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N Engl J Med. 2016 Oct 27;375(17):1638-1648. doi: 10.1056/NEJMoa1609409. Epub 2016 Oct 5.

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis.

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From the Section of Anaesthetics, Pain Medicine and Intensive Care Medicine, the Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare NHS Trust (A.C.G., F.A.-B., J.B.-L.), Bloomsbury Institute of Intensive Care Medicine, the Division of Medicine, University College London (M.S.), Imperial Clinical Trials Unit Imperial College London (S.S., M.C., F.A.-B., J.B.-L., D.A.), the Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine (A.J.M.), and the Division of Critical Care, University College London Hospitals (D.B.), London, Warwick Clinical Trials Unit, University of Warwick and Heart of England NHS Foundation Trust, Coventry (G.D.P.), the Centre for Experimental Medicine, Queen's University of Belfast (D.F.M., J.J.M.), and the Regional Intensive Care Unit, the Royal Hospitals (D.F.M., J.J.M.), Belfast, the Department of Critical Care, Gloucestershire Hospitals NHS Foundation Trust, Cheltenham (R.M.L.O.), Intensive Care Unit, Antrim Area Hospital, Antrim (C.L.N.), Intensive Care Unit, Poole Hospital NHS Foundation Trust, Poole (H.R.), and Intensive Care Unit, Leeds Teaching Hospitals NHS Trust, Leeds (A.B.) - all in the United Kingdom; and the Department of Medicine, University of California at San Francisco, San Francisco (K.D.L.).



Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis.


We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events.


The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], -0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, -4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04).


The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039 .).

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