Ann Thorac Surg 2007;83:160
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Invited commentary
Michael E. Jessen, MD
Department of Cardiovascular & Thoracic Surgery, University of Texas Southwestern Medical Ctr, 5323 Harry Hines Blvd Dallas, TX 75390-8879
(Email: michael.jessen{at}utsouthwestern.edu).
Although infrequent, the occurrence of acute lung injury (ALI) after cardiopulmonary bypass (CPB) remains a serious problem. In this report, Wakayama and colleagues [1] describe the effect of Sivelestat (Ono Pharmaceutical Co. Ltd, Osaka, Japan), a neutrophil elastase inhibitor, on the development of ALI after exposure to lipopolysaccharide (LPS) and CPB. In a rabbit model, the combination of LPS and CPB led to an elevation in elastase activity and interleukin-8 levels, an accumulation of polymorphonuclear neutrophils in the bronchoalveolar area, and a marked decline in oxygenation after CPB. All of these effects were significantly attenuated by pretreatment with Sivelestat. These data are intriguing and suggest that this novel drug may provide a new weapon in our limited arsenal against this serious complication of extracorporeal circulation. The drug competitively inhibits neutrophil elastase activity and is not de-stabilized by reactive oxygen species. It can specifically inhibit tissue-bound neutrophil elastase, providing a benefit beyond available strategies to reduce the inflammatory response. A clinical trial to test whether this drug can prevent post-CPB ALI would seem to be indicated.
One must be cautious in assuming that a clinical trial will show similarly impressive benefits. The inflammatory response is very complex and drugs or techniques designed to alter specific parts of this multifaceted process may prove less effective in the clinical arena. A phase 3 study of Sivelestat conducted in Japan in intensive care unit (ICU) patients suggested that the drug improved pulmonary function and reduced ICU length of stay. However, a subsequent multicenter, prospective randomized trial of this drug (the STRIVE [Sivelestat Trial in ALI Patients Requiring Mechanical Ventilation] study [2]) in a heterogeneous acute lung injury population demonstrated no effect on 28 day all-cause mortality, and the study was stopped prematurely by the Data Safety Monitoring Board after noting a trend toward a higher long-term mortality rate in the Sivelestat group. We must await a formal clinical trial to gain further insight into the ultimate benefits of this drug in patients. For now, Wakayama and colleagues [1] have provided important experimental data on the potential benefits of Sivelestat and have produced an impressive experimental model that may be used to test other interventions that may advance our understanding of the biologic mechanisms behind this serious sequela of cardiopulmonary bypass.
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References
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- Wakayama F, Fukuda I, Suzuki Y, Kondo N. Neutrophil elastase inhibitor, Sivelestat, attenuates acute lung injury after cardiopulmonary bypass in the rabbit endotoxemia model Ann Thorac Surg 2007;83:153-160.[Abstract/Free Full Text]
- Zeihler BG, Artigas A, Vincent J-L, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study Crit Care Med 2004;32:1695-1702.[Medline]
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Neutrophil Elastase Inhibitor, Sivelestat, Attenuates Acute Lung Injury After Cardiopulmonary Bypass in the Rabbit Endotoxemia Model
- Fuminori Wakayama, Ikuo Fukuda, Yasuyuki Suzuki, and Norihiro Kondo
Ann. Thorac. Surg. 2007 83: 153-160.
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[Full Text]
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