title: Effect of a selective neutrophil elastase inhibitor on mortality and ventilator-free days in patients with increased extravascular lung water: a post hoc analysis of the PiCCO Pulmonary Edema Study.
abstract: BACKGROUND
  Neutrophil elastase plays an important role in the development and progression of acute respiratory distress syndrome (ARDS). Although the selective elastase inhibitor, sivelestat, is widely used in Japan for treating ARDS patients, its effectiveness remains controversial. The aim of the current study was to investigate the effects of sivelestat in ARDS patients with evidence of increased extravascular lung water by re-analyzing a large multicenter study database.
  
  
  METHODS
  A post hoc analysis of the PiCCO Pulmonary Edema Study was conducted. This multicenter prospective cohort study included 23 institutions in Japan. Adult mechanically ventilated ARDS patients with an extravascular lung water index of >10 mL/kg were included and propensity score analyses were performed. The endpoints were 28-day mortality and ventilator-free days (VFDs).
  
  
  RESULTS
  Patients were categorized into sivelestat (n = 87) and control (n = 77) groups, from which 329 inverse probability-weighted group patients (162 vs. 167) were generated. The overall 28-day mortality was 31.1% (51/164). There was no significant difference in 28-day mortality between the study groups (sivelestat vs. control; unmatched: 29.9% vs. 32.5%; difference, -2.6%, 95% confidence interval (CI), -16.8 to 14.2; inverse probability-weighted: 24.7% vs. 29.5%, difference, -4.8%, 95% CI, -14.4 to 9.6). Although administration of sivelestat did not alter the number of ventilator-free days (VFDs) in the unmatched (9.6 vs. 9.7 days; difference, 0.1, 95% CI, -3.0 to 3.1), the inverse probability-weighted analysis identified significantly more VFDs in the sivelestat group than in the control group (10.7 vs. 8.4 days, difference, -2.3, 95% CI, -4.4 to -0.2).
  
  
  CONCLUSIONS
  Although sivelestat did not significantly affect 28-day mortality, this treatment may have the potential to increase VFDs in ARDS patients with increased extravascular lung water. Prospective randomized controlled studies are required to confirm the results of the current study.
authors.affiliation: Department of Emergency and Critical Care Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603 Japan ; Department of Clinical Epidemiology and Health Economics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tagami
authors.affiliation: Department of Emergency and Critical Care Medicine, Aizu Chuo Hospital, Fukushima, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Tosa
authors.affiliation: Department of Emergency and Critical Care Medicine, Aizu Chuo Hospital, Fukushima, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Omura
authors.affiliation: Department of Emergency and Critical Care Medicine, Nara Medical University, Nara, Japan.
authors.forename: Hidetada
authors.initials: H
authors.lastname: Fukushima
authors.affiliation: Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Yamaguchi, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: Department of Emergency and Critical Care Medicine, Tohoku University Hospital, Miyagi, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Endo
authors.affiliation: Emergency and Critical Care Medical Center, Osaka City General Hospital, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Rinka
authors.affiliation: Department of Emergency and Critical Care Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Murai
authors.affiliation: Division of Emergency and Critical Care Medicine, Department of Acute Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamaguchi
authors.affiliation: Shock Trauma and Emergency Medical Center, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yoshikawa
authors.affiliation: Department of Emergency and Critical Care Medicine, Nippon Medical School Chiba Hokusou Hospital, Chiba, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Saito
authors.affiliation: Department of Emergency and Critical Care Medicine, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Uzu
authors.affiliation: Critical Care Medicine, Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kase
authors.affiliation: Department of Anesthesia and Intensive Care, Hiroshima City Hospital, Hiroshima, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takatori
authors.affiliation: Advanced Emergency and Critical Care Center, Kansai Medical University Takii Hospital, Osaka, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Izumino
authors.affiliation: Intensive Care Unit, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Intensive Care Unit, Kobe City Medical Center General Hospital, Hyogo, Japan.
authors.forename: Ryutarou
authors.initials: R
authors.lastname: Seo
authors.affiliation: Department of Emergency and Critical Care Medicine, Kansai Medical University, Osaka, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Kitazawa
authors.affiliation: Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Sugita
authors.affiliation: Department of Intensive Care Medicine, Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Emergency and Critical Care Medicine, Social Insurance Chukyo Hospital, Aichi, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kuroki
authors.affiliation: Department of Emergency and Critical Care Medicine, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Irahara
authors.affiliation: Emergency and Critical Care Medicine, National Hospital Organization Disaster Medical Center, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanemura
authors.affiliation: Department of Emergency and Critical Care Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603 Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Division of Emergency Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kushimoto
keywords: Acute lung injury; Extravascular lung water; Pulmonary edema; Pulmonary vascular permeability index; Transpulmonary thermodilution technique