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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.

Orme RM, Perkins GD, McAuley DF, Liu KD, Mason AJ, Morelli A, Singer M, Ashby D, Gordon AC - Trials (2014)

Bottom Line: In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. anthony.gordon@imperial.ac.uk.

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).

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LeoPARDS proposed trial flow diagram. CCMDS, Critical Care Minimum Data Set; ICU, Intensive Care Unit; SOFA, Serial Organ Failure Assessment.
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Figure 1: LeoPARDS proposed trial flow diagram. CCMDS, Critical Care Minimum Data Set; ICU, Intensive Care Unit; SOFA, Serial Organ Failure Assessment.

Mentions: Our sample size of 500 patients will provide more than 90% power to detect a 0.5 point difference in the mean SOFA score assuming a SD of 1.5 [3]. In this previous validation study a 1 point rise in the mean SOFA score was associated with a significant mortality increase (mean SOFA 2.1 to 3.0 = 20%, 3.1 to 4.0 = 36.1% and 4.1 to 5.0 = 73.1% mortality; odds ratio 3.06, 95% CI 2.36 to 3.97). We will recruit an additional 3% (16 patients) to account for potential loss to follow-up and withdrawal of consent, as seen in previous UK ICU trials [37], giving a total of 516 patients with 258 in each arm (Figure 1).


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

Orme RM, Perkins GD, McAuley DF, Liu KD, Mason AJ, Morelli A, Singer M, Ashby D, Gordon AC - Trials (2014)

LeoPARDS proposed trial flow diagram. CCMDS, Critical Care Minimum Data Set; ICU, Intensive Care Unit; SOFA, Serial Organ Failure Assessment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061524&req=5

Figure 1: LeoPARDS proposed trial flow diagram. CCMDS, Critical Care Minimum Data Set; ICU, Intensive Care Unit; SOFA, Serial Organ Failure Assessment.
Mentions: Our sample size of 500 patients will provide more than 90% power to detect a 0.5 point difference in the mean SOFA score assuming a SD of 1.5 [3]. In this previous validation study a 1 point rise in the mean SOFA score was associated with a significant mortality increase (mean SOFA 2.1 to 3.0 = 20%, 3.1 to 4.0 = 36.1% and 4.1 to 5.0 = 73.1% mortality; odds ratio 3.06, 95% CI 2.36 to 3.97). We will recruit an additional 3% (16 patients) to account for potential loss to follow-up and withdrawal of consent, as seen in previous UK ICU trials [37], giving a total of 516 patients with 258 in each arm (Figure 1).

Bottom Line: In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. anthony.gordon@imperial.ac.uk.

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).

Show MeSH
Related in: MedlinePlus