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An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial

Robert M L’E Orme1, Gavin D Perkins2, Daniel F McAuley3, Kathleen D Liu4, Alexina J Mason5, Andrea Morelli6, Mervyn Singer7, Deborah Ashby5 and Anthony C Gordon8*

Author Affiliations

1 Department of Critical Care, Cheltenham General Hospital, Sandford Road, Cheltenham GL53 7AN, UK

2 Warwick Clinical Trials Unit and Heart of England NHS Foundation Trust, Warwick Medical School, University of Warwick, Gibbet Hill, Coventry CV4 7AL, UK

3 Centre for Infection and Immunity, Queens University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK

4 Divisions of Nephrology and Critical Care Medicine, Departments of Medicine and Anesthesia, University of California, 521 Parnassus Avenue, Box 0532, San Francisco, CA 94143, USA

5 School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK

6 Department of Anaesthesiology and Intensive Care, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy

7 Bloomsbury Institute of Intensive Care, University College London, Gower Street, London WC1E 6BT, UK

8 Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK

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Trials 2014, 15:199  doi:10.1186/1745-6215-15-199

Published: 2 June 2014

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.

Trial registration

Current controlled trials ISRCTN12776039 (19 September 2013)

Keywords:
Levosimendan; Shock; Septic; Multiple Organ Failure; Intensive Care; Critical Care; Randomized Controlled Trial