Impact of levosimendan on brain injury patterns in a lamb model of infant cardiopulmonary bypass

Abstract

Background:The effects of levosimendan (Levo) on injury patterns in the immature brain following cardiopulmonary bypass (CPB) are unknown. Methods: Eighteen 3-to 4-wk-old anesthetized lambs, instrumented with vascular catheters and aortic and right carotid artery flow probes, were allocated to non-CPB, CPB, or CPB+Levo groups (each n = 6). After 120 min CPB with 90 min aortic cross-clamp, CPB animals received dopamine, and CPB+Levo animals both dopamine and Levo, for 4 h. All lambs then underwent brain magnetic resonance imaging, followed by postmortem brain perfusion fixation for immunohistochemical studies. results: In CPB lambs, aortic (P < 0.05) and carotid artery (P < 0.01) blood flows fell by 29 and 30%, respectively, between 2 and 4 h after cross-clamp removal but were unchanged in the CPB+Levo group. No brain injury was detectable with magnetic resonance imaging in either CPB or CPB+Levo lambs. However, on immunohistochemical analysis, white matter astrocyte density of both groups was higher than in non-CPB lambs (P < 0.05), while white matter microglial density was higher (P < 0.05), but markers of cortical oxidative stress were less prevalent in CPB+Levo than CPB lambs. conclusion: While Levo prevented early postoperative falls in cardiac output and carotid artery blood flow in a lamb model of infant CPB, this was associated with heterogeneous neuroglial activation and manifestation of markers of oxidative stress. n eurodevelopmental impairment affects up to one half of all survivors of infant heart surgery, with the spectrum ranging from gross and fine motor deficits, visuospatial difficulties, and impaired cognition to delay in speech and language development (1-5). The mechanisms contributing to brain injury in infants with congenital heart disease are complex and multifactorial, with no consistent improvement in neurodevelopmental outcomes achieved despite major advances in pediatric cardiac surgery and survival. A recent report from the Pediatric Heart Network and the National Heart, Lung, and Blood Institute working group reaffirmed the importance of trials aimed at evaluating novel therapies to address this problem (6).Younger infants undergoing surgery for congenital heart disease are most susceptible to developing brain injury (7,8).The perioperative interval represents a high-risk period with often extended duration of cardiopulmonary bypass (CPB) at the time of the first surgical procedure, as well as significant circulatory disturbance postoperatively. The avoidance of a low cardiac output (CO) state, which can complicate the postoperative course of a proportion of infants after cardiac surgery and which may contribute to later impairment, is a major focus of postoperative care after infant heart surgery. The PRIMACORP study demonstrated the efficacy of intravenous milrinone in preventing this phenomenon in a cohort of children undergoing intracardiac repairs (9). Our laboratory subsequently demonstrated that the inodilator levosimendan (Levo) (Simdax, Abbott, Botany, Australia) was at leas...

Levosimendan alone and in combination with valsartan prevents stroke in Dahl salt-sensitive rats

“…Moreover, a recent report showed that levosimendan was beneficial in a model of injury to the immature brain following cardiopulmonary bypass (Namachivayam et al, 2014). Finally, Varvarousi et al (2014) described positive effects of levosimendan in post-cardiac arrest brain injury, and Bleilevens et al (2014) showed that levosimendan treatment significantly reduces cerebral infarct size in the cortex in a rat model.…”

Utilisation du levosimendan chez l’enfant

“…Plusieurs travaux se sont intéressés aux propriétés neuroprotectrices du levosimendan. Chez des agneaux ayant subit un clampage aortique de 90 minutes sous CEC, le levosimendan, en augmentant le débit dans les artères carotides, était responsable d'une baisse significative des marqueurs de stress oxydatif dans le cerveau, confirmant ainsi son potentiel neuroprotecteur dans le cadre d'une chirurgie cardiaque [59]. Une étude récente, réalisée chez le rat, a donné des résultats spectaculaires et encourageants pour le traitement des lésions cérébrales ischémiques.…”

Safety of Intracoronary Human Cord Blood Stem Cells in a Lamb Model of Infant Cardiopulmonary Bypass

“…Anesthesia, surgical preparation, cardiovascular instrumentation, and physiological measurements were performed as detailed in the Appendix and according to our previous work [5,10,11].…”

“…The infant CPB circuit details are presented in the Appendix, as previously reported [11]. After CPB was instituted, the ascending aorta was cross-clamped, and induction blood cardioplegia was infused over 3 minutes through a cannula inserted proximal to the cross-clamp to arrest the heart.…”