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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*

doi: 10.1097/SLA.0b013e31829d686b
Randomized Controlled Trials

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.

Supplemental Digital Content is Available in the Text.Acute lung injury and subclinical systemic and pulmonary inflammation are common postesophagectomy. Simvastatin pretreatment reduced systemic and pulmonary inflammation as well as systemic and pulmonary epithelial injury and endothelial dysfunction.

*Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University of Belfast, Belfast, Ireland

Department of Anaesthesia, Royal Victoria Hospital, Belfast, Ireland

Department of Cardio-Thoracic Surgery, Royal Victoria Hospital, Belfast, Ireland

§Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland

Cardiovascular Research Institute, University of California, San Francisco, CA

National Heart and Lung Institute, Royal Brompton Hospital, London; and

**Clinicial Research Support Centre, Royal Hospitals, Belfast, UK.

Reprints: Cecilia M. O'Kane, PhD, Room 1.14, Health Sciences Building, 97 Lisburn Road, Belfast BT9 7BL. E-mail:

Supported by the HSC R&D Division of the Public Health Agency. M.J.G. was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. C.M.O'K. was funded by a DH/NI HSC R&D Clinician Scientist Fellowship.

Clinical trial registered with (ISRCTN56543987), ethics committee (07/NIR02/83), and MHRA (EudraCT number: 2007−002454−37).

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Disclosure: The authors declare no conflicts of interest.

© 2014 by Lippincott Williams & Wilkins.