Successful Use of Levosimendan in Four Critically Ill Neonates With Pulmonary Hypertension: A Case Series

Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening condition resulting from failure of the pulmonary vascular resistance to drop after birth, leading to right-to-left shunting and severe hypoxemia. It affects around 0.2% of term and up to 2% of preterm neonates. Management focuses on pulmonary vasodilation and maintaining systemic hemodynamic stability [1]. Levosimendan, an inodilator acting as a calcium sensitizer, positive inotrope, and vasodilator, has shown promising effects in adult and pediatric populations with cardiac dysfunction, but data in neonates remain limited [2]. Unlike conventional inotropes, it enhances myocardial contractility without raising oxygen consumption or causing calcium overload [3]. Here, we report the off-label use of levosimendan in four critically ill neonates with PPHN and circulatory instability, all of whom responded favorably without adverse effects. Patient 1 was a term neonate (37 weeks, 3080 g) admitted to the NICU at 2 h of life with pneumothorax, which resolved conservatively. On day 2, she developed worsening respiratory distress requiring intubation and mechanical ventilation until day 8. At 16 days of age, she deteriorated again and was reintubated. Echocardiography revealed moderate PPHN with normal myocardial anatomy. Sildenafil and dopamine were started, but despite therapy, she progressed to severe PPHN (maximum OI 32 on day 23), requiring HFOV and intravenous iloprost (up to 20 ng/kg/min). Milrinone was not trialed in this case. Levosimendan (0.1 mcg/kg/min) was initiated on day 23, resulting in gradual improvement in hemodynamics without adverse effects. The patient was later diagnosed with alveolar capillary dysplasia and died at 5 months of age. Patient 2, born at 29 + 4 weeks of gestation (1030 g), developed respiratory distress soon after birth, requiring transient intubation. On day 3, she developed septic shock with secondary PPHN (moderate severity) requiring reintubation, broad-spectrum antibiotics, and multiple inotropes (adrenaline, noradrenaline, vasopressin) and hydrocortisone. Milrinone was started on day 5 and continued for 8 days, but PPHN persisted despite therapy. Levosimendan (0.25 mcg/kg/min) was initiated on day 13 for refractory PPHN due to elevated pulmonary vascular resistance, leading to rapid stabilization and successful weaning from inotropes by day 20 and extubation by day 31. Patient 3, a late preterm twin (35 + 1 weeks, 2220 g), was admitted at 36 h of life with respiratory distress and hemodynamic instability. Echocardiography revealed suprasystemic pulmonary pressures and right ventricular hypertrophy, consistent with severe PPHN. Initial treatment with milrinone, vasopressin, and inhaled nitric oxide failed to achieve improvement. Therefore, iloprost and levosimendan (up to 0.2 mcg/kg/min) were initiated on day 3, resulting in progressive hemodynamic stabilization. The infant was successfully weaned off oxygen by day 12, with no adverse effects observed. Patient 4, an extremely preterm neonate (25 + 5 weeks, 850 g), developed PPHN (moderate-to-severe, OI 38) on postnatal day 66 while on mechanical ventilation. HFOV and vasopressors (adrenaline, vasopressin) were used; milrinone was not administered. Given persistent hemodynamic instability, levosimendan (0.2 mcg/kg/min) was introduced for ten days, leading to gradual and sustained improvement in both pulmonary and systemic circulation without side effects. Parental written informed consent was obtained for all patients, and this report was approved by the Institutional Scientific Review Board of the University Hospital of Ioannina (approval no: 385). Levosimendan offers a distinctive pharmacodynamic and pharmacokinetic profile that may be particularly advantageous in neonates with PPHN and circulatory compromise. It acts as a calcium-sensitizing inodilator, enhancing myocardial contractility through troponin-C binding while promoting vasodilation by opening adenosine triphosphate–sensitive potassium channels in vascular smooth muscle [2, 3]. This dual action improves both cardiac output and pulmonary vasodilation without substantially increasing myocardial oxygen consumption—a property that distinguishes it from catecholamine and phosphodiesterase-inhibitor inotropes [3]. Pharmacokinetic data in infants are limited but suggest a pattern broadly comparable to adults, albeit with longer elimination due to immature hepatic metabolism. In a prospective pharmacokinetic study in children undergoing cardiac surgery, Turanlahti et al. reported a terminal half-life of approximately 2 h for the parent drug and up to 80 h for its active metabolite OR-1896, accounting for the prolonged inodilatory effect lasting up to a week after infusion [4]. This long-acting metabolite likely explains the sustained hemodynamic improvement observed in our series, particularly in Patients 2–4, where stabilization persisted several days beyond infusion cessation. Continuous electrocardiographic, invasive arterial pressure, and serial echocardiographic monitoring were employed throughout treatment in all four neonates. The infusion rates in our cohort (0.1–0.25 µg/kg/min) were guided by clinical severity and the presence or absence of concomitant inotropes. Lower initial doses (0.1 µg/kg/min) were chosen in Patient 1, who was hemodynamically fragile but not catecholamine-dependent, whereas higher rates (0.2–0.25 µg/kg/min) were used in Patients 2–4 to overcome refractory pulmonary hypertension under multiple inotropic agents. No bolus loading dose was given, consistent with pediatric safety recommendations to avoid transient hypotension [4, 5]. Dose titration was individualized according to mean arterial pressure, oxygenation index (OI), and right-ventricular performance on serial echocardiography. The onset of improvement varied from 12 to 48 h after infusion initiation. In Patient 2, progressive stabilization permitted complete withdrawal of catecholamines within 7 days and extubation by day 31. In Patient 3, echocardiographic indices of right-ventricular function improved within 24 h, allowing discontinuation of vasopressin and inhaled nitric oxide. Patient 4, an extremely preterm neonate, showed gradual recovery over ten days with sustained improvement in oxygenation and systemic perfusion. In all cases, no arrhythmias, hypotension, or electrolyte disturbances were observed. The absence of rebound pulmonary hypertension after discontinuation supports the role of the long-acting metabolite in maintaining vascular relaxation. Levosimendan was integrated into complex multimodal regimens tailored to each infant's hemodynamic profile. In Patients 2 and 4, the initiation of levosimendan enabled tapering and eventual discontinuation of adrenaline and noradrenaline within the first week of therapy. In Patient 3, the agent replaced milrinone as the principal inodilator following the failure of inhaled nitric oxide and vasopressin. In contrast, Patient 1 received levosimendan without preceding milrinone, due to concern for systemic hypotension. Across all four cases, levosimendan served either as a rescue or replacement therapy, facilitating reduction of catecholamine exposure and minimizing risks associated with adrenergic overstimulation. Neonatal reports on levosimendan remain scarce but encouraging. De Carolis et al. described two term neonates with ischemic heart failure and PPHN who demonstrated marked hemodynamic improvement within 24 h of infusion, without adverse effects [5]. Schroeder et al. more recently evaluated 24 preterm infants with pulmonary hypertension or myocardial dysfunction and similarly observed enhanced right-ventricular performance and oxygenation indices without major side effects [6]. Our observations align closely with these reports, further suggesting that levosimendan can be safely administered to both preterm and term neonates, even in the presence of severe circulatory instability. Compared with prior pediatric data, where the drug was largely restricted to perioperative settings, our series extends its potential role to non-surgical PPHN refractory to conventional therapy. The consistent clinical and echocardiographic improvement, coupled with excellent tolerability, underscores its promise as an adjunctive or rescue inodilator in the neonatal intensive-care setting. This small case series reinforces the feasibility and apparent safety of levosimendan in critically ill neonates with PPHN and circulatory failure. Individualized dosing based on hemodynamic monitoring, gradual titration, and avoidance of loading boluses appear prudent. The reproducible temporal pattern of improvement—within one to 2 days of infusion—and the ability to wean from catecholamines support its clinical utility. While mechanistic rationale and early clinical data are compelling, robust pharmacokinetic and randomized controlled studies remain essential to define optimal dosing, timing, and long-term outcomes in the neonatal population. Dr. Aikaterini Kantzavelou, Prof. Vasileios Giapros and Dr. Nichitas Chatzigiannis conceptualized and designed the study, drafted the initial manuscript, and contributed to its review and revision. Dr. Maria Mpaltogianni developed the data collection instruments, oversaw and coordinated data collection, and provided a critical review of the manuscript. Natalia Atzemoglou Contributed to the Drafting of the Initial Manuscript. All authors have approved the final version of the manuscript as submitted and take full responsibility for all aspects of the work. Aikaterini Kantzavelou: writing – original draft, writing – review and editing, investigation. Nikitas Chatzigiannis: supervision, investigation, conceptualization. Maria Baltogianni: conceptualization, supervision, investigation. Natalia Atzemoglou: investigation. Vasileios Giapros: conceptualization, investigation, supervision, writing – review and editing. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Scientific Review Board of the University Hospital of Ioannina (approval no. 385). Parental informed consent for publication was obtained for all cases. The authors have no conflicts of interest to declare. The data that support the findings of this study are available from the corresponding author upon reasonable request.