Orme, Robert M., Perkins, Gavin D., McAuley, Daniel F., Liu, Kathleen D., Mason, Alexina J., Morelli, Andrea, Singer, Mervyn, Ashby, Deborah and Gordon, Anthony C. (2014) An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan dysfunction in Sepsis (LeoPARDS ) : protocol for a randomized controlled trial. Trials, Volume 15 (Number 1). Article number 199. doi:10.1186/1745-6215-15-199 ISSN 1745-6215.

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Abstract

Background
Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.

Methods/Design
This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 μg.kg-1.min-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients will be recruited from approximately 25 ICUs in the United Kingdom.

Discussion
This trial will test the efficacy of levosimendan to reduce acute organ dysfunction in adult patients who have septic shock and evaluate its biological mechanisms of action.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Septicemia -- Treatment, Critical care medicine
Journal or Publication Title:	Trials
Publisher:	Biomed Central
ISSN:	1745-6215
Official Date:	2 June 2014
Dates:	Date Event 2 June 2014 Published 16 May 2014 Accepted 11 January 2014 Submitted
Volume:	Volume 15
Number:	Number 1
Article Number:	Article number 199
DOI:	10.1186/1745-6215-15-199
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	28 December 2015
Date of first compliant Open Access:	28 December 2015
Funder:	Medical Research Council (Great Britain) (MRC), National Institute for Health Research (Great Britain) (NIHR), Intensive Care Society (Great Britain) (ICS)

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