Cardiopulmonary bypass (CPB) has been implicated as a cause of acute lung injury (ALI) in cardiac surgical patients. We used a bronchoscopic microsampling (BMS) probe to examine alveolar biochemical constituents and evaluated the effect of sivelestat sodium hydrate, a novel synthesized polymorphonuclear (PMN) neutrophil elastase inhibitor, on ALI induced by CPB. Twelve patients undergoing aortic valve replacement were treated with either sivelestat 0.2 mg/kg/h (sivelestat group, n=6) or 0.9% saline (control group, n=6) from the start of surgery. Samples were collected by the BMS probe at three time points: after tracheal intubation, 1 h after CPB introduction, and 3 h after CPB termination. Pulmonary function was assessed perioperatively. There were no differences in baseline characteristics. The concentration of PMN elastase was significantly suppressed in the sivelestat group, compared with the control group (P=0.001). The sivelestat group also had lower levels of interleukin-6 and interleukin-8. Alveolar-arterial oxygen difference markedly increased, and a worsening of the PaO(2)/FiO(2) ratio indicated severe impairment after CPB. However, sivelestat attenuated the pattern of physiological deterioration of gas exchange. Sivelestat may attenuate neutrophil elastase or proinflammatory cytokines, and improve pulmonary dysfunction in patients undergoing CPB.

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Sivelestat, a neutrophil elastase inhibitor, has been shown to attenuate pulmonary injury during ischemia and reperfusion by improving microcirculation and may be effective as a cardioprotective agent. Isolated rat hearts were Langendorff-perfused (constant pressure, 75 mmHg) with oxygenated Krebs-Henseleit bicarbonate buffer (KHB). The optimal sivelestat concentration at 19 micromol/l was revealed because left ventricular developed pressure (LVDP) recovery in 19 micromol/l sivelestat was highest among 0.19, 1.9, 19, 190, and 1900 micromol/l sivelestat (26+/-10, 33+/-7, 56+/-5*, 35+/-2, and 15+/-5%, respectively; *P<0.01). In order to examine the optimal administration timing, sivelestat was administered at pre- and post-ischemic phases. LVDP recovery and troponin-T were observed in pre-, post-ischemic sivelestat groups and control. After 60 min-reperfusion, LVDP recoveries were 42+/-10*, 45+/-19*, and 14+/-5%, respectively (*P<0.01 compared to control), and troponin-T values were 4+/-1, 2+/-1**, and 8+/-2, respectively (**P<0.05 compared to control). Acetylcholine-induced increase in coronary flow was also investigated to examine the sivelestat's cardioprotective mechanism. Ischemia-reperfusion (I/R) impaired the acetylcholine-induced increase in coronary flow (maximal changes: sham, 125+/-11%; I/R, 98+/-3; P<0.01) and this impairment was attenuated by sivelestat-perfusion at reperfusion (maximal change: 112+/-7%; P<0.05 vs. I/R). Sivelestat attenuates coronary endothelial ischemia-reperfusion injury and improves myocardial protection even when administered at the reperfusion period. This suggests a role for sivelestat in the preservation of coronary endothelial function enhancing myocardial protection.

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Intermittent arrest with esmolol did not enhance protection of intermittent crossclamping with fibrillation; however, multiple esmolol infusions during global ischemia provided improved protection. Administration (constant flow or constant pressure) of arresting solutions influenced outcome only during continuous infusion. Multidose esmolol arrest may be a beneficial alternative to intermittent crossclamping with fibrillation or conventional cardioplegia.

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