1. No significant difference was observed in 28-day mean SOFA score or overall mortality in patients who received levosimendan vs. controls.
2. A significant increase in successful weaning from mechanical ventilation was observed in controls vs. patients who received levosimendan.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Septic shock is a state of life threatening end-organ damage due to severe systemic hypotension and low cardiac output. While catecholamines are often among the first-line pharmacologic agents in the treatment of septic shock, they are not without significant side effect profiles in such unstable patients. For this reason, the calcium sensitizer levosimendan has been investigated for the treatment of septic shock due its action as a positive cardiac inotrope that minimally increases myocardial oxygen demand.
The Levosimendan for the prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS) trial, was a double-blind, randomized clinical trial to test the effects of addition of levosimendan to standard care for septic shock. The primary trial outcome was mean 28-day (or sooner) Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes included 28-day overall mortality and time to weaning of mechanical ventilation. For the primary outcome, a nonsignificant difference was observed between the levosimendan and control groups. For the mentioned secondary outcomes, a nonsignificant difference was observed between the groups in overall mortality and a significant difference was observed in ventilator weaning in favor of the control group. This study draws strength from thorough analyses of the varying primary and secondary outcomes, such as reporting of individual component SOFA scores for five organ systems and of survival and toxicity outcomes at differing points in the hospital courses. The generalizability of the study appears to be limited by its use of indistinct definitions of standard therapy for septic shock.
Relevant Reading: Levosimendan: current data, clinical use and future development
In-Depth [randomized controlled trial]: Patients in this study were randomized in a 1:1 ratio to receive either one 24-hour infusion of levosimendan (n = 259) or placebo (n = 257). The mean difference in the primary outcome, 28-day SOFA score, between the levosimendan group vs. the control group was 0.61 (95%CI −0.07 to 1.29; p = 0.053). All secondary outcomes demonstrated nonsignificant between group differences with the only exceptions being supraventricular tachyarrhythmia, 3.1% in the levosimendan group vs 0.4% in the placebo group, (absolute difference 2.7%; 95%CI 0.1 to 5.3, p = 0.04) and successful weaning of mechanical ventilation by 28 days in favor of the control group (HR 0.77; 95%CI 0.60 to 0.97; p = 0.03). Notable nonsignificant different secondary outcomes included overall mortality at 28 days of 34.5% in the levosimendan group vs. 30.9% in the placebo group (absolute difference 3.6%; 95%CI −4.5 to 11.7; p = 0.43).
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