Differential Hemodynamic Effects of Levosimendan in a Porcine Model of Neonatal Hypoxia-Reoxygenation

Abstract

Background: Neonatal asphyxia can be complicated by myocardial dysfunction with secondary alterations in pulmonary and regional hemodynamics. Levosimendan is a calcium-sensitizing inotrope that may support cardiac output, but little is known regarding its differential hemodynamic effects in asphyxiated neonates. Methods: Mixed breed piglets (1–4 days old, weight 1.6–2.3 kg) were acutely instrumented. Normocapnic alveolar hypoxia (10–15% oxygen) was induced for 2 h, followed by reoxygenation with 100% (1 h) and then 21% oxygen (3 h). At 2 h of reoxygenation, after volume loading (Ringer’s lactate 10 ml/kg), either levosimendan (0.1 or 0.2 µg/kg/min) or D₅W (placebo) was infused for 2 h in a blinded, block-randomized fashion (n = 7–8/group). The systemic, pulmonary and regional (carotid, superior mesenteric and renal) hemodynamics were compared. Results: At 0.1 and 0.2 µg/kg/min, levosimendan significantly increased cardiac output (121 and 123% of pretreatment, respectively) and heart rate, and decreased systemic vascular resistance without causing hypotension. Pulmonary arterial pressure and estimated pulmonary vascular resistance were significantly increased from pretreatment baseline in 0.1 but not 0.2 µg/kg/min levosimendan. Levosimendan infusion had no effects on regional hemodynamics. Myocardial efficiency but not oxygen consumption increased with 0.1 µg/kg/min levosimendan without significant effects on plasma troponin and myocardial lactate levels. Conclusions: In newborn piglets following hypoxia-reoxygenation injury, levosimendan improves cardiac output but has no marked effects in carotid, superior mesenteric and renal perfusion. It appears that various doses of levosimendan increase the cardiac output through different mechanisms. Further investigations are needed to examine the effectiveness of levosimendan as a cardiovascular supportive therapy either alone or in conjunction with other inotropes in asphyxiated neonates.

Utilisation du levosimendan chez l’enfant

“…Ainsi, le levosimendan semble extrêmement intéressant en cas d'hypertension artérielle pulmonaire persistante du nouveau-né responsable d'insuffisance cardiaque sévère [49]. Sur un modèle porcin d'hypoxie-réoxygénation néonatale (deux heures de fraction inspirée en oxygène (FiO 2 ) entre 10 et 15 %, suivies d'une heure de FiO 2 à 21 %), une dose de 0,2 mg/kg/min permettait une amélioration significative de la fonction cardiaque sans hypotension systémique franche [50].…”

Common Hemodynamic Problems in the Neonate

“…A small observational study in term infants showed a good response to norepinephrine [19] . Other agents such as milrinone [20] and levosimendan [21] have been suggested, and some animal models do show possible pulmonary vasodilatation with milrinone [22] , but there is no clinical research data to support their use.…”

Inotropic Support in the NICU: Ever More Compounds in Search of Guidance?

“…age, weight, peripartal asphyxia, renal failure) into account. Similarly, reported pharmacodynamic outcome measures were mixed (cliniIn this edition of Neonatology , two studies about levosimendan in low cardiac output states in an animal hypoxic-ischemic encephalopathy model and in 2 human neonates with persistent pulmonary hypertension (PPHN) are published [1,2] . Levosimendan is a Ca 2+ sensitizer with positive inotrope and lusitrope effects.…”

“…Lusitrope effects occur by preventing diastolic calcium overload compared to other adrenergic agents so diastolic relaxation is improved without increased myocardial oxygen consumption. By opening ATP-sensitive potassium channels, vasodilation of the smooth muscles occurs with coronary vasodilation and decrease in systemic and pulmonary vascular resistance (PVR) [1][2][3] . These properties make this inotropic theoretically also useful in neonates.…”

“…However, no controlled studies have been published, and suggestions are based on animal research [6] . The levosimendan papers provide observational evidence that this compound should be added to this list [1,2] .…”