Sivelestat Attenuates Lung Injury in Surgery for Congenital Heart Disease With Pulmonary Hypertension

• Published in: The Annals of thoracic surgery Vol. 96; no. 6; pp. 2184 - 2191
• Main Authors: Nomura, Norikazu, MD, PhD, Asano, Miki, MD, PhD, Saito, Takayuki, MD, PhD, Nakayama, Takuya, MD, PhD, Mishima, Akira, MD, PhD
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.12.2013
• Subjects: Blood Pressure; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Cardiothoracic Surgery; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Glycine - administration & dosage; Glycine - analogs & derivatives; Glycine - therapeutic use; Heart Septal Defects, Ventricular - complications; Heart Septal Defects, Ventricular - physiopathology; Heart Septal Defects, Ventricular - surgery; Humans; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - physiopathology; Hypertension, Pulmonary - surgery; Infant; Infant, Newborn; Intraoperative Period; Lung Injury - prevention & control; Male; Prospective Studies; Serine Proteinase Inhibitors - administration & dosage; Serine Proteinase Inhibitors - therapeutic use; Sulfonamides - administration & dosage; Sulfonamides - therapeutic use; Surgery; Treatment Outcome; Vascular Resistance - drug effects; endothelial leukocyte adhesion molecule-1; Rp/Rs; pulmonary hypertension; ratio of pulmonary to systemic arterial systolic pressure; CK-MB; ratio of pulmonary to systemic arterial blood flow; ICAM-1; PaO2/FiO2; analysis of variance; ANOVA; cardiopulmonary bypass; Aa-D o 2; intensive care unit; alveolar-arterial oxygen tension gradient; ventricular septal defect; interleukin; creatine kinase-myocardial band; intercellular adhesion molecule-1; IL; VSD; Pp/Ps; ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen; PMN; CPB; ratio of pulmonary to systemic vascular resistance; PH; ICU; ELAM-1; polymorphonuclear; Qp/Qs; 20; Aa-Do2; Aa-Do
• ISSN: 0003-4975; 1552-6259
• DOI: 10.1016/j.athoracsur.2013.07.017

Background Pulmonary hypertension associated with congenital heart disease increases the risk of surgery using cardiopulmonary bypass. Sivelestat is a neutrophil elastase inhibitor thought to have a prophylactic effect against lung injury after surgery using bypass. We elucidated that Sivelestat had the protective effect on lung in patients with congenital heart disease and pulmonary hypertension who underwent surgery using bypass. Methods This study was a controlled prospective randomized trial and enrolled 13 neonates or infants with ventricular septal defect and pulmonary hypertension. The patients were assigned to either sivelestat with the dose of 0.2 mg/kg per hour (sivelestat group, n = 7) or saline (placebo group, n = 6) from the start of bypass until 6 hours after bypass. Proinflammatory cytokines and adhesion molecules on leukocytes were measured at 10 time points during the above period. Pulmonary function was assessed perioperatively. Results Compared with the placebo group, the sivelestat group had significantly lower values of alveolar-arterial oxygen tension gradient at 24 hours ( p = 0.038) and at 48 hours ( p = 0.028) after bypass, and significantly better balance of hydration at 48 hours after bypass ( p =  0.012). The sivelestat group also showed significantly lower plasma levels of interleukin-8 immediately after bypass ( p = 0.041) and interleukin-10 at 15 minutes after removal of the aortic cross-clamp ( p = 0.048), and immediately after bypass ( p = 0.037). Conclusions Administration of sivelestat during bypass prevented pulmonary damage and activities of proinflammatory cytokines at the cardiac operation in neonates or infants. Our results show that sivelestat may be considered to protect pulmonary function against the injury by bypass.