Gordon, Anthony C., Perkins, Gavin D., Singer, Mervyn, McAuley, Daniel F., Orme, Robert M.L., Santhakumaran, Shalini, Mason, Alexina J., Cross, Mary, Al-Beidh, Farah, Best-Lane, Janis, Brealey, David, Nutt, Christopher L., McNamee, James J., Reschreiter, Henrik, Breen, Andrew, Liu, Kathleen D. and Ashby, Deborah (2016) Levosimendan for the prevention of acute organ dysfunction in sepsis. New England Journal Of Medicine , 375 (17). pp. 1638-1648. doi:10.1056/NEJMoa1609409 ISSN 0028-4793.

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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.)

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Septicemia -- Treatment , Clinical trials
Journal or Publication Title:	New England Journal Of Medicine
Publisher:	Massachusetts Medical Society
ISSN:	0028-4793
Official Date:	27 October 2016
Dates:	Date Event 27 October 2016 Published 5 October 2016 Available
Volume:	375
Number:	17
Page Range:	pp. 1638-1648
DOI:	10.1056/NEJMoa1609409
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Date of first compliant deposit:	21 March 2017
Date of first compliant Open Access:	5 April 2017
Funder:	National Institute for Health Research (Great Britain) (NIHR), Tenax Therapeutics (Firm)

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