Effects of Neutrophil Elastase Inhibitor on Progression of Acute Lung Injury After Liver Transplantation

Abstract

We read with interest the article recently published in Transplantation by Uchida et al. (1) describing protective function of neutrophil elastase (NE) inhibitor in liver ischemia-reperfusion injury. The authors concluded that NE inhibition may represent an effective therapeutic option in liver transplantation (LT). Despite recent advances in surgical techniques and perioperative management, LT has a relatively high in-hospital mortality and morbidity rate (2). In addition to ischemia-reperfusion injury, pulmonary complications including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) frequently occur after LT. If uncontrolled, ALI/ARDS leads to in-hospital death. Therefore, prevention of postoperative ALI/ARDS is important to reduce in- hospital mortality after LT. Pulmonary endothelial barrier disruption plays a critical role in the development of ALI/ARDS. Especially, neutrophils and NE play important roles in endothelial injury and increased vascular permeability, which are the characteristics of ALI/ARDS (3). Pulmonary vascular hyperpermeability, a cause of hypoxemia during the early postoperative course, could be caused by NE released from neutrophils accumulating in the lung (4). Sivelestat (ONO Pharmacol, Osaka, Japan) is a synthetic selective inhibitor of NE (5). In the field of organ transplantation, there have been some reports showing beneficial effects of Sivelestat in lung or liver ischemia-reperfusion injury in experimental animal model (1, 6, 7). However, there has been no clinical study examining its usefulness in LT. In this study, we therefore conducted a prospective, nonrandomized, clinical pilot study to examine the effect of Sivelestat on postoperative ALI in patients undergoing LT. Between April 2007 and May 2008, 62 consecutive adult patients who underwent living donor LT at Kyoto University Hospital were prospectively enrolled in the study. After matching for underlying disease, the patients were nonrandomly assigned to receive a continuous intravenous infusion of 300 mg/kg per day of Sivelestat (Sivelestat group, n=31) dissolved in 50 mL of saline or saline only (control group, n=31) just after admission to the intensive care unit after surgery. The patients in both the groups were treated until the ratio of arterial oxygen tension (PaO2)-to-the fractional concentration of inspired oxygen (FiO2) (PF ratio) was more than 300. Blood samples for arterial blood gas analysis were drawn twice daily throughout the experiment. The duration of systemic inflammatory response syndrome (SIRS) was also measured. The definition for SIRS was in accordance with that of the American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference (8). The protocol was approved by the ethical committee of Kyoto University Hospital following the guidelines of the 1975 Declaration of Helsinki. The written informed consent was obtained from each patient before participation in the study. Continuous variables were expressed as the means±SD, or as the median and range, and the differences in continuous variables were analyzed by Student's t test. Comparisons of the categorical or ordinal variables were performed using chi-square test or Fisher exact test where appropriate. A P value less than 0.05 was considered significant. The characteristics of patients including age, gender, underlying disease, Child-Pugh classification, and model for end-stage liver disease score, were not different between the two groups. The decrease in the PF ratio after surgery shown in the control group was prevented in the Sivelestat group (Fig. 1). The PF ratios on the first, second, and third postoperative days (PODs) in the Sivelestat group were significantly higher than those in the control group (POD1, 322±74 vs. 258±90, P=0.002; POD2, 318±106 vs. 224±88, P=0.002; and POD3, 330±91 vs. 214±82, P<0.001), whereas the PF ratio on intensive care unit admission was lower in the Sivelestat group than that in the control group (324±87 vs. 359±90, P=0.160). Moreover, the duration of SIRS was significantly shorter in the Sivelestat group compared with that in the control group (2.3±2.1 days vs. 3.7±3.7 days, P=0.023).FIGURE 1.: The ratio of arterial oxygen tension to the fractional concentration of inspired oxygen (PF ratio) after surgery. The decrease in PF ratio after surgery shown in the control group was prevented in the Sivelestat group. ICU, intensive care unit; POD, postoperative day.This is the first report that shows the preventive effect of Sivelestat against ALI after living donor LT in clinical settings. Several studies suggested that Sivelestat improved ALI partially by inhibiting inflammation or nuclear factor-κB activity (6, 9, 10). Although plasma levels of proinflammatory and antiinflammatory cytokines were not examined in this study, the amelioration of posttransplant ALI might be partially caused by its antiinflammatory effect. Further investigations are thus required to elucidate mechanism of the preventive effect of Sivelestat against ALI. Randomized controlled trials of Sivelestat for posttransplant ALI after LT are needed to confirm this finding. Toshimi Kaido Shinji Uemoto Division of Hepato-Biliary-Pancreatic and Transplant Surgery Department of Surgery Graduate School of Medicine Kyoto University Kyoto, Japan