Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery

Abstract

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.

Cardiovascular Drug Therapy for Human Newborn: Review of Pharmacodynamic Data

“…However, the peripheral oxygenation differed between both groups along this time period, showing an increase in the levosimendan group and a decrease in the milrinone group. In the same study, there were no significant differences between groups regarding serial echocardiography parameters; however lactate level was increased in the milrinone group [63].…”

“…Cerebral and peripheral tissue oxygenation measured by NIRS have been found to be increased with levosimendan in a group of newborns undergoing corrective surgery for heart disease [63].…”

Peripheral Muscle Near-Infrared Spectroscopy in Neonates: Ready for Clinical Use? A Systematic Qualitative Review of the Literature

“…Twenty-one studies were identified to use peripheral muscle NIRS measurements as a single method [1,3,6,7,8,9,10,11,12,13,14,15,16,17,18,19,23,24,25,27,28] (table 1), 17 studies combined cerebral and peripheral muscle NIRS measurements [20,21,22,29,30,31,32,33,34,35,36,37,38,39,40,41,42] (table 2) and 1 study used multi-site NIRS measurements [43] (table 2) in human neonates. Two randomized studies were identified [12,36]. Two additional publications were included because they provided important general information about peripheral NIRS measurements [44,45].…”

“…In a phase I, randomized study, Pellicer et al [36] investigated the haemodynamic effects of the routinely used milrinone, a selective phosphodiesterase III inhibitor, that has inotropic and lusitropic effects on the myocardium and a relaxing effect on the vascular muscle, and the novel molecule levosimendan in neonates undergoing cardiovascular surgery using NIRS measurements to assess changes in cerebral and peripheral perfusion and oxygenation. The study provided data on the early intraoperative use of both inodilators, but also emphasized the persistent haemodynamic effects of levosimendan after the end of drug infusion.…”

A Specific and Sensitive HPLC–MS/MS Micromethod for Milrinone Plasma Levels Determination After Inhalation in Cardiac Patients

“…16 Furthermore, milrinone was recently tested in the context of postsurgical support for neonates after cardiovascular surgery. 17 Milrinone now seems like a pediatric treatment option that would greatly benefit from pharmacokinetic characterization and dose optimization. For doing so, a low plasma volume analytical method and a higher degree of sensitivity are required in particular for inhaled milrinone studies.…”