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Annals of Surgery:
doi: 10.1097/SLA.0b013e31829d686b
Randomized Controlled Trials

Effect of Simvastatin on Physiological and Biological Outcomes in Patients Undergoing Esophagectomy: A Randomized Placebo-Controlled Trial

Shyamsundar, Murali PhD*; McAuley, Daniel F. MD*; Shields, Martin O. MD; MacSweeney, Rob FRCA*; Duffy, Martin J. MD*; Johnston, Julian R. MD; McGuigan, Jim FRCS(Ed); Backman, Janne T. MD§; Calfee, Carolyn S. MD; Matthay, Michael M. MD; Griffiths, Mark J. PhD; McDowell, Cliona MSc**; Elborn, Stuart J. MD*; O'Kane, Cecilia M. PhD*

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Abstract

Objective: To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy.

Background: One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI.

Methods: We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin–creatinine ratio.

Results: Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin–creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P = 0.1).

Conclusions: In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.

© 2014 by Lippincott Williams & Wilkins.

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