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Levosimendan for the prevention of acute organ dysfunction in sepsis

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Title: Levosimendan for the prevention of acute organ dysfunction in sepsis
Authors: Gordon, AC
Perkins, GD
Singer, M
McAuley, DF
Orme, RML
Santhakumaran, S
Mason, AJ
Cross, M
Al-Beidh, F
Best-Lane, J
Brealey, D
Nutt, CL
McNamee, JJ
Reschreiter, H
Breen, A
Liu, KD
Ashby, D
Item Type: Journal Article
Abstract: BACKGROUND Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. METHODS 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. RESULTS 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). CONCLUSIONS 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.)
Issue Date: 5-Oct-2016
Date of Acceptance: 22-Sep-2016
URI: http://hdl.handle.net/10044/1/41182
DOI: https://dx.doi.org/10.1056/NEJMoa1609409
ISSN: 0028-4793
Publisher: Massachusetts Medical Society
Start Page: 1638
End Page: 1648
Journal / Book Title: New England Journal of Medicine
Volume: 375
Copyright Statement: Copyright © 2016 Massachusetts Medical Society. All rights reserved.
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
11/14/08
WSSA_P52845
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
INTERNATIONAL CONSENSUS DEFINITIONS
RANDOMIZED CONTROLLED-TRIAL
SEPTIC SHOCK SEPSIS-3
ACUTE KIDNEY INJURY
HEART-FAILURE
CRITICALLY ILL
CLINICAL-TRIAL
BLOOD-PRESSURE
VASOPRESSIN
NOREPINEPHRINE
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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