From the Journals

Levosimendan does not reduce organ dysfunction risk in sepsis


Levosimendan does not reduce the likelihood of severe organ dysfunction in adults with sepsis, nor does it lower the mortality rate, according to research presented at the annual congress of the European Society of Intensive Care Medicine and published in the New England Journal of Medicine.

Levosimendan is a calcium-sensitizing drug with inotropic and vasodilatory properties, which is commonly used to treat decompensated heart failure. “Small studies that have investigated the use of levosimendan in patients with septic shock have shown improvements in hemodynamic variables, microcirculatory flow, and renal and hepatic function, as compared with dobutamine,” wrote Anthony C. Gordon, MD, of Imperial College London and Imperial College Healthcare NHS Trust and his coauthors.

A meta-analysis also supported the use of levosimendan in patients with sepsis, but the authors noted that only 125 patients were included in that analysis (N Engl J Med. 2016 Oct 5. doi: 10.1056/NEJMoa1609409).

In the Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis (LeoPARDS) trial, 516 patients were randomized to 24 hours of a blinded infusion either of levosimendan (.05-0.2 mcg per kilogram of body weight per minute) or placebo in addition to standard care.

Researchers saw no significant difference in the mean daily Sequential Organ Failure Assessment (SOFA) score between the two groups (mean difference, 0.61; 95% confidence interval, −0.07 to 1.29; P = .053). When the SOFA score was analyzed by system, the mean daily cardiovascular score was significantly higher in the levosimendan group, compared with the placebo group, indicating greater dysfunction in that system.

“The cardiovascular SOFA score was higher in the levosimendan group than in the placebo group, which reflects the higher doses of norepinephrine that were required to maintain the mean arterial pressure,” researchers reported.

There was no significant difference in 28-day mortality between the levosimendan and placebo groups (34.5% vs. 30.9%; 95% CI, −4.5 to 11.7; P = .43), and both groups had a similar number of catecholamine-free days. However, among the patients who required ventilation at baseline, those treated with levosimendan were less likely than those given placebo to be successfully weaned from ventilation over the 28-day follow-up.

Patients treated with levosimendan also had a higher incidence of serious adverse events, and supraventricular tachyarrhythmia was significantly more common in the levosimendan group than in the placebo group (3.1% vs. 0.4%; 95% CI, 0.1- 5.3; P = .04).

The two groups showed similar cardiac index, stroke volume, central venous oxygen saturations or pressure, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, and serum creatinine and bilirubin levels.

The authors drew attention to several limitations of the study, including the fact that levosimendan was added to standard care rather than being compared with an alternative inotrope such as dobutamine.

“Less than 10% of the patients in the placebo group received dobutamine, although the rate of use in the placebo group was higher than in the levosimendan group and may explain in part why the cardiac index and stroke volume were not higher in the levosimendan group than in the placebo group,” they wrote.

The study did not include echocardiographic analysis to discover any changes in myocardial function with levosimendan, and there were only a small number of patients with low cardiac index.

“Therefore, this trial cannot provide guidance as to which inotrope is best to use in the management of sepsis if a low cardiac index is present,” the authors said. “The target mean arterial pressure of 65-70 mm Hg, which was recommended in the protocol and reiterated at investigator meetings, was frequently exceeded (as in other trials involving patients with shock), which suggests that the norepinephrine doses that were administered could have been reduced in the two trial groups.”

The study was supported by the Medical Research Council and National Institute for Health Research, United Kingdom, and Tenax Therapeutics. Four authors declared grants, personal fees, advisory board positions, and other funding from the pharmaceutical industry, including one author receiving support from Tenax Therapeutics. No other conflicts of interest were declared.

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