Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis
Open accessAbstract
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 .).
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Specialist consultation appears to be associated with improved patient outcomes for a variety of infectious syndromes.
“Specialist consultation appears to be associated with improved patient outcomes for a variety of infectious syndromes (295-300).”
From Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. (2021) · cites this paper as [297]
The Conclusions (p. 2) address levosimendan added to standard treatment for sepsis, not specialist consultation. A search for specialist consultation and infectious-disease consultation found no passage linking consultation to patient outcomes across infectious syndromes; the mention of consulting fees in the Discussion (p. 11) is unrelated. (LLM, conf=0.77)
Experimental — accuracy not yet measuredThe LeoPARDS trial found levosimendan compared with no inotropic agents was associated with lower likelihood of successful weaning from mechanical ventilation and higher risk of supraventricular tachyarrhythmia.
“Data from the LeoPARDS trial (n = 515) showed that levosimendan versus no inotropic agents was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrythmia [373].”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [373]
A meta-analysis of three RCTs found levosimendan compared with no inotropic agents did not impact mortality.
“A meta-analysis of three RCTs (n = 781) showed that levosimendan, compared to no inotropic agents, did not impact mortality (RR 0.87; 95% CI 0.59–1.28).”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [373]
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- Authors
- Gordon, A. C., Perkins, G. D., Singer, M., McAuley, D. F., Orme, R. M. L., Santhakumaran, S., Mason, A. J., Cross, M., Al-Beidh, F., Best-Lane, J., Brealey, D., Nutt, C. L., McNamee, J. J., Reschreiter, H., Breen, A., Liu, K. D., & Ashby, D.
- Affiliations
- Imperial College Healthcare NHS Trust (GB)
- Queen's University Belfast (GB)
- University College Hospital (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-10-27
- Volume
- 375
- Issue
- 17
- Pages
- 1638-1648
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2529283167
- Cited by
- 372
- References
- 42
- Citations by year
- 2026: 23 · 2025: 49 · 2024: 28 · 2023: 26 · 2022: 33 · 2021: 45 · 2020: 24 · 2019: 48 · 2018: 37 · 2017: 50 · 2016: 9
- FWCI
- 44.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (publishedVersion, other-oa)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Intensive Care Foundation
- Tenax Therapeutics
- National Institute for Health and Care Research (NF-SI-0514-10139, NIHR/CS/009/007)
- Imperial College London
- Imperial College Healthcare NHS Trust
- Public Health Agency (COM/4700/12)
- Medical Research Council (MC_G1002460)
- Efficacy and Mechanism Evaluation Programme
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- sepsis, acute organ dysfunction, inotropic agents, SOFA score, 28-day mortality, weaning from mechanical ventilation, supraventricular tachyarrhythmias, intensive care, vasopressors, organ failure prevention, adverse events, cost-effectiveness
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