Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial

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Title: Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial
Authors: Gordon, AC
Santhakumaran, S
Al-Beidh, F
Orme, RML
Perkins, GD
Singer, M
McAuley, DF
Mason, AJ
Ward, J
O'Dea, K
Felton, T
Cross, M
Best-Lane, J
Lexow, J
Campbell, A
Ashby, D
Item Type: Journal Article
Abstract: Background: In septic shock, cardiovascular resuscitation using catecholamine vasopressors and inotropes is standard therapy but catecholamines have important side-effects. Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may have a role in sepsis. Objectives: In adult septic shock 1. Does levosimendan reduce the incidence and severity of acute organ dysfunction ? 2. What is the effect of levosimendan on individual organ function ? 3. What is the safety profile of levosimendan? Design: Multi-centre, randomised, double-blind, parallel-group, placebo-controlled study. Setting: UK Intensive Care Units Participants: Adult patients who have sepsis and cardiovascular failure requiring vasopressors to maintain blood pressure despite adequate fluid resuscitation. Interventions: Levosimendan 0.05 to 0.2 µg/kg/min vs. placebo for 24 hour, in addition to standard care, within 24 hours of meeting inclusion criteria. Primary outcome measure: Mean SOFA score on ICU after randomisation to a maximum of 28 days. Secondary outcome measures: Time to extubation Survival upto 6 months Serious Adverse Events Results: 2382 patients were screened at 34 centres, of whom 516 were randomised to treatment, 259 allocated to levosimendan and 257 to placebo. Baseline characteristics were well balanced across treatment arms. There was no significant difference in mean (±SD) SOFA score in the levosimendan group (6.7 ± 4.0) compared with placebo (6.1 ± 3.9); (mean difference 0.61, 95%CI -0.07 to 1.29). 28-day mortality was 34.5% versus 30.9% in the levosimendan and placebo groups respectively (absolute difference 3.6%, 95%CI -4.5 to 11.7). Patients in the levosimendan group were less likely to be successfully extubated over 28 days than the placebo group (hazard ratio 0.77, 95%CI 0.60 to 0.97). More patients in the levosimendan group had supraventricular tachyarrhythmias, (3.1% versus 0.4% absolute difference 2.7%, 95%CI 0.1 to 5.3), but there was no overall difference in serious adverse events. Conclusions: In the population of septic shock patients randomised to treatment in this study, addition of levosimendan to standard medical care did not reduce organ dysfunction or mortality. Levosimendan was associated with a reduced likelihood of successful extubation and an increased risk of supraventricular tachyarrhythmias. Limitations: This was a trial of levosimendan added to standard care rather than a comparison against an alternative inotrope, such as dobutamine. There were no echocardiographic analyses performed to provide detailed information about changes in myocardial function. Therefore this trial cannot provide guidance as to which inotrope (if any) is best to use in the management of sepsis if a very low cardiac index is present. Future work: Levosimendan could be compared against dobutamine and placebo in patients with a very low cardiac output in sepsis to test which, if any, inotrope should be used in this select group.
Date of Acceptance: 13-Jun-2018
URI: http://hdl.handle.net/10044/1/61458
ISSN: 2050-4365
Publisher: NIHR Health Technology Assessment Programme
Journal / Book Title: Efficacy and Mechanism Evaluation
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: National Institute for Health Research
National Institute for Health Research
National Institute for Health Research
Tenax Therapeutics Inc
Funder's Grant Number: NIHR/CS/009/007
NIHR Fellowship
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Division of Surgery
Faculty of Medicine
Epidemiology, Public Health and Primary Care

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