Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

Abstract Abstract• References• Author information Background: Inodilators are routinely used in cardiovascular surgery with cardiopulmonary bypass (CPB). Information regarding safety and tolerability of the novel molecule, levosimendan (LEVO), in newborns is anecdotal; no pharmacokinetic data in this population are available. Methods: This was a phase I, randomized, and blinded study. Neonates undergoing surgical repair for congenital heart defects received stepwise dose increases of milrinone (MR; 0.5–1 μg/kg/min, n = 9) or LEVO (0.1–0.2 μg/kg/min, n = 11) as an i.v. continuous infusion, starting before CPB. Infants had continuous, time-locked, physiological, and near-infrared spectroscopy (NIRS) (cerebral and peripheral) recordings during the first 24 h, and at 48 and 96 h postsurgery. Serial biochemistry and pharmacokinetic studies were performed. Results: During the first 24 h postsurgery, patients showed time-related, group-independent increased cerebral tissue oxygenation and decreased diastolic blood pressure; in addition, group-dependent differences in heart rate and peripheral perfusion were found. Early postsurgery, MR-treated infants showed lower pH, higher glycemia, and higher inotrope score. The groups differed in cerebral NIRS-derived variables from 24 to 96 h. Study drug withdrawal at 96 h was more frequent with LEVO. LEVO intermediate metabolites were detected in plasma at day 14 after surgery. Conclusion: LEVO is well tolerated in critically ill neonates. LEVO may have advantages over MR in terms of the dosing regimen. View full text At a glance Figures View all figures Figure 1: Evolution of the continuous physiological and NIRS variables in the milrinone (black line) and levosimendan (gray line) study groups throughout the first 24 h postsurgery (expressed in min). Mixed linear models show (mean, SEM) (a) a time-related treatment effect on heart rate (beats per min) (P = 0.0213); (b) a time-related, group-independent effect on diastolic blood pressure (mm Hg) (P = 0.0098); (c) a time-dependent increase in the cerebral tissue oxygenation index (%; P = 0.0439); and (d) cerebral intravascular oxygenation (μmol/l; P = 0.0177); (e) a time-dependent decrease in cerebral fractional oxygen extraction (%; P = 0.0311); and (f) group-dependent differences in peripheral intravascular oxygenation (μmol/l; P = 0.0195). NIRS, near infrared spectroscopy. Figure 2: The lines represent the average mean value (left y-axis) of (a) the cerebral tissue oxygenation index (%) and (b) the fractional oxygen extraction (%) in the milrinone (dashed line) and levosimendan (gray line) study groups. Bars (right y-axis) show the number of patients still receiving INDs at the various time points (T1, first 24 h; T2, at 48 h; T3, at 96 h after surgery) in the milrinone (white bar) and levosimendan (gray bar) study groups. IND, inodilator. Figure 3: Evolution of (a) pH, (b) lactate (mmol/l), (c) glycemia (mg/dl), and (d) inotrope score (3) in the milrinone (dashed line) and levosimendan (gray line) study groups from baseline (BL) immediately presurgery, throughout the first 96 h after surgery. *P < 0.05; **P = 0.075. Figure 4: Indicators of plasma concentration. (a) Median (dots) and IQR (vertical whiskers) of levosimendan (gray circles, solid line) and metabolites OR1855 (white circles, solid line) and OR1896 (gray circles, dashed line) plasma concentrations in relation to time. (b) Median (gray circles, solid line) and IQR (vertical whiskers) of milrinone plasma concentration in relation to time. Milrinone elimination phase is marked by an arrow. The horizontal whiskers indicate the IQR time when blood samples were obtained, representing differences in milrinone withdrawal. IQR, interquartile range.