Does levosimenden improve outcomes in patients with sepsis?

What is food to one man is bitter poison to others. – Lucretius.

Gordon et al. Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis. New England Journal of Medicine. 2016 DOI: 10.1056/NEJMoa1609409



Catecholamines remain first-line in treating septic shock, following fluid resuscitation, however high doses cause myocardial injury, peripheral ischaemia and poor outcomes. Levosimendan, a calcium sensitising drug, increases myocardial contractility with minimal increase in oxygen demand. Small studies favour levosimendan vs. dobutamine in haemodynamic variables, renal and hepatic function. A recent 125 patient meta-analysis supports use in sepsis.


Study Aim

To test whether the addition of levosimendan to standard care would reduce the severity of organ dysfunction among patients with septic shock and to assess its safety profile in patients with this condition.



  • Multi-centre, randomised, double blind, placebo controlled trial
  • 34 ICUs in UK (Including Royal Free)
  • Funders/sponsors had no role in study design, analysis or publication
  • Variable block randomisation (4 and 6)
  • Trial specific labelling and packaging of drug – packs identical
  • Patients and clinical and research staff unaware of trial-group assignment throughout trial
  • Patients randomised to receive a levosimendan / placebo on a fixed protocol
  • Other aspects of care as per clinician (surviving sepsis guidelines)


Outcome Measures

  • Primary outcome measure:
    • Mean daily Sequential Organ Failure Assessment (SOFA) score while on ICU, measured from randomisation to max 28 days (the daily score was totalled and divided by length of stay)
  • Secondary Outcome Measures:
    • Individual SOFA components
    • Catecholamine-free days, ventilator-free days
    • Time to wean from mechanical ventilation
    • Proportion of pts with major acute kidney event
    • Mortality rate at 28 days, ICU discharge and hospital discharge
    • Length of stay on ITU
    • Serious adverse effects



2382 patients eligible, 516 underwent randomization. Most excluded due to being outside recruitment window or having treatment limitations in place. The study and placebo groups well matched in demographics, physiological parameters and severity of illness (APACHE II scores)

  • Levosimendan was not associated with less severe organ dysfunction in patients with septic shock
  • Patients receiving levosimendan did, however, have higher heart rates and an increased risk of SVT and underwent mechanical ventilation for longer
  • There was more noradrenaline use in levosimendan group



Study strengths:

  • Clear question to be answered
  • Sample size met, low dropout of data and intention to treat, all patients accounted for
  • Good randomisation
  • Blinded – however side effect profile of levosimendan may have made it apparent that a particular patient was on it
  • Very well matched groups at baseline – taking into account potential confounders such as severity of illness, degree of inotrope use etc.
  • The stats – very reasonable, with limited post hoc analysis. Attempt to correct for severity of illness, age, ICU


Potential weakness:

  • Tests drug vs placebo and not another agent, eg dobutamine
  • Is SOFA scoring the best marker for organ dysfunction?
  • Potential use of ECHO to provide more detailed idea on changes in cardiovascular function
  • Was the predetermined difference in sofa score effect of 0.5 big enough?


Discussion from journal club

This was a well conducted study and results applicable to our practice. In terms of the race of patients recorded, the spread mirrored the UK population, however the results may not be applicable in other countries. Catecholamines are known to consume calcium. As the mechanism of action of levosimendan relies on calcium availability, it may have been beneficial to measure calcium levels.


Summary by Dr Paavan Gorur

A Second Opinion

Find out what others think of this trial over at The Bottom Line

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s