摘要信息：Background:Pulmonary hypertension associated with congenital heart disease increases the risk of surgery using cardiopulmonary bypass. Sivelestat is a neutrophil elastase inhibitor thought to have a prophylactic effect against lung injury after surgery using bypass. We elucidated that Sivelestat had the protective effect on lung in patients with congenital heart disease and pulmonary hypertension who underwent surgery using bypass. Methods:This study was a controlled prospective randomized trial and enrolled 13 neonates or infants with ventricular septal defect and pulmonary hypertension. The patients were assigned to either sivelestat with the dose of 0.2 mg/kg per hour (sivelestat group, n = 7) or saline (placebo group, n = 6) from the start of bypass until 6 hours after bypass. Proinflammatory cytokines and adhesion molecules on leukocytes were measured at 10 time points during the above period. Pulmonary function was assessed perioperatively. Results:Compared with the placebo group, the sivelestat group had significantly lower values of alveolar-arterial oxygen tension gradient at 24 hours (p = 0.038) and at 48 hours (p = 0.028) after bypass, and significantly better balance of hydration at 48 hours after bypass (p = 0.012). The sivelestat group also showed significantly lower plasma levels of interleukin-8 immediately after bypass (p = 0.041) and interleukin-10 at 15 minutes after removal of the aortic cross-clamp (p = 0.048), and immediately after bypass (p = 0.037). Conclusions:Administration of sivelestat during bypass prevented pulmonary damage and activities of proinflammatory cytokines at the cardiac operation in neonates or infants. Our results show that sivelestat may be considered to protect pulmonary function against the injury by bypass. Keywords: 20; ANOVA; Aa-Do(2); CK-MB; CPB; ELAM-1; ICAM-1; ICU; IL; PH; PMN; PaO2/FiO2; Pp/Ps; Qp/Qs; Rp/Rs; VSD; alveolar-arterial oxygen tension gradient; analysis of variance; cardiopulmonary bypass; creatine kinase-myocardial band; endothelial leukocyte adhesion molecule-1; intensive care unit; intercellular adhesion molecule-1; interleukin; polymorphonuclear; pulmonary hypertension; ratio of pulmonary to systemic arterial blood flow; ratio of pulmonary to systemic arterial systolic pressure; ratio of pulmonary to systemic vascular resistance; ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen; ventricular septal defect.

摘要信息：Purpose:Several reports indicate that a neutrophil elastase inhibitor, sivelestat, may have prophylactic efficacy against a systemic inflammatory response after cardiovascular surgery with cardiopulmonary bypass (CPB). We evaluated the clinical pulmonary and cardiac effects of sivelestat. Methods:We performed a retrospective study of 25 pediatric patients who underwent elective cardiovascular surgery with CPB for ventricular septal defect with pulmonary hypertension. Ten patients received 0.2 mg x kg(-1) x h(-1) sivelestat; the other is patients were the control group. There were no significant differences in demographic characteristics between the two groups. The P(a)O(2)/fractional inspired oxygen (F(I)O(2); P/F) ratio, the respiratory index (RI), and the fractional area change (FAC) of the left ventricle (LV) in the postoperative course were measured. Results:The P/F ratio was higher in the sivelestat group compared with the control group and there were significant differences between the two groups immediately after weaning form CPB, and at 12 h after weaning from CPB (P < 0.05). The RI was lower in the sivelestat group compared with the control group and there were significant differences between the two groups at immediately after weaning from CPB, and at 6 h and 12 h after CPB (P < 0.05). The FAC of the LV was significantly better in the sivelestat group and there was a significant difference between the two groups on postoperative day (POD) 3 (P < 0.05). Conclusion:We have shown that pediatric patients who underwent cardiovascular surgery with CPB who received sivelestat had a higher P/F ratio, a lower RI, and better FAC of the LV in the postoperative course.

摘要信息：Cardiopulmonary bypass (CPB) elicits a systemic inflammatory response. Our previous reports revealed that prophylactic sivelestat administration at CPB initiation suppresses the postoperative acute inflammatory response due to CPB in pediatric cardiac surgery. The purpose of this study was to compare the effects of sivelestat administration before CPB and at CPB initiation in patients undergoing pediatric open-heart surgery. Twenty consecutive patients weighing 5-10 kg and undergoing ventricular septal defect closure with CPB were divided into pre-CPB (n = 10) and control (n = 10) groups. Patients in the pre-CPB group received a 24 h continuous intravenous infusion of 0.2 mg/kg/h sivelestat starting at the induction of anesthesia and an additional 0.1 mg/100 mL during CPB priming. Patients in the control group received a 24-h continuous intravenous infusion of 0.2 mg/kg/h sivelestat starting at the commencement of CPB. Blood samples were tested. Clinical variables including blood loss, water balance, systemic vascular resistance index, and the ratio between partial pressure of oxygen and fraction of inspired oxygen (P/F ratio) were assessed. White blood cell count and neutrophil count as well as C-reactive protein levels were significantly lower in the pre-CPB group according to repeated two-way analysis of variance, whereas platelet count was significantly higher. During CPB, mixed venous oxygen saturation remained significantly higher and lactate levels lower in the pre-CPB group. Postoperative alanine aminotransferase and blood urea nitrogen levels were significantly lower in the pre-CPB group than in the control group. The P/F ratio was significantly higher in the pre-CPB group than in the control group. Fluid load requirement was significantly lower in the pre-CPB group.Administration of sivelestat before CPB initiation is more effective than administration at initiation for the suppression of inflammatory responses due to CPB in pediatric open-heart surgery, with this effect being confirmed by clinical evidence.

摘要信息：Cardiopulmonary bypass (CPB) evokes activation of a systemic inflammatory response. Sivelestat has been used clinically to treat acute lung injury associated with systemic inflammatory response syndrome. This prospective, doubleblind, randomized study was designed to evaluate the effects of sivelestat in the perioperative period of elective pediatric open-heart surgery with CPB. Twenty-six consecutive pediatric patients weighing between 5 and 10 kg and undergoing open-heart surgery with CPB were divided into a sivelestat group (n = 13) and a control group (n = 13). The patients in the sivelestat group were administered a continuous intravenous infusion of 0.2 mg/kg/hour of sivelestat, and the patients in the control group were administered the same volume of 0.9% saline from the initiation of CPB to 24 hours after surgery. Blood samples were drawn for the measurement of cytokines, polymorphonuclear elastase (PMN-E), white blood cell count (WBC), neutrophil count (NC), and C-reactive protein (CRP). There were no significant differences in cytokine data between the two groups. The peak PMN-E and WBC levels were significantly increased in the control group (P = 0.049, P = 0.039). The WBC and NC levels immediately after surgery in the control group were significantly greater than those in the sivelestat group (P = 0.049, P = 0.044). The peak CRP level in the control group was significantly greater than the sivelestat group (P = 0.04), and the CRP level on postoperative day 4 in the control group was significantly greater than in the sivelestat group (P = 0.014). This study showed that sivelestat attenuates the perioperative inflammatory response in pediatric heart surgery with CPB.

摘要信息：Cardiopulmonary bypass (CPB) elicits a systemic inflammatory response. The neutrophil elastase inhibitor sivelestat is known to suppress this systemic inflammatory response, which can eventually result in acute organ failure. The prophylactic effect of sivelestat on acute lung injury, especially in pediatric cardiac surgery, remains unclear. This prospective double-blind, randomized study evaluated the perioperative prophylactic effect of sivelestat in patients undergoing elective pediatric open heart surgery with CPB. Thirty consecutive patients, weighing 5-10 kg and undergoing open heart surgery with CPB, were assigned to sivelestat (n = 15) or control (n = 15) groups. From CPB initiation to 24 h after surgery, patients in the sivelestat group received a continuous intravenous infusion of 0.2 mg/kg/h sivelestat, whereas patients in the control group received the same volume of 0.9% saline. Blood samples were collected, and levels of interleukin (IL)-6, IL-8, tumor necrosis factor alpha, polymorphonuclear elastase (PMN-E), C-reactive protein (CRP), as well as the white blood cell (WBC) count, platelet count, and neutrophil count (NC) were measured. PMN-E levels, IL-8 levels, WBC count, NC, and CRP levels were significantly lower, and platelet count was significantly higher in the sivelestat group, according to repeated two-way analysis of variance. The activated coagulation time was significantly shorter in the sivelestat group, similarly, blood loss was significantly less in the sivelestat group. In conclusion, Sivelestat attenuates perioperative inflammatory response and clinical outcomes in patients undergoing pediatric heart surgery with CPB.

摘要信息：Background:Neutrophil infiltration plays a critical role in the pathogenesis of acute lung injury following liver transplantation (LT). Neutrophil elastase is released from neutrophils during pulmonary polymorphonuclear neutrophil activation and sequestration. The aim of the study was to investigate whether the inhibition of neutrophil elastase could lead to the restoration of pulmonary function following LT. Methods:In in vivo experiments, lung tissue and bronchoalveolar lavage fluid (BALF) were collected at 2, 4, 8, and 24 h after rats were subjected to orthotopic autologous LT (OALT), and neutrophil infiltration was detected. Next, neutrophil elastase inhibitors, sivelestat sodium hydrate (exogenous) and serpin family B member 1 (SERPINB1) (endogenous), were administered to rats before OALT, and neutrophil infiltration, pulmonary oxidative stress, and barrier function were measured at 8 h after OALT. Results:Obvious neutrophil infiltration occurred from 2 h and peaked at 8 h in the lungs of rats after they were subjected to OALT, as evidenced by an increase in naphthol-positive cells, BALF neutrophil elastase activity, and lung myeloperoxidase activity. Treatment with neutrophil elastase inhibitors, either sivelestat sodium hydrate or SERPINB1, effectively reduced lung naphthol-positive cells and BALF inflammatory cell content, increased expression of lung HO-1 and tight junction proteins ZO-1 and occludin, and increased the activity of superoxide dismutase. Conclusion:Neutrophil elastase inhibitors, sivelestat sodium hydrate and SERPINB1, both reduced lung neutrophil infiltration and pulmonary oxidative stress and finally restored pulmonary barrier function.

摘要信息：The purpose of this study was to evaluate the effect of sivelestat sodium hydrate, a selective inhibitor of neutrophil elastase in the systemic inflammatory response, pulmonary function, and the postoperative clinical course following esophagectomy. Patients with hypoxia associated with surgical stress in the intensive care unit (ICU) immediately after an esophagectomy were eligible for this study. The degree of hypoxia was calculated according to the ratio of arterial oxygen tension (PaO(2)) to the fractional concentration of inspired oxygen (FiO(2))-PaO(2)/FiO(2). Patients with PaO(2)/FiO(2) < 300 mmHg were enrolled in this study. Seven patients were treated with sivelestat, and 10 were not so treated. The degree of hypoxia, the criteria for systemic inflammatory response syndrome (SIRS), and the postoperative clinical course were compared between the two groups. The postoperative decreases in the PaO(2)/FiO(2) ratio were significantly suppressed in the sivelestat group (p < 0.05, by analysis of variance, or ANOVA). Furthermore, 9 of the 10 control group patients developed SIRS on postoperative day 2, whereas only 2 of 7 of the sivelestat group patients developed SIRS (p < 0.05). The postoperative increases in the heart rate were significantly suppressed in the sivelestat group (p < 0.05, ANOVA). The postoperative decreases in the platelet counts were significantly suppressed in the sivelestat group (p < 0.05, ANOVA). The duration of mechanical ventilation and the length of ICU stay for the sivelestat group were shorter than that for the control group. We demonstrated that the postoperative decreases in the PaO(2)/FiO(2) ratio following esophagectomy were significantly suppressed in the sivelestat-treated group. This clinical study showed that a neutrophil elastase inhibitor may thus be a potentially useful drug for treating acute lung injury following esophagectomy.

摘要信息：The objective of the study was to evaluate the efficacy of sivelestat, a selective neutrophil elastase inhibitor, on body fluid balance after transthoracic esophagectomy. Esophagectomy with elective lymphadenectomy may induce excessive release of neutrophil elastase, which then promotes vascular permeability and an excessive water shift from the intravascular space to the peripheral compartment. Body fluid imbalance after esophagectomy often leads to circular instability, a decrease of urine output, and a delay in the shift to a diuretic state. The study was designed as a case-control study with a historical control group. A retrospective analysis was performed to examine our hypothesis that sivelestat improves abnormal body fluid retention and prevents subsequent pulmonary complications. To reveal the direct influence of sivelestat on the postoperative course, we avoided using steroids or other diuretic agents. Eighty-eight patients who underwent thoracic esophagectomy with extended lymphadenectomy from 2000 to 2008 were divided into two groups: those treated from 2003 to 2008, who all received postoperative administration of sivelestat (n=60); and those treated from 2000 to 2002, who did not receive sivelestat and were used as the control group (n=28). Both groups received fluid management using the same protocol. The time to reach a diuretic state, time until extubation of the tracheal tube, and development of delayed respiratory dysfunction were compared between the groups using univariate and multivariate analysis. The time until a shift to a diuretic state was significantly shorter after treatment with sivelestat (p<0.0001) and with a shorter operation time (p<0.0001). The tracheal tube was extubated significantly earlier in the sivelestat group (p<0.0001) and the incidence of delayed respiratory dysfunction was also significantly lower (p=0.0028) in this group. Multivariate logistic regression analysis showed that a delay in a shift to a diuretic state was a strong independent risk factor for the time to tracheal extubation (odds ratio 2.539, p=0.0056) and occurrence of delayed respiratory dysfunction (odds ratio 1.989, p=0.0104). Sivelestat treatment was not independently associated with reduced pulmonary complications, but the diuretic state was strongly regulated by sivelestat treatment (odds ratio 0.044, p=0.0003). Thus, administration of sivelestat has a beneficial influence on recovery from body water imbalance through a more rapid return to a diuretic state after esophagectomy, which contributes to prevention of subsequent pulmonary complications.

摘要信息：Post-operative pulmonary complications such as systemic inflammatory response syndrome (SIRS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are strongly associated with morbidity and mortality after esophagectomy. Post-operative administration of sivelestat sodium hydrate (sivelestat), a selective inhibitor of neutrophil elastase (NE), has been shown to improve the post-operative clinical course after esophagectomy. This study aimed to evaluate the effect of prophylactic administration of sivelestat on bronchial inflammatory responses. We randomized 24 patients into two groups. One group received 0.2 mg/kg/h sivelestat from the induction of anesthesia to post-operative day 1 (sivelestat group) and the other group received the same amount of physiological saline (control group). Bronchial alveolar epithelial lining fluid (ELF) samples were obtained from both groups at the induction of anesthesia and at the end of surgery. The serum and ELF levels of interleukin (IL)-6 and IL-8 were measured by enzyme-linked immunosorbent assay, and NE activity was spectrophotometrically determined using the same samples. Although IL-6 levels in the ELF significantly increased at the end of surgery compared with the pre-operative levels in both groups, the IL-8 levels and NE activity did not significantly increase at the end of the surgery compared to the corresponding pre-operative values in the sivelestat group. Moreover, IL-8 levels and NE activity in the ELF were significantly reduced at the end of surgery in the sivelestat group compared with corresponding values in the control group. The durations of ALI and ARDS were apparently shorter in the sivelestat group and the duration of SIRS was significantly shorter in the sivelestat group compared to the control group. We demonstrated that prophylactic use of sivelestat mitigated bronchial inflammation by suppressing NE activity and IL-8 levels in the ELF and shortened the duration of SIRS after transthoracic esophagectomy.

摘要信息：Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase (NE), and is effective in acute lung injury associated with systemic inflammatory response syndrome (SIRS). The effect of Sivelestat for postoperative clinical courses after transthoracic esophagectomy was investigated. Consecutive patients with carcinoma of the thoracic esophagus who underwent transthoracic esophagectomy between 2003 and 2004 were assigned to the Sivelestat-treated group (n = 18), and those between 1998 and 2003 were assigned to the control group (n = 25). The morbidity rate, duration of postoperative SIRS, mechanical ventilation, and intensive care unit (ICU) stay, and the sum of the sequential organ failure assessment scores at all time points after the operation were compared. Serum NE activities and serum concentrations of TNF-alpha, IL-1beta, IL-6, and high mobility group box chromosomal protein 1 (HMGB1) were measured. Postoperative complications developed in three patients in the control group, and one in the Sivelestat-treated group. The durations of SIRS, mechanical ventilation, and ICU stay were significantly shorter in the Sivelestat-treated group. Even in patients without complications, the durations of mechanical ventilation, and ICU stay were also significantly shorter, and the arterial oxygen pressure/fraction of inspired oxygen ratio at postoperative day 1 was significantly higher in the Sivelestat-treated group. Serum NE activities and serum concentrations of IL-1beta, IL-6, and HMGB1 were significantly suppressed in the Sivelestat-treated group. Postoperative Sivelestat treatment after transthoracic esophagectomy improves the condition of SIRS and postoperative clinical courses, even in patients without complications.