The Effect of Levosimendan Versus Milrinone on the Occurrence Rate of Acute Kidney Injury Following Congenital Heart Surgery in Infants: A Randomized Clinical Trial*

Abstract

Objectives: It has been shown that, in contrast to other inotropic agents, levosimendan improves glomerular filtration rate after adult cardiac surgery. The aim of this study was to investigate the efficacy of levosimendan, compared with milrinone, in preventing acute kidney dysfunction in infants after open-heart surgery with cardiopulmonary bypass. Design: Two-center, double-blinded, prospective, randomized clinical trial. Setting: The study was performed in two tertiary pediatric centers, one in Sweden (Gothenburg) and one in Finland (Helsinki). Patients: Infants between 1 and 12 months old, diagnosed with Tetralogy of Fallot, complete atrioventricular septal defect or nonrestrictive ventricular septal defect, undergoing total corrective cardiac surgery with cardiopulmonary bypass. Interventions: Seventy-two infants were randomized to receive a perioperative infusion of levosimendan (0.1 µg/kg/min) or milrinone (0.4 µg/kg/min). The infusion was initiated at the start of cardiopulmonary bypass and continued for 26 hours. Measurements and Main Results: The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. Secondary outcomes included the following: 1) acute kidney injury according to the serum creatinine criteria of the Kidney Diseases: Improving Global Outcomes; 2) acute kidney injury with serum creatinine corrected for fluid balance; 3) plasma neutrophil gelatinase-associated lipocalin; 4) cystatin C; 5) urea; 6) lactate; 7) hemodynamic variables; 8) use of diuretics in the PICU; 9) need of dialysis; 10) length of ventilator therapy; and 11) length of PICU stays. There was no significant difference in postoperative serum creatinine between the treatment groups over time (p = 0.65). The occurrence rate of acute kidney injury within 48 hours was 46.9% in the levosimendan group and 39.5% in the milrinone group (p = 0.70). There were no significant differences in other secondary outcome variables between the groups. Conclusions: Levosimendan compared with milrinone did not reduce the occurrence rate of acute kidney injury in infants after total corrective heart surgery for atrioventricular septal defect, ventricular septal defect, or Tetralogy of Fallot.

An evidence-based review of the use of vasoactive and inotropic medications in post-operative paediatric patients after cardiac surgery with cardiopulmonary bypass from 2000 to 2020

“…Five studies focused on safety and side effects (Table 3). 11,[19][20][21]25,38,47 Collectively, selected studies reported on 12 medications in 2856 children: 15 studies focused on neonates or infants, and included 969 patients; 12 studies specified a surgical repair or congenital heart defect as part of the study population, including 5 studies that included only Norwood patients. All medications were given between the end of a bypass through the first 72 hours postoperatively.…”

“…Levosimendan is a calcium sensitiser, binding to the cardiac troponin C protein and preventing binding of troponin I for sustained cardiac myocyte contraction. [64][65][66] We examined 13 studies on 867 patients focused on the administration of levosimendan 10,16,[28][29][30][32][33][34][36][37][38] : 7 studies were retrospective, and 6 were prospective randomised controlled trials. The dosing range was 0.05-0.2 μg/kg/minute for 48-72 hours with or without a loading dose of 12-15 μg/kg.…”

“…32 However, 6 studies compared levosimendan to milrinone and showed mixed data regarding superiority. [33][34][35][36][37][38] Three studies were randomised controlled trials and 3 were retrospective for a total of 236 patients. There were no consistent differences in inotropic requirements or rates of low cardiac output syndrome between the levosimendan group and milrinone groups, and there was mixed data comparing rates of renal failure with levosimendan versus milrinone.…”

“…There were no consistent differences in inotropic requirements or rates of low cardiac output syndrome between the levosimendan group and milrinone groups, and there was mixed data comparing rates of renal failure with levosimendan versus milrinone. 19,34,37,38 Nevertheless, five out of the six studies suggested that levosimendan is as safe and effective as milrinone. These studies had wide age variance, as well as variation in cardiac defects.…”

A Tale of 2 Inodilators: Much Ado About Nothing?

“…The study by Thorlacius et al was a secondary analysis of the authors' previously published study evaluating effect of milrinone versus levosimendan on the occurrence rate of acute kidney injury after congenital heart surgery. 6 The initial study design was a randomized, prospective, double-blinded clinical drug trial based at 2 pediatric tertiary university hospitals. A total of 72 patients were enrolled, with ages ranging between 1 and 12 months.…”