Tiejun Wu,1,* Tao Wang,2,* Jinjiao Jiang,3 Yue Tang,3 Lina Zhang,1 Zhiming Jiang,4 Fen Liu,4 Guiqing Kong,2 Tingfa Zhou,5 Ruijin Liu,5 Haipeng Guo,6 Jie Xiao,6 Wenqing Sun,7 Yuye Li,7 Yingying Zhu,8 Quan Liu,8 Weifeng Xie,9 Yan Qu,9 Xiaozhi Wang2 

1Department of Critical Care Medicine, Liaocheng People’s Hospital, Liaocheng, 252004, People’s Republic of China; 2Department of Intensive Care unit, Binzhou Medical University Hospital, Binzhou, 256699, People’s Republic of China; 3Department of Critical Care Medicine, Provincial Hospital of Shandong First Medical University, Jinan, 250021, People’s Republic of China; 4Department of Critical Care Medicine, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250013, People’s Republic of China; 5Department of Critical Care Medicine, Linyi People’s Hospital, Linyi, 276034, People’s Republic of China; 6Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China; 7Department of Respiratory Intensive Care Unit, Shandong Public Health Clinical Centre, Jinan, 250102, People’s Republic of China; 8Department of Critical Care Medicine, Tai’an Central Hospital, Taian, 271002, People’s Republic of China; 9Department of Critical Care Medicine, Qingdao Municipal Hospital, Qingdao, 266071, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xiaozhi Wang; Tiejun Wu, Email hxicuwxz@163.com; tiejunwu@hotmail.com

Objective: Neutrophil elastase (NE) plays an important role in the development of acute respiratory distress syndrome (ARDS). Sivelestat sodium, as a selective NE inhibitor, may improve the outcomes of patients with sepsis-induced ARDS in previous studies, but there is a lack of solid evidence. This trial aimed to evaluate the effect of sivelestat sodium on oxygenation in patients with sepsis-induced ARDS.
Methods: We conducted a multicenter, double-blind, randomized, placebo-controlled trial enrolling patients diagnosed with sepsis-induced ARDS admitted within 48 hours of the advent of symptoms. Patients were randomized in a 1:1 fashion to sivelestat or placebo. Trial drugs were administered as a 24-hour continuous intravenous infusion, for a minimum duration of 5 days and a maximum duration of 14 days. The primary outcome was the proportion of PaO2/FiO2 ratio improvement on Day 5 after randomization, defined by a greater than 50% improvement in PaO2/FiO2 compared with that on ICU admission or PaO2/FiO2 reached over 300 mmHg on Day 5.
Results: The study was stopped midway due to a potential between-group difference in mortality observed during the interim analysis. Overall, a total of 70 patients were randomized, of whom 34 were assigned to receive sivelestat sodium and 36 placebo. On day 5, 19/34 (55.9%) patients in the sivelestat group had PaO2/FiO2 ratio improvement compared with 7/36 (19.4%) patients in the placebo group (risk difference, 0.36; 95% CI, 0.14 to 0.56, p< 0.001). The Kaplan–Meier curves showed a significantly improved 28-day survival rate in patients receiving sivelestat than those not (hazard ratio, 0.32; 95% CI, 0.11 to 0.95; p=0.041).
Conclusion: In patients with sepsis-induced ARDS, sivelestat sodium could improve oxygenation within the first five days and may be associated with decreased 28-day mortality.

Keywords: sepsis, acute respiratory distress syndrome, neutrophil elastase, sivelestat, oxygenation