Effects of levosimendan on renal blood flow and glomerular filtration in patients with acute kidney injury after cardiac surgery: a double blind, randomized placebo-controlled study

Abstract

Background: Acute kidney injury (AKI) is a common and serious complication after cardiac surgery, and current strategies aimed at treating AKI have proven ineffective. Levosimendan, an inodilatating agent, has been shown to increase renal blood flow and glomerular filtration rate in uncomplicated postoperative patients and in patients with the cardiorenal syndrome. We hypothesized that levosimendan through its specific effects on renal vasculature, a preferential vasodilating effect on preglomerular resistance vessels, could improve renal function in AKI-patients with who did not have clinical indication for inotropic support.

Methods: In this single-center, double-blind, randomized controlled study, adult patients with postoperative AKI within 2 days after cardiac surgery, who were hemodynamically stable with a central venous oxygen saturation (ScvO₂) ≥ 60% without inotropic support were eligible for inclusion. After randomization, study drug infusions, levosimendan (n = 16) or placebo (n = 13) were given for 5 h. A bolus infusion of levosimendan (12 µg/kg), were given for 30 min followed by 0.1 µg/kg/min for 5 h. Renal blood flow and glomerular filtration rate were measured using infusion clearance of para-aminohippuric acid and a filtration marker, respectively. As a safety issue, norepinephrine was administered to maintain mean arterial pressure between 70-80 mmHg. Intra-group differences were tested by Mann-Whitney U-tests, and a linear mixed model was used to test time and group interaction.

Results: Twenty-nine patients completed the study. At inclusion, the mean serum creatinine was higher in the patients randomized to levosimendan (148 ± 29 vs 127 ± 22 µmol/L, p = 0.030), and the estimated GFR was lower (46 ± 12 vs 57 ± 11 ml/min/1.73 m², p = 0.025). Levosimendan induced a significantly (p = 0.011) more pronounced increase in renal blood flow (15%) compared placebo (3%) and a more pronounced decrease in renal vascular resistance (- 18% vs. - 4%, respectively, p = 0.043). There was a trend for a minor increase in glomerular filtration rate with levosimendan (4.5%, p = 0.079), which did differ significantly from the placebo group (p = 0.440). The mean norepinephrine dose was increased by 82% in the levosimedan group and decreased by 29% in the placebo group (p = 0.012).

Conclusions: In hemodynamically stable patients with AKI after cardiac surgery, levosimendan increases renal blood flow through renal vasodilatation. Trial registration NCT02531724, prospectly registered on 08/20/2015. https://clinicaltrials.gov/ct2/show/NCT02531724?cond=AKI&cntry=SE&age=1&draw=2&rank=1.

Fig. 1

COSORT flow diagram

Fig. 2

Renal blood flow and glomerular filtration rate before (baseline) and after study drug administration (treatment). p Values indicate difference between groups (time × group interaction from linear mixed model) and difference within groups (Wilcoxon signed rank test)