frequency 12-18 times/min, once every 30min.Before anesthesia induction(T0), before pneumoperitoneum(T1), 2h after pneumoperitoneum(T2), before extubation(T3), 24h after operation(T4), arterial blood was collected to detect partial pressure of oxygen(PaO2), oxygenation index(OI). And mean airway pressure(Pmean), peak airway pressure(Ppeak)at T1-3 were recorded.Venous blood was collected at T0, T3 and T4 to detect serum concentrations of interleukin-6(IL-6), interleukin-8(IL-8)and tumor necrosis factor-alpha(TNF-α).@*Results@#At T3, the PaO2 of G1 group, G2 group and G3 group were (457±60)mmHg, (460±49)mmHg and (510±45)mmHg, respectively.At T4, the PaO2 of the three groups were (90±6)mmHg, (92±7)mmHg and (96±7)mmHg, respectively.The PaO2 in G1 group and G2 group were lower thanthose in G3 group at T3-4(t=3.872, 3.850, 4.186, 2.513, all P<0.05). At T2, the OI of the three groups were (460±44), (462±37) and (481±31), respectively.At T3, the OI of the three groups were (460±51), (475±62) and (504±38), respectively.The OI in G1 group and G2 group were lower than those in group G3 at T2-3(t=2.142, 3.753, 2.209, 2.170, all P<0.05). At T2, the Pmean of G1 group, G2 group and G3 group were (10.5±1.5)cmH2O, (11.2±1.9)cmH2O and (9.5±0.9)cmH2O, respectively, the Ppeak of the three groups were (22.3±3.0)cmH2O, (24.0±3.3)cmH2O and (22.3±2.9)cmH2O, respectively.At T3, the Pmean of the three groups were (10.9±1.1)cmH2O, (11.1±1.8)cmH2O and (9.8±0.9)cmH2O, respectively, the Ppeak of the three groups were (22.8±2.7)cmH2O, (24.1±2.1)cmH2O and (21.6±2.0)cmH2O, respectively.The Pmean in G1 group and G2 group at T2-3 were lower than those in G3 group(t=3.061, 4.580, 5.759, 4.305, 3.746, all P<0.05), the Ppeak in G2 group at T2-3 were lower than those in G3 group(t=2.952, 4.630, all P<0.05). At T4, the serum concentrations of IL-6 of G1 group, G2 group and G3 group were (151±28)ng/L, (152±20)ng/L and (136±18)ng/L, respectively, the IL-8 levels of the three groups were (468±28)ng/L, (359±65)ng/L and (327±51)ng/L, respectively, the TNF-α levels of the three groups were (1.09±0.20)ng/L, (1.08±0.20)ng/L and (0.94±0.20)ng/L, respectively.The concentrations of IL-6, IL-8 and TNF-α at T4 in G1 group and G2 group were higher than those in G3 group(t=2.428, 4.094, 2.536, 4.251, 2.807, 3.128, 4.119, 2.592, 3.446, 2.555, all P<0.05).@*Conclusion@#The combination of ulinastatin and lung-protective ventilation provides protective effects on lungs and exerts better efficacy than either alone.

Effects of ulinastatin combined with furosemide on myocardial enzymes, renal function and adverse reactions in patients with acute renal failure after cardiopulmonary resuscitation / 中国基层医药

Objective@#To explore the effects of ulinastatin combined with intravenous pump injection of furosemide on myocardial enzymes, renal function and adverse reactions in patients with acute renal failure(ARF) after cardiopulmonary resuscitation(CPR).@*Methods@#From January 2016 to May 2018, 117 patients with ARF after successful CPR in the Second People's Hospital of Hefei were divided into observation group(n=59) and control group(n=58) using simple random method.The control group received routine treatment, while the observation group added ulinastatin combined with intravenous pump infusion of furosemide.Myocardial enzymology, renal function, metabolism, inflammatory index, adverse reaction and survival rate were compared.@*Results@#Three and 7 days after treatment, the hydroxybutyrate dehydrogenase(HDBH), isoenzymes of creatine kinase isoenzyme(CK-MB) and mitochondrial aspartate aminotransferase isoenzyme(m-AST) were decreased in the two groups, and compared with the control group, which of the observation group were lower [HDBH: (231.42±31.15)U/L vs.(268.59±34.87)U/L; F=12.01, P=0.00; CK-MB: (32.38±4.15)ng/mL vs.(37.57±3.96)ng/mL; F=15.12, P=0.00; m-AST: (25.18±4.24)U/L vs.(33.92±5.60)U/L; F=12.36, P=0.00]. After treatment, the blood urea nitrogen(BUN), 24h urine protein quantity and creatinine(Cr) in the two groups increased firstly and then decreased, and compared with the control group, those of the observation group were lower[BUN: (7.02±1.66)mmol/L vs.(8.47±1.38)mmol/L; F=11.24, P=0.00; Cr: (82.69±9.87)μmol/L vs.(90.18±10.37)μmol/L; F=10.39, P=0.00; 24h urine protein quantity: (15.43±2.17)mg vs.(18.62±3.14)mg; F=11.06, P=0.00]. Three and 7 days after treatment, the levels of blood lactic acid(Lac), hypersensitive C-reactive protein(hs-CRP) and tumor necrosis factor-α(TNF-α) were decreased in the two groups, and compared with the control group, those of the observation group were lower [Lac: (1.18±0.27)mmol/L vs.(2.17±0.34)mmol/L, F=16.29, P=0.00; hs-CRP: (4.89±0.81)mg/L vs.(6.17±1.10)mg/L, F=13.41, P=0.00; TNF-α: (72.18±7.62)ng/L vs.(83.16±7.79)ng/L, F=11.39, P=0.00]. The incidence rates of adverse reactions in the observation group and the control group were 5.09% and 1.72%, respectively, the difference was statistically significant(χ2=0.24, P=0.62). The survival rates in the observation group and the control group were 50 cases (84.75%) and 39 cases (67.24%) respectively, the difference was statistically significant(χ2=4.92, P=0.02).@*Conclusion@#Intravenous pump injection of furosemide combined with ulinastatin can protect the heart and kidney, and improve the survival rate of patients with ARF after CPR and it is worthy of popularizing.

Protective effect of ulinastatin on myocardial injury after cardiopulmonary resuscitation in pigs / 中华急诊医学杂志

Objective@#To evaluate the protective effect of ulinastatin (UTI) on myocardial injury after post-cardiac arrest syndrome (PCAS) of cardiopulmonary resuscitation in pigs.@*Methods@#Twelve male 3-4 months pigs were randomly divided into two groups, UTI group and control group. The ventricular fibrillation (VF) animal model was replicated by programmed stimulation method. Among the 12 pigs, 11 pigs were successfully resuscitated by CPR after 5 min VF, of which, 6 pigs were in the UTI group and 5 pigs in the control group. Immediately after resuscitation, pigs in the UTI group was given 100 kU dissolved in 5 mL normal saline with slowly injection every 3 h until 24 h after recovery (no drug was given at 24 h). In the control group, 5 mL normal saline was given with same delivery time and frequency as that in the UTI group. The venous blood of the pigs was collected at VF, 2, 4, 6, 12, and 24 h after ROCS, and tumor necrosis factor -α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), malondialdehyde (MDA), and ischemia modified albumin (IMA) were measured by enzyme-linked immunosorbent assay (ELISA) method. Because IMA was sensitive and increased rapidly, venous blood was detected at 1 h after ROSC, and the rest test time were same with the rest of the blood factors. Statistical analysis was performed using LSD-t test and variance analysis. The pigs were sacrificed 24 h after ROSC, and specimens from heart tissue were taken for HE staining.@*Results@#Before ventricular fibrillation in three groups, there was no significant difference in serum levels of inflammatory cytokines, oxidative stress indexes, and myocardial ischemia markers between the two groups (P>0.05). At 2 h after ventricular fibrillation, the levels of TNF-α and IL-6 level in the UTI group was significantly lower than those in the control group. At 4 h, MDA level in the UTI group was significantly lower than that in the control group (P<0.05); IMA was significantly increased at 1 h after ROSC, and the level of 1 h in the UTI group was significantly lower than that in the control group (P<0.05), but was not statistically significant at 12 h between the two groups (P>0.05). HE staining results showed that the damage degree of myocardial tissue in the UTI group was significantly lower than that in the control group at 24 h after ROSC.@*Conclusions@#UTI can significantly antagonize inflammatory response, reduce oxidative stress, and improve the myocardial tissue injury after resuscitation. It can protect myocardial injury after cardiopulmonary resuscitation.

Ulinastatin via stabilizing endothelial junction protein to ameliorating hyper-permeability of vascular endothelial cell induced by matrix metalloproteinase-9 / 中国中西医结合急救杂志

Objective To investigate the role and mechanism of ulinastatin on the hyper-permeability of vascular endothelial cell induced by matrix metalloproteinase-9 (MMP-9). Methods Human umbilical vein endothelial cells (HUVEC) were cultured in vitro to establish a complete monolayer vascular endothelial cell model. The monolayer vascular endothelial cells were randomly divided into three groups: blank control group [phosphate buffered saline (PBS) added], MMP-9 model group (1 mg/L MMP-9 added) and ulinastatin group (1 mg/L MMP-9 and 1 000 kU/L ulinastatin added). The permeability of monolayer vascular endothelial cells was measured by fluorescein isothiocyanate (FITC)-labeled dextran (FD40) leaking method; the soluble vascular endothelial cells calcium dependent adherin (VE-cadherin) concentration in culture solution was determined by enzyme linked immunosorbent assay (ELISA);the protein expression levels of zonular occlusion protein-1 or tight junction (ZO-1), VE-cadherin, claudin-5 were detected by Western Blot and immunofluorescence methods. Results Compared with the blank control group, the permeability of vascular endothelial cells in MMP-9 model group was significantly increased [(cm2/h, ×10-2):3.35±0.56 vs. 0.94±0.06, P < 0.05]; the concentrations of soluble VE-cadherin in the Transwell upper and lower chambers were increased significantly [upper chamber (μg/L): 5.02±0.40 vs. 3.83±0.42, lower chamber (μg/L):4.92±1.05 vs. 3.24±1.24, both P < 0.05]; the protein expression levels of ZO-1, VE-cadherin and claudin-5 were significantly decreased [ZO-1/β-actin: 0.152±0.067 vs. 0.262±0.090, VE-cadherin/β-actin: 0.137±0.048 vs. 0.246±0.094, claudin-5/β-actin: 0.148±0.062 vs. 0.336±0.119, all P < 0.05], and obvious rupture sites appeared in their fluorescent patterns, and fluorescent particles were significantly reduced; compared with MMP-9 model group, the permeability of vascular endothelial cells in ulinastatin group was significantly decreased [(cm2/h, ×10-2): 1.80±0.34 vs. 3.35±0.56, P < 0.05]; the soluble VE-cadherin concentrations were significantly reduced in upper and lower chambers than those in the MMP-9 model group [upper chamber (μg/L): 4.41±0.37 vs. 5.02±0.40, lower chamber (μg/L):3.85±1.04 vs. 4.92±1.05, both P < 0.05], the expressions of endothelial junction protein were significantly increased in ulinastatin group (ZO-1/β-actin: 0.229±0.097 vs. 0.152±0.067, VE-cadherin/β-actin: 0.236±0.089 vs. 0.137±0.048, claudin-5/β-actin: 0.262±0.101 vs. 0.148±0.062, all P < 0.05], and the continuity of their fluorescent patterns and fluorescent particles were both increased. Conclusion The in vitro experiment showed that the hyper-permeability of vascular endothelial cells induced by MMP-9 can be attenuated by ulinastatin through decreasing the destruction of VE-cadherin and maintaining the protein expression levels of ZO-1, VE-cadherin and claudin-5 in vascular endothelial cells.

Effects of ulinastatin combined with furosemide on myocardial enzymes,renal function and adverse reactions in patients with acute renal failure after cardiopulmonary resuscitation / 中国基层医药

Objective To explore the effects of ulinastatin combined with intravenous pump injection of furosemide on myocardial enzymes ,renal function and adverse reactions in patients with acute renal failure ( ARF) after cardiopulmonary resuscitation (CPR).Methods From January 2016 to May 2018,117 patients with ARF after successful CPR in the Second Peopleˊs Hospital of Hefei were divided into observation group ( n ＝59) and control group(n＝58) using simple random method.The control group received routine treatment ,while the observation group added ulinastatin combined with intravenous pump infusion of furosemide .Myocardial enzymology, renal function, metabolism,inflammatory index,adverse reaction and survival rate were compared.Results Three and 7 days after treatment,the hydroxybutyrate dehydrogenase ( HDBH), isoenzymes of creatine kinase isoenzyme ( CK －MB) and mitochondrial aspartate aminotransferase isoenzyme (m－AST) were decreased in the two groups ,and compared with the control group,which of the observation group were lower [HDBH:(231.42 ±31.15)U／L vs.(268.59 ±34.87)U／L; F＝12.01,P＝0.00;CK－MB:(32.38 ±4.15)ng／mL vs.(37.57 ±3.96) ng／mL;F＝15.12,P＝0.00;m－AST:(25.18 ±4.24) U／L vs.(33.92 ±5.60) U／L;F＝12.36,P＝0.00].After treatment,the blood urea nitrogen (BUN),24h urine protein quantity and creatinine ( Cr) in the two groups increased firstly and then decreased ,and compared with the control group ,those of the observation group were lower [BUN:(7.02 ±1.66)mmol／L vs.(8.47 ± 1.38)mmol／L;F＝11.24,P＝0.00;Cr:(82.69 ±9.87) μmol／L vs.(90.18 ±10.37) μmol／L;F＝10.39,P＝0.00;24h urine protein quantity:(15.43 ±2.17) mg vs.(18.62 ±3.14) mg;F＝11.06,P＝0.00].Three and 7 days after treatment,the levels of blood lactic acid (Lac),hypersensitive C－reactive protein(hs－CRP) and tumor necrosis factor－α( TNF－α) were decreased in the two groups ,and compared with the control group ,those of the observation group were lower [ Lac:(1.18 ±0.27) mmol／L vs.(2.17 ±0.34) mmol／L,F ＝16.29, P ＝0.00;hs－CRP:(4.89 ±0.81)mg／L vs.(6.17 ±1.10) mg／L,F＝13.41,P＝0.00;TNF－α:(72.18 ±7.62) ng／L vs. (83.16 ±7.79)ng／L,F＝11.39,P＝0.00].The incidence rates of adverse reactions in the observation group and the control group were 5.09% and 1.72%,respectively,the difference was statistically significant (χ2 ＝0.24,P＝0.62).The survival rates in the observation group and the control group were 50 cases (84.75%) and 39 cases (67.24%) respectively,the difference was statistically significant (χ2 ＝4.92,P＝0.02).Conclusion Intravenous pump injection of furosemide combined with ulinastatin can protect the heart and kidney ,and improve the survival rate of patients with ARF after CPR and it is worthy of popularizing.

Effect of ulinastatin on isoflurane-induced neuronal apoptosis in the hippocampus of rats / 南方医科大学学报

OBJECTIVE@#To investigate the effect of ulinastatin pretreatment on isoflurane-induced mitochondria-dependent neuronal apoptosis in the hippocampus of rats.@*METHODS@#Thirty-six male SD rats were randomly assigned into control group, isoflurane group and ulinastatin group. In the latter two groups, the rats were subjected to acute exposure to 0.75% isoflurane for 6 h and pretreated with 50 000 U/kg of ulinastatin before isoflurane exposure, respectively. After the treatments, apoptosis of the hippocampal neurons was detected using TUNEL assay, and the mitochondrial membrane potential (△ ψm) was measured using JC-1 mitochondrial membrane potential kit; cytochrome C release and caspase-3 activity were examined with Western blotting, and intracellular reactive oxygen species (ROS) was detected using the fluorescent probe H2DCFDA.@*RESULTS@#Compared with those in the control group, the rats with acute exposure to isoflurane showed markedly increased TUNEL-positive cells in the hippocampus ( < 0.05), which were obviously reduced by ulinastatin pretreatment ( < 0.05). The △ψm of the hippocampal neurons was significantly reduced after isoflurane exposure ( < 0.05), and was partly recovered by ulinastatin pretreatment ( < 0.05). Acute exposure to isoflurane resulted in obviously increased cellular ROS, cytochrome C release and caspase-3 activity in the hippocampal neurons ( < 0.05), and these changes were significantly inhibited by ulinastatin pretreatment ( < 0.05).@*CONCLUSIONS@#Ulinastatin pretreatment provides neuroprotection against isoflurane-induced apoptosis of the hippocampal neurons in rats possibly by inhibiting mitochondria-dependent apoptosis pathway.

Mechanism of ulinastatin in reducing lung inflammatory injury in rats with hemorrhagic shock / 南方医科大学学报

OBJECTIVE@#To investigate the effect of ulinastatin on the inflammatory mediators and their signaling pathways miR-146a/TLR4/NF-κB in rats with hemorrhagic shock.@*METHODS@#Seventy-two SD rats were randomly assigned into shock without resuscitation group (SR group, =24), acetated Ringer's solution resuscitation group (AR group, =24) and ulinastatin treatment group (=24). In all the 3 groups hemorrhagic shock models were established by femoral artery bleeding (with the mean arterial pressure maintained at 30-40 mmHg) without resuscitation (in SR group) or with resuscitation (in AR and ulinastatin groups) using acetated Ringer's solution for 30 min at 60 min after the onset of shock. At 1, 4, and 6 h after the shock onset or immediately after shock if the rats died, the lung tissues were taken for measurement of mRNA expressions of miR-146a, tumor necrosis factor- (TNF-), interleukin-1 (IL-1), IL-4, IL-6 and IL-10 using real-time quantitative PCR and the protein expressions of TLR4, MyD88, IκB-, p-IκB-, NF-κB p65, IRAK4, p-IRAK4 (Thr345, Ser346), p-IRAK4 (Thr342) and TRAF6 using Western blotting. The lung histopathology of the rats was examined under optical microscope with HE staining.@*RESULTS@#Compared with the SR group, the rats in the AR group showed slightly alleviated inflammatory infiltration in the lung tissues with significantly increased mRNA levels of miR-146a, IL-4 and IL-10 ( < 0.05) and protein expressions of IκB-, p-IRAK4 (Thr342) and p-IRAK4 (Thr345, ser346) ( < 0.05), and decreased mRNA levels of TNF-, IL-1 and IL-6 ( < 0.05) and protein expressions of TLR4, MyD88, NF-κB p65, p-IκB-, IRAK-4 and TRAF6 ( < 0.05). Compared with those in AR group, the rats in ulinastatin group showed further alleviation of inflammatory lung tissue injury, with increased mRNA levels of miR-146a, IL-4 and IL-10 ( < 0.01) and protein expressions of IκB-, p-IRAK4 and p-IRAK4 ( < 0.01) and decreased mRNA levels of TNF-, IL-1 and IL-6 ( < 0.01) and protein expressions of TLR4, MyD88, NF-κB p65, p-IκB-, IRAK-4 and TRAF6 ( < 0.01).@*CONCLUSIONS@#Ulinastatin combined with acetated Ringer's solution resuscitation alleviates lung inflammations in rats with hemorrhagic shock possibly by enhancing miR-146a expression to regulate TLR4/NF-κB signaling pathway through a negative feedback mechanism and thus modulate the balance of pro-inflammatory and anti-inflammatory factors.

Effects of ulinastatin on rat postoperative ileus and intestinal barrier function / 中国药理学通报

Aim To study the effect of ulinastatin(UTI) on postoperative ileus(POI) and the intestinal barrier function in SD rats. Methods UTI was injected in three doses before, after and during abdominal surgery in SD rats. Evans blue was given by gavage 48 hours after the surgery and gastrointestinal propulsion rate was measured 30 minutes later. The end of ileum was collected for HE staining and AB/PAS staining to make tissue sections. The morphology of the intestinal villi and the number of goblet cells were observed under a light microscope. D-lactate and endotoxin kits were used to evaluate intestinal permeability. cDNA was extracted from the intestinal tissues to detect the levels of inflammatory factors and intestinal barrier-related genes by qPCR. Results In POI model group, the gastrointestinal propulsion rate decreased, and villi structure of small intestine was severely damaged; the levels of D-lactate, endotoxin and inflammatory factor mRNA increased; the number of goblet cells in crypt increased; the levels of MUC2 and MUC3 mRNA increased; the level of HD5 mRNA decreased. Pretreatment with medium dose UTI could significantly reverse the above situation. Conclusions Pretreatment with medium dose UTI can effectively reduce the intestinal inflammation and restore partially the intestinal barrier function in POI rats, thus preventing and treating the decrease of gastrointestinal propulsion rate caused by POI.

Protective effect of ulinastatin on myocardial injury after cardiopulmonary resuscitation in pigs / 中华急诊医学杂志

Objective To evaluate the protective effect of ulinastatin (UTI) on myocardial injury after post-cardiac arrest syndrome (PCAS) of cardiopulmonary resuscitation in pigs.Methods Twelve male 3-4 months pigs were randomly divided into two groups,UTI group and control group.The ventricular fibrillation (VF) animal model was replicated by programmed stimulation method.Among the 12 pigs,11 pigs were successfully resuscitated by CPR after 5 min VF,of which,6 pigs were in the UTI group and 5 pigs in the control group.Immediately after resuscitation,pigs in the UTI group was given 100 kU dissolved in 5 mL normal saline with slowly injection every 3 h until 24 h after recovery (no drug was given at 24 h).In the control group,5 mL normal saline was given with same delivery time and frequency as that in the UTI group.The venous blood of the pigs was collected at VF,2,4,6,12,and 24 h after ROCS,and tumor necrosis factor-α (TNF-α),interleukin-6 (IL-6),superoxide dismutase (SOD),malondialdehyde (MDA),and ischemia modified albumin (IMA) were measured by enzymelinked immunosorbent assay (ELISA) method.Because IMA was sensitive and increased rapidly,venous blood was detected at 1 h after ROSC,and the rest test time were same with the rest of the blood factors.Statistical analysis was performed using LSD-t test and variance analysis.The pigs were sacrificed 24 h after ROSC,and specimens from heart tissue were taken for HE staining.Results Before ventricular fibrillation in three groups,there was no significant difference in serum levels of inflammatory cytokines,oxidative stress indexes,and myocardial ischemia markers between the two groups (P＞0.05).At 2 h after ventricular fibrillation,the levels of TNF-α and IL-6 level in the UTI group was significantly lower than those in the control group.At 4 h,MDA level in the UTI group was significantly lower than that in the control group (P＜0.05);IMA was significantly increased at 1 h after ROSC,and the level of 1 h in the UTI group was significantly lower than that in the control group (P＜0.05),but was not statistically significant at 12 h between the two groups (P＞0.05).HE staining results showed that the damage degree of myocardial tissue in the UTI group was significantly lower than that in the control group at 24 h after ROSC.Conclusions UTI can significantly antagonize inflammatory response,reduce oxidative stress,and improve the myocardial tissue injury after resuscitation.It can protect myocardial injury after cardiopulmonary resuscitation.

Effect of Ulinastatin on the iron metabolism, severity and prognosis of septic patients / 中华急诊医学杂志

Objective To explore the effect of Ulinastatin on the iron metabolism,severity and prognosisof septic patients.Methods A total of 98 septic patients who met the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) were collected in the Emergency Intensive Care Unit of First Affiliated Hospital of Dalian Medical University from January 2017 to December 2017.Patients were randomly divided into the conventional treatment group (n=49) and Ulinastatin group (n=49).In addition,healthy volunteers matched for gender and age were selected as the control group (n=20).On days 1 (when enrolled for healthy volunteers),3 and 7 after admission peripheral venous blood was collected for routine blood test;the levels of plasma ferritin,erythropoietin (EPO),soluble transferrin receptor (sTFR),hepcidin and intedeukin-6 (IL-6) were measured using enzyme-linked immunosorbent assay (ELISA) and the sTFR/log ferritin index was calculated.SOFA score was assessed and the survival time was recorded within 28 days after admission.Results On days 1,3,and 7 after admission red cell distribution width and plasma EPO,sTFR,hepcidin,ferritin and IL-6 were significantly increased and hemoglobin and sTFR/log ferritin were significantly decreased in the conventional treatment group compared with those in the control group (all P＜0.05);on days 3 and 7 after admission plasma hepcidin,ferritin and IL-6 were significantly decreased and plasma EPO and sTFR/log ferritin were significantly increased in the Ulinastatin group compared with those in the conventional treatment group (all P＜0.05).On day 7 after admission SOFA score in the Ulinastatin group was significantly decreased compared with that in the conventional treatment group [(5.2±2.3) vs (6.4±2.7),P=0.019)].There was no significant difference in the 28-day survival rate (47％ vs 43％) and the survival time (18 d vs 9 d) after admission between the conventional treatment and Ulinastatin groups (both P＞0.05).Conclusions Iron metabolism disorder and inflammatory anemia occur in the early stage of septic patients.Ulinastatin might improve the iron metabolism disorder and the severity,but it cannot significantly improve anemia and prognosis of septic patients.

Changes of inflammatory factors after hepatic cystic echinococcosis surgery and intervention of ulinastatin in Qinghai area / 中国血吸虫病防治杂志

Objective To observe the changes of inflammatory factors after the hepatic cystic echinococcosis surgery and explore the intervention effect of ulinastatin on postoperative inflammatory factors. Methods Sixty patients with hepatic cystic echinococcosis were selected and randomly divided into a control group and ulinastatin intervention group according to whether or not use ulinastatin. The peripheral venous blood was extracted in all the patients and the levels of IL-6, IL-8, IL-9, and IL-10 were detected by the ELISA method on the day before operation, 1 day, 3 days, 5 days and 7 days after operation, respectively. The data was statistical analyzed to detect the relationships between/among the inflammatory factors mentioned above and ulina-statin and time. Results The variation of the levels of IL-6, IL-8, IL-9, and IL-10 were changed by the intervention of ulina-statin at different time. The differences of the levels of IL-6, IL-8, IL-9, and IL-10 between the ulinastatin intervention group and the control group were not significant on the day before operation, 1 day and 3 days after operation (t = -1.15 to 1.82, all P > 0.05), but the levels of IL-6, IL-8, IL-9, and IL-10 of the ulinastatin intervention group were significantly lower than those of the control group and there were statistically significant differences 5 days and 7 days after the operation (t = 3.22 and 23.51, both P<0.05) . Conclusion Ulinastatin has a good effect in inhibiting the inflammatory factors and can protect and repair the postoperative hepatic injury as well in patients with hepatic cystic echinococcosis.