Levosimendan to prevent acute organ dysfunction in sepsis: the LeoPARDS RCT
Authors: Gordon Anthony C , Santhakumaran Shalini , Al-Beidh Farah , Orme Robert ML , Perkins Gavin D , Singer Mervyn , McAuley Daniel F , Mason Alexina J , Ward Josie K , O’Dea Kieran P , Felton Timothy , Cross Mary , Best-Lane Janis , Lexow Jonas , Campbell Ashley , Ashby Deborah 
Published: November 2018

BackgroundIn septic shock, cardiovascular resuscitation using catecholamine vasopressors and inotropes is standard therapy, but catecholamines have important side effects. Levosimendan (Simdax®; Orion Pharma, Newbury, UK) is a calcium-sensitising drug with inotropic and other properties that may have a role in sepsis.ObjectivesTo determine, in adult septic shock, whether or not levosimendan reduces the incidence and severity of acute organ dysfunction, the effect of levosimendan on individual organ function and the safety profile of levosimendan.DesignMulticentre, randomised, double-blind, parallel-group, placebo-controlled study.SettingUK intensive care units.ParticipantsAdult patients with sepsis and cardiovascular failure requiring vasopressors to maintain blood pressure despite adequate fluid resuscitation.InterventionLevosimendan, at a dosage of 0.05–0.2 µg/kg/minute, compared with placebo for 24 hours, in addition to standard care, within 24 hours of meeting inclusion criteria.Main outcome measureThe primary outcome was mean Sequential Organ Failure Assessment (SOFA) score on the intensive care unit after randomisation to a maximum of 28 days. Secondary outcomes were time to extubation, survival up to 6 months and serious adverse events.ResultsIn total, 2382 patients were screened at 34 centres, of whom 516 were randomised to treatment, 259 to levosimendan and 257 to placebo. Baseline characteristics were well balanced across treatment arms. There was no significant difference in mean ± standard deviation (SD) SOFA score between the levosimendan group (6.7, SD 4.0) and the placebo group (6.1, SD 3.9) [mean difference 0.61, 95% confidence interval (CI) –0.07 to 1.29]. The 28-day mortality rate was 34.5% and 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 patients in 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% vs. 0.4%; absolute difference 2.7%, 95% CI 0.1% to 5.3%), but there was no overall difference in serious adverse events.ConclusionsIn the population of septic shock patients randomised to treatment in this study, the 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.LimitationsThis was a trial of levosimendan added to standard care rather than a comparison against an alternative inotrope such as dobutamine. No echocardiographic analyses were 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 workLevosimendan 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.Trial registrationCurrent Controlled Trials ISRCTN12776039.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. Study drugs were provided by Orion Pharma and additional research funds were provided by Tenax Therapeutics. The study was supported by the NIHR Biomedical Research Centre based at Imperial College, London, and the UK Intensive Care Foundation.