Septic shock is a life-threatening condition resulting from serious infection.
Adding levosimendan to the usual care of adults with septic shock did not reduce the risk of death up to 28 days, nor the degree of damage to essential body organs. It probably also increased patients’ risk of abnormally fast heart rate and increased the time they needed mechanical ventilation.
This large NIHR-supported trial included adults in UK intensive care units. It is the largest to date and presents the best evidence currently available on use of levosimendan in this group. Early smaller studies had shown promising effects on markers of heart function and blood supply in patients with septic shock.
Levosimendan is licensed in several countries to treat heart failure, but does not currently have approval from the US Food and Drug Administration.
Why was this study needed?
There are 150,000 cases of severe sepsis in the UK every year, with 44,000 deaths. Mortality is very high, 30 to 40% even with the best available treatment.
Severe infections can lead to septic shock with failure of the heart, kidneys and other essential body systems. Intensive care is directed at supporting these systems while the infection is brought under control.
Drugs similar to adrenaline are commonly used to increase the power of the heart and to improve blood flow around the body. Levosimendan works in slightly different ways to improve heart function and also relaxes blood vessels to improve the circulation.
Smaller studies in severe sepsis have shown that levosimendan improves measurements of the circulation, kidney and liver function. These studies were not large enough to find whether important outcomes such as survival or kidney failure were improved.
There was a need for a larger study to determine whether levosimendan has a place in the management of adults with septic shock.
What did this study do?
This study recruited 516 adult patients from 34 intensive care units in the UK who had septic shock and been treated with vasopressors for at least four hours previously. These criteria may mean that the study included patients who were less severely ill than in some of the earlier studies. Adults were randomized to receive levosimendan or placebo in addition to usual intensive care management by the local clinicians, according to the “Surviving Sepsis Campaign” guidelines. The trial was double-blind, with neither patients nor assessors aware of treatment given.
The main outcome was the daily change in a composite organ failure score (SOFA: Sequential Organ Failure Assessment) over the subsequent stay in intensive care up to a maximum of 28 days. The score has a top score of 20. Other outcomes included 28-day mortality, kidney function, time to weaning from mechanical ventilation, and adverse events.
What did it find?
- There was no difference in mean SOFA score between the levosimendan and placebo groups (6.68 vs. 6.06; mean difference, 0.61; 95% confidence interval [CI] −0.07 to 1.29).
- There was no difference in mortality at 28 days, which was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference 3.6%; 95% CI −4.5 to 11.7).
- Levosimendan did not reduce the number of acute kidney events, 57.4% in the levosimendan group and 54.3% in the placebo group (absolute difference 3.1%, 95% CI -5.5 to 11.6).
- Successful weaning from mechanical ventilation was less likely in the levosimendan group over the period of 28 days (hazard ratio 0.77, 95% CI 0.60 to 0.97). Differences between the groups before inclusion in the study may have accounted for this.
- More patients in the levosimendan group had abnormal fast heart rhythms (3.1% vs. 0.4%; absolute difference 2.7 percentage points, 95% CI 0.1 to 5.3). Again, there were differences between the groups before inclusion in the study which may have accounted for this.
What does current guidance say on this issue?
There is no current NICE guidance on the use of levosimendan in acute sepsis. It was evaluated in 2003 but not recommended as it was not marketed in the UK at that time.
The current Society of Critical Care Medicine’s Surviving Sepsis Campaign guidelines do not include the use of levosimendan.
Levosimendan has marketing authorisation in a large number of countries, including the UK, but does not currently have US FDA approval.
What are the implications?
Levosimendan did not reduce mortality or major organ failure in this large well conducted study. On this basis, levosimendan cannot be recommended in the usual management of patients with septic shock.
There were more fast heart rhythms and mechanical ventilation was longer in those who received the drug, but some caution is needed in interpretation as there were differences between the study groups which could explain these findings.
Earlier smaller studies showed potential improvements in measurements of kidney, liver and lung function but this larger study does not show improved outcomes in organ function or mortality.
Citation and Funding
Gordon AC, Perkins GD, Singer M, et al. Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med. 2016;375:1638-1648.
This project was funded by the National Institute for Health Research / Medical Research Council Efficacy and Mechanism Evaluation Programme (project number 11/14/08) and by Tenax Therapeutics, Inc.
The National Institute for Health Research also provided funding through a fellowship and the NIHR Comprehensive Biomedical Research Centre based at Imperial College London.
The U.K. Intensive Care Foundation provided general research support.
Morelli A, De Castro S, Teboul J-L, et al. Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med. 2005;31(5):638-44.
Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-10.
Zangrillo A, Putzu A, Monaco F, et al. Levosimendan reduces mortality in patients with severe sepsis and septic shock: a meta-analysis of randomized trials. J Crit Care. 2015;30(5): 908-13.
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