A prophylaxis study of acute exacerbation of interstitial pneumonia after lung cancer surgery

Introduction Acute exacerbation of interstitial pneumonia (AE-IP) is a lethal complication after lung surgery. We conducted a prospective, multi-institutional phase II trial to assess the efficacy and safety of prophylactic measures. Method Patients with lung cancer with dorsal subpleural fibrotic changes occupying three or more segments of both lower lobes and planned anatomical lung resection were enrolled. Prior to surgery, patients received a 125-mg bolus injection of methylprednisolone and continuous intravenous infusion of sivelestat sodium hydrate (sivelestat) for 2 days. Results Sixty-nine patients were analysed. Preoperative high-resolution computed tomography (HRCT) showed 37 (53.6%) cases presented with usual interstitial pneumonia (UIP) and possible UIP pattern. There were 60 lobectomies and 9 segmentectomies. Thirty-eight cases were in clinical stage I. No adverse events associated with prophylaxis were observed. There were four cases of AE-IP (5.8%), higher than the expected 2.0%. Three of the four cases showed inconsistencies with the UIP pattern in preoperative HRCT and were pathologically diagnosed as UIP. All patients died of respiratory failure. Overall, 89.9% were diagnosed as idiopathic interstitial pneumonias; UIP was found in 48 patients (69.6%). Severe post-operative complications occurred in 11.6% of the cases. There were 35 deaths, 17 cases of lung cancer and 11 cases related to interstitial pneumonias. The overall survival rate at 3 years was 41.8% of the total and 47.2% of cases with clinical stage I. Conclusions Perioperative use of sivelestat and low-dose methylprednisolone in patients with anatomical lung resection was safe but did not prove to be a prophylactic effect for AE-IP.

Neutrophil Elastase Inhibitors Suppress Oxidative Stress in Lung during Liver Transplantation

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.

A Protective Effect of Sivelestat From Ischemia/Reperfusion Injury in a Porcine Hepatectomy Model

Summary of background data: Sivelestat sodium hydrate (Sive), a neutrophil elastase inhibitor, has been approved as a worldwide therapeutic drug for acute lung injury associated with systemic inflammatory response syndrome. Yet how Sive influences hepatic ischemic reperfusion (I/R) injury and liver regeneration has not been clarified. Objective: We investigated the effect of Sive against hepatic I/R injury and liver regeneration using porcine hepatectomy model, and found that Sive contributes significantly in increasing the liver volume. Methods: We induced 1-hour ischemia by occluding the vessels and the bile duct of the right and median lobes. About 40% left hepatectomy was performed after reperfusion. A total of 6 animals received Sive (10 mg/kg/h) intravenously and 6 control animals received physiologic saline (10 mg/kg/h) from commencement of laparotomy. Remnant liver volume, hemodynamics, and liver function test were compared between the groups. Expressions of TRL4 mRNA in hepatic tissues were examined using RT-PCR. Apoptosis and cell proliferation were demonstrated by TUNEL staining. Results: AST, LDH, and LA levels at 5 minutes after reperfusion were significantly lower in Sive group than in the control group. Sive significantly increased the liver volume, yet did not have any effect for liver regeneration. Conclusion: Sive is considered to reduce hepatic injury in the early phase of I/R injury.

Abstract 122: Sivelestat Sodium Hydrate Treatment for Patients with Kawasaki Disease refractory to initial intravenous immunoglobulin therapy

Background: There are still no definite treatments for refractory Kawasaki disease (KD). In this pilot study, we evaluated the safety and efficacy of a new protocol consisting of sivelestat sodium hydrate (SSH) combined with additional intravenous immune globulin (IVIG) for KD patients who were resistant to initial IVIG therapy. Methods: We prospectively collected clinical data of KD patients who were resistant to initial IVIG (2g/kg for one day) and received SSH (0.2mg/kg/hour for consecutive 5 days) combined with additional IVIG (2g/kg for one day) as a second-line therapy at Chiba University hospital between December 2006 and March 2014. We defined patients who remained febrile (37.5°C or more of an axillary temperature) after 36 to 48 hours after start of initial IVIG therapy or who had recrudescent fever associated with other symptoms of Kawasaki disease as being resistant to initial IVIG. Results: Thirty five KD patients were enrolled in this study. No serious adverse effect was noted. The median total duration of fever was 8 days (range 6 to 17 days) and the incidence of coronary artery lesion (CAL) was 5.7% (2 of 35 patients). Among a total of 35 patients, 24 (69%) of them responded promptly to be afebrile 36 to 48 hours after the start of the additional IVIG with SSH. One of these 24 patients developed CAL. The other 11 (31%) failed to become afebrile 36 to 48 hours after the start of the additional IVIG with SSH therapy. Of these 11 patients, one developed CAL. Before initial IVIG, there was no difference in demographic and laboratory data except the age, body weight and % Neutrophils. However, after initial IVIG therapy, there appeared significant difference in % Neutrophils and C-reactive protein levels and both of which were higher in additional IVIG with SSH therapy non-responders than in responders. Conclusions: Additional IVIG combined with SSH for the additional treatment of KD patients who were refractory to initial IVIG therapy was safe and the incidence of CAL is acceptable considering the severity of patients in this study.