摘要信息：Purpose: This study aimed to evaluate the efficacy of sivelestat sodium on mortality, oxygenation index, and serum markers in patients with acute respiratory distress syndrome (ARDS) associated with Coronavirus Disease 2019 (COVID-19). Methods: A retrospective analysis was conducted on adult inpatients admitted to the Intensive Care Unit (ICU). The study compared clinical characteristics, laboratory indices, and mortality rates between patients treated with and without sivelestat sodium. Cox regression analysis was employed to assess the effect of sivelestat sodium on the risk of death, oxygenation index, and improvement of serum markers in patients with COVID-19-associated ARDS. Results: A total of 110 patients with COVID-19-associated ARDS were included, with 45 patients in the sivelestat group and 65 patients in the control group. The overall patient mortality rate was 69.1%, with 62.2% in the sivelestat group and 73.8% in the control group. After five days of treatment, the median change from baseline in the oxygenation index was 21 mmHg in the medicated group and -31 mmHg in the control group (p < 0.05). Analysis of the oxygenation index as a clinical endpoint event showed a significantly higher rate of improvement in the sivelestat group compared to the control group (57.8% vs. 38.5%, p < 0.05), and the odds of raising the oxygenation index after treatment were 2.05 times higher in the sivelestat group than in the control group (HR = 2.05, 95%CI: 1.02-4.15, p < 0.05). Among patients with a baseline oxygenation index < 200 mmHg, patients in the sivelestat group had an 86% lower risk of death compared to the control group (HR = 0.14, 95%CI: 0.02-0.81, p < 0.05). Conclusions: Sivelestat sodium demonstrated a significant improvement in the oxygenation index of patients with COVID-19-associated ARDS and was found to considerably reduce the risk of death in patients with a baseline oxygenation index of <200 mmHg.

摘要信息：Introduction: Sivelestat is neutrophil elastase inhibitor, which is widely used in Japan for the treatment of acute lung injury. However, the clinical efficacy of the medication has not been convincingly demonstrated. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials on sivelestat for the treatment of acute lung injury and acute respiratory distress syndrome. Studies were identified using MEDLINE, EMBASE, Cochrane library, conference proceedings, and references of included studies. Authors were contacted if necessary. ICHUSHI, the Japanese database for medical literature and conference proceedings was also used for the search, since many studies on sivelestat were published in Japanese language and not registered in major databases such as MEDLINE. The primary outcome was mortality within 28-30 days after randomization. Relative risks were pooled with the random effect model. Results: 8 trials were included in the analysis. There was no difference in mortality within 28-30 days after randomization (relative risk 0.95, 95% confidence interval 0.72 to 1.26). Subgroup analysis conducted only on studies conducted in Japan showed the same result (0.59, 0.28 to 1.28). There was no difference in mechanical ventilation days (standardized mean difference -0.43, -1.12 to 0.27), but sivelestat was associated with a better short term PaO(2)/FiO(2) ratio (0.30, 0.05 to 0.56). Heterogeneity was not significant for the main analysis and funnel plot did not suggest publication bias. Conclusion: Sivelestat was not associated with decreased mortality, even when including studies published in Japanese language.

摘要信息：Background and objective:Neutrophil elastase (NE) may play a key role in the development of acute lung injury (ALI) or ARDS. NE activity (NEA) was measured in patients with ALI treated with a selective NE inhibitor. Methods:NEA and NE-alpha1-antitrypsin (NE-AT) complex were measured in plasma before, during and after the administration of the selective NE inhibitor, sivelestat, in 32 patients with a diagnosis of ALI or ARDS. NEA index (NEAI) was calculated as NEA/NE-AT. The sequential organ failure assessment (SOFA) score and the ratio PaO(2)/fraction of inspired oxygen (FiO(2)) were measured. Results:NEA and NE-AT was raised in all patients. Sivelestat reduced NEAI and NEA (P < 0.01 for both) but not NE-AT and NEA, and NEAI returned to pretreatment levels. NEA correlated closely with NE-AT before, but not after treatment. No relationship was observed between these indices and SOFA score or PaO(2)/FiO(2) ratio. Conclusions:Sivelestat reduced NEA and NEAI in patients with ALI or ARDS suggesting NE inhibition. A larger study is needed to determine the relationship of NEA, NE-AT and NEAI with the outcome of ALI/ARDS. Background and objective:Neutrophil elastase (NE) may play a key role in the development of acute lung injury (ALI) or ARDS. NE activity (NEA) was measured in patients with ALI treated with a selective NE inhibitor. Methods:NEA and NE-alpha1-antitrypsin (NE-AT) complex were measured in plasma before, during and after the administration of the selective NE inhibitor, sivelestat, in 32 patients with a diagnosis of ALI or ARDS. NEA index (NEAI) was calculated as NEA/NE-AT. The sequential organ failure assessment (SOFA) score and the ratio PaO(2)/fraction of inspired oxygen (FiO(2)) were measured. Results:NEA and NE-AT was raised in all patients. Sivelestat reduced NEAI and NEA (P < 0.01 for both) but not NE-AT and NEA, and NEAI returned to pretreatment levels. NEA correlated closely with NE-AT before, but not after treatment. No relationship was observed between these indices and SOFA score or PaO(2)/FiO(2) ratio. Conclusions:Sivelestat reduced NEA and NEAI in patients with ALI or ARDS suggesting NE inhibition. A larger study is needed to determine the relationship of NEA, NE-AT and NEAI with the outcome of ALI/ARDS.

摘要信息：Purpose:We assessed the effects of a neutrophil elastase inhibitor, sivelestat, on respiratory and organ functions as well as on the mortality of patients with acute respiratory distress syndrome (ARDS) associated with systemic inflammatory response syndrome (SIRS). Methods:We retrospectively divided 25 patients who fulfilled the diagnostic criteria for SIRS and ARDS into two groups. One group (S group, n = 12) received a continuous infusion of sivelestat (0.2 mg.kg(-1).h(-1)), and the other did not (C group, n = 13). Results:Between days 1 and 10, the Pa(O2)/FI(O2) ratio in the S group significantly improved from 119.1 +/- 51.1 to 214.4 +/- 88.2 mmHg (P < 0.05). Furthermore, the S group spent significantly fewer days on a ventilator than the C group (16.7 +/- 5.8 vs 26.6 +/- 14.3 days; P < 0.05). The length of the intensive care unit stay was also significantly shorter for the S group than for the C group (18.7 +/- 4.9 vs 27.5 +/- 13.5 days; P < 0.05). However, the mortality rate at 29 days did not statistically differ between the two groups. Conclusion:Our results suggested that sivelestat has a beneficial effect only on the pulmonary function of ARDS patients with SIRS.

摘要信息：Background:Neutrophil elastase, alveolar thrombin generation, and fibrin deposition play crucial roles in the development of acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation (DIC). However, the usefulness of combination therapy with a selective neutrophil elastase inhibitor, sivelestat, and recombinant human soluble thrombomodulin (rhTM) for patients with ARDS and DIC remains unknown. Methods:We conducted a retrospective data analysis of 142 ARDS patients with DIC to assess the effects of sivelestat combined with rhTM. Patients were divided into four groups: control (no sivelestat or rhTM treatment), sivelestat treatment alone, rhTM treatment alone, and combined treatment with sivelestat and rhTM. A Cox proportional hazard model was used to assess subject mortality rates. The efficacy of these drugs was evaluated based on survival rate, number of ventilator-free days, and change in PaO2/FIO2 (P/F) ratios and DIC scores before and at 7 days after a diagnosis of ARDS with DIC. Results:Multivariate analysis showed that patient age, combination therapy, gas exchange, organ failure, cause, associated disease score, and serum C-reactive protein levels were predictors of mortality for patients with ARDS and DIC. As compared with untreated controls, combination therapy significantly improved the 60-day survival rate of patients with ARDS and DIC. There were significantly more ventilator-free days for those who received combination therapy than for untreated controls. P/F ratios and DIC scores were significantly improved with sivelestat alone, rhTM alone, or their combination as compared with untreated controls. Conclusion:Our results suggest that combined treatment with sivelestat and rhTM has beneficial effects on survival and the respiratory and DIC status of patients with ARDS and DIC.

摘要信息：Evidence has linked neutrophil elastase to acute respiratory distress syndrome (ARDS), suggesting that inhibiting the activity of this enzyme could prevent the development and progression of ARDS. However, few clinical trials have examined this notion. We therefore examined the effects of ONO-5046 (sivelestat, a specific inhibitor of neutrophil elastase; sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylaminobenzoyl]amino-acetate tetrahydrate]) in a randomized, double-blinded trial in patients with ARDS. We randomly assigned 24 patients with ARDS to groups that received conventional therapy without or with sivelestat (0.2 mg. kg(-1). h(-1)) for 14 days. The variables of interest associated with clinical outcome were the duration of mechanical ventilation; changes in oxygenation from baseline; changes in cytokine levels from baseline; number of patients alive at 30 days who did not need mechanical ventilation; and mortality rate. The length of intensive care unit stay, number of ventilation days, and mortality rates did not statistically differ between groups. ARDS was more persistent in the control than in the sivelestat group (control, 19.5 +/- 7.4 days; sivelestat, 13.5 +/- 5.9 days; P = 0.039). Neutrophil elastase activity significantly differed between groups at 72 h after treatment. Levels of interleukin-6 were lower in the sivelestat group than in the controls at 24, 48, and 72 h after treatment. ONO-5046 apparently did not affect survival or the duration of mechanical ventilation.

摘要信息：Background and objective:The efficacy of sivelestat, a neutrophil elastase inhibitor, for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remains controversial. We investigated the role of sivelestat in ALI/ARDS patients on mortality as an end point between the sivelestat group and the non-sivelestat group within 7 days of admission. Methods:This study was performed using the Japanese nationwide administrative database (Diagnostic Procedure Combination; DPC) in 2012. We employed the propensity score weighting method with a Cox proportional hazards model to compare the mortality between the sivelestat group and the non-sivelestat group. Results:A total of 4276 patients were eligible for this study; 1997 patients were treated with sivelestat and 2279 patients did not receive sivelestat within 7 days of admission. After adjusting for confounds, the mortality within 3 months was significantly lower in the sivelestat group compared with the non-sivelestat group (weighted hazard ratio: 0.83; 95% CI: 0.75-0.93; P < 0.002). Multiple regression analysis revealed that younger age, absence of cancer, no need for haemodialysis and no use of high-dose methylprednisolone were significantly correlated with treatment success (survive). Conclusion:These results of this retrospective and observational study suggest that administration of sivelestat within 7 days of admission may improve the prognosis of patients with ALI/ARDS. To our knowledge, this is the largest study to evaluate the efficacy of sivelestat on ALI/ARDS. Keywords: acute lung injury; acute respiratory distress syndrome; inverse probability of treatment weighting; nationwide administrative database; sivelestat.

摘要信息：Background:Sivelestat is widely used in treating acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), although the clinical efficacy of sivelestat remains controversial. This study aimed to evaluate the impact of sivelestat in patients with ALI/ARDS. Methods:Electronic databases, PubMed, Embase, and the Cochrane Library, were searched to identify trials through April 2017. Randomized controlled trials (RCTs) were included irrespective of blinding or language that compared patients with and without sivelestat therapy in ALI/ARDS. A random-effects model was used to process the data, and the relative risk (RR) and standard mean difference (SMD) with corresponding 95% confidence intervals (CIs) were used to evaluate the effect of sivelestat. Results:Six RCTs reporting data on 804 patients with ALI/ARDS were included. Overall, no significant difference was found between sivelestat and control for the risk of 28-30 days mortality (RR: 0.94; 95% CI: 0.71-1.23; P = 0.718). Sivelestat therapy had no significant effect on ventilation days (SMD: 0.05; 95% CI: -0.27 to 0.38; P = 0.748), arterial oxygen partial pressure (PaO2)/fractional inspired oxygen (FiO2) level (SMD: 0.48; 95% CI: -0.45 to 1.41; P = 0.315), and intensive care unit (ICU) stays (SMD: -9.87; 95% CI: -24.30 to 4.56; P = 0.180). The results of sensitivity analysis indicated that sivelestat therapy might affect the PaO2/FiO2level in patients with ALI/ARDS (SMD: 0.87; 95% CI: 0.39 to 1.35; P < 0.001). Conclusions:Sivelestat therapy might increase the PaO2/FiO2level, while it had little or no effect on 28-30 days mortality, ventilation days, and ICU stays. These findings need to be verified in large-scale trials.

摘要信息：Background:Acute respiratory distress syndrome (ARDS) is one of the most organ dysfunctions in sepsis. Although the development of therapeutic strategies such as protective mechanical ventilation technology has improved the mortality of ARDS patients, there is currently no effective drug for reducing the associated mortality. Our study aims to investigate the efficacy, safety, and pharmacoeconomics of sivelestat sodium in patients with septic ARDS, for providing the basis on clinical use of this drug. Methods:This was a retrospective study of 140 patients with septic ARDS. Clinical information including general conditions, mechanical ventilation time, drug cost parameters, and adverse reactions. The partial pressure of O2/fraction of inspired oxygen (PaO2/FiO2), acute physiology and chronic health evaluation score (APACHE II score) and sequential organ failure assessment (SOFA score) are for assessing the severity illness. To evaluate the efficacy of sivelestat sodium on septic ARDS patients by comparing length of mechanical ventilation and intensive care unit (ICU) hospitalization, cost of hospitalization and mortality between the two groups. Results:There were no significant differences in the incidence of organ failure, biochemical data, blood gas analysis, acute physiology and chronic health evaluation (APACHE II score), and SOFA score between the two groups on the day of admission. The PaO2/FiO2, APACHE II score, and SOFA score of the sivelestat sodium group were significantly better than in the control group (P<0.05). The length of mechanical ventilation, length of ICU hospitalization, and cost of ICU hospitalization were all lower in the sivelestat sodium group (P<0.05). No adverse events were reported during the study period. Conclusions:Sivelestat sodium significantly improves the oxygenation in patients with septic ARDS, together with reducing mechanical ventilation, ICU hospitalization, and medical costs.

摘要信息：【摘要】目的 探讨中性粒细胞弹性蛋白酶(NE)抑制剂西维来司他钠在重症监护室(ICU)急性肺损伤(ALI)患者中应用的有效性和安全性。方法回顾性分析2020年6月至2021年6月郑州大学第一附属医院 ICU 171 例 ALI患者，其中西维来司他钠组 77 例，常规治疗组 94例。收集患者的临床资料，包括急性生理和慢性健康评分Ⅱ(APACHE Ⅱ)、Mumray 肺损伤评分、氧合指数(PaO,FiO,)、炎症因子(I-6、IL-10、TNF-α )，并统计无呼吸机天数(VED)、ICU 住院天数及 28 d病死率等，来评估西维来司他钠对 ICU 中 ALI治疗的有效性。同时，记录西维来司他钠使用后 30d内患者不良反应及化验指标来评估其应用的安全性。结果与常规治疗相比，西维来司他钠治疗7d后氧合指数、Mumray 肺损伤评分、I-6、IL-10、TNF-a 均明显改善，差异有统计学意义。与常规治疗组相比，西维来司他钠组 VFD 更长(P=0.0119 )，ICU 住院天数更少(P0.0269 )，差异具有统计学意义。西维来司他钠组病死率为 14.29%，常规治疗组病死率为 22.34%,两组间病死率差异无统计学意义。西维来司他钠使用后 30 d内未增加患者不良反应，安全性良好,结论 重症监护室急性肺损伤患者使用西维来司他钠治疗安全性良好，较常规治疗更有效。