There has been a lot of discussion regarding the LEOPARDS trial on FOAMed recently. Particularly after the ESICM meeting in Milan.
The drug Levosimendan was thought to be of some hope in the treatment of sepsis…to better current Vaso/Inotherapy we currently use (starving coronary blood flow, pushing the heart too hard and causing horrendous peripheral ischaemia etc etc).
It works as a calcium-sensitizing drug producing inotropic and vasodilator effects. It has been used mainly to treat decompensated heart failure. It causes increased myocardial contraction with a minimal increase in oxygen demand, and does not impair diastolic relaxation. Small studies demonstrated improvements in hemodynamic variables, microcirculatory flow, renal and hepatic function as compared with dobutamine. It may also have anti-inflammatory, anti oxidative and anti-apoptotic effects. As well as all of this, it may protect from ischemia and reperfusion injury. A recent meta-analysis supported the use of levosimendan in patients with sepsis, but only 125 patients in total had been treated. So sounds good….doesn’t it?!
What did they do…
Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis Trial
Intervention arm: Intravenous infusion of levosimendan 0.05 to 0.20 μg/kg/min for 24 hours in addition to standard care (clinician discretion to start only when ideal resuscitation status with IV fluids to obtain MAP 65-70mmHg / CVP>8 or >12 ventilated / peripheral perfusion optimal on clinical examination; other measures of cardiac output optimised). The study drug was commenced at 0.1 µg/kg/min, then increased after 2-4 hours to 0.2 µg/kg/min for the remaining 20-22 hours (maximum 24 hour infusion). The study drug was not be started until the treating physician was confident that adequate fluid resuscitation has been achieved and the patient has reached their target mean arterial pressure (suggested target 65-70 mmHg and the aforementioned other parameters above)
Placebo arm: Standard care and the placebo infusion for the same time.
Dobutamine was recommended if clinically indicated (e.g for low cardiac output state after fluid resuscitation), with lowering of the dose once adequate oxygen delivery had been achieved
What did they find…
Mean SOFA Score – No significant difference 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)
Death at 28 days, at ICU discharge and at hospital discharge – no statistical difference between patients in the levosimendan and placebo group
28 day mortality – 34.5% vs 30.9% P=0.43
Mortality at ICU discharge – 32.2% vs 29.6% P=0.59
Mortality at hospital discharge – 37.6% vs 32.8% P=0.3
CVS instability – 13.5% in the levosimendan group vs 7.7% in the placebo group; which led to cessation of the drug. More SVT’s in the LVS group 3.1% vs 0.4%; P=0.04
MAP lower – in the levosimendan group in the first 24 hours
More Norad – given to the rate and duration of norepinephrine infusion were higher on the levosimendan group
Higher heart rate – in LVS group in 1st 4 days
Weaning delay – longer time to extubation in the LVS group Vs placebo.
No difference in:
median number of catecholamine free days
median number of ventilation free days
incidence & duration of renal failure
median length of ICU and hospital stay
Any life threatening arrhythmias, myocardial infarction or acute coronary syndrome
Were there any glitches to this study…?
No bedside echo’s performed, so no one directly looked at filling or CVS dynamics.
Target MAP’s were frequently exceeded, therefore clinicians drifted outside the recommended study targets.
SOFA scores are not a direct mortality definer. They are an indicator. Averaged over time too, means that other cofounding variables were kicked out here somewhat.
So what then….??
Adding in 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!
To be honest, we are continually looking for miracle drugs in sepsis…we can’t find them despite desperately trying (à la activated Protein C)!! We are currently undertaking a similar trial of an angiotensin II analogue on our unit (ATHOS). See pic below!! We await the results in due course. I suspect, we will see much the same thing here too.
I won’t be using levosimendan on my septic patients. Why face the potential for even worse haemodynamics when things are bad enough for these patients? The fight against sepsis goes on!!!