Evaluation of levosimendan as treatment option in a large case-series of preterm infants with cardiac dysfunction and pulmonary hypertension

Abstract

Levosimendan as a calcium-sensitizer is a promising innovative therapeutical option for the treatment of severe cardiac dysfunction (CD) and pulmonary hypertension (PH) in preterm infants, but no data are available analyzing levosimendan in cohorts of preterm infants. The design/setting of the evaluation is in a large case-series of preterm infants with CD and PH. Data of all preterm infants (gestational age (GA) < 37 weeks) with levosimendan treatment and CD and/or PH in the echocardiographic assessment between 01/2018 and 06/2021 were screened for analysis. The primary clinical endpoint was defined as echocardiographic response to levosimendan. Preterm infants (105) were finally enrolled for further analysis. The preterm infants (48%) were classified as extremely low GA newborns (ELGANs, < 28 weeks of GA) and 73% as very low birth weight infants (< 1500 g, VLBW). The primary endpoint was reached in 71%, without difference regarding GA or BW. The incidence of moderate or severe PH decreased from baseline to follow-up (24 h) in about 30%, with a significant decrease in the responder group (p < 0.001). The incidence of left ventricular dysfunction and bi-ventricular dysfunction decreased significantly from baseline to follow-up (24 h) in the responder-group (p = 0.007, and p < 0.001, respectively). The arterial lactate level decreased significantly from baseline (4.7 mmol/l) to 12 h (3.6 mmol/l, p < 0.05), and 24 h (3.1 mmol/l, p < 0.01). Conclusion: Levosimendan treatment is associated with an improvement of both CD and PH in preterm infants, with a stabilization of the mean arterial pressure during the treatment and a significant decrease of arterial lactate levels. Future prospective trials are highly warranted. What is Known: • Levosimendan as a calcium-sensitizer and inodilator is known to improve the low cardiac output syndrome (LCOS), and improves ventricular dysfunction, and PH, both in pediatric as well as in adult populations. Data related to critically ill neonates without major cardiac surgery and preterm infants are not available. What is New: • This study evaluated the effect of levosimendan on hemodynamics, clinical scores, echocardiographic severity parameters, and arterial lactate levels in a case-series of 105 preterm infants for the first time. Levosimendan treatment in preterm infants is associated with a rapid improvement of CD and PH, an increase of the mean arterial pressure, and a significant decrease in arterial lactate levels, as surrogate marker for a LCOS. • How this study might affect research, practice, or policy. As no data are available regarding the use of levosimendan in this population, our results hopefully animate the research community to conduct future prospective trails analyzing levosimendan in randomized controlled trials (RCT) and observational control studies. Additionally, our results potentially motivate clinicians to introduce levosimendan as second second-line therapy in cases of severe CD and PH in preterm infants without improvement using standard treatment strategies.

Vasoactive Management of Pulmonary Hypertension and Ventricular Dysfunction in Neonates Following Complicated Monochorionic Twin Pregnancies: A Single-Center Experience

“…We could demonstrate that recipient and donor twins frequently present a need for iNO treatment due to early PH, and second-and third-line drugs such as sildenafil (i.v./orally) might be useful in selected cases with severe PH and without a response to iNO treatment. The association of levosimendan treatment with improvements in PH and CD severity in preterm and term infants was demonstrated in two previous studies from our group [26,27]. The calcium sensitizer levosimendan has the pharmacological potential to positively influence pulmonary vascular resistance by the following mechanisms: (a) calcium sensitization with a lusitropic/inotropic/vasodilating effect, (b) phosphodiesterase-3 inhibition, and (c) the vasodilation of smooth muscle cells by affecting ATP-depending potassium channels.…”

“…Postnatal treatment with vasoactive drugs was due to the decision of the attending physician, according to in-hospital standards of clinical management. The echocardiographic assessment of PH or right-, left-, or bi-ventricular dysfunction (RVD, LVD, BVD) used in our department was described previously [25,27]. For the present study, the echocardiographic diagnostic reports of the attending physicians were retrospectively reviewed, and PH (moderate to severe), any cardiac dysfunction (CD), and subclassification into RVD/LVD/BVD were stated as present or not present according to the documented report/echocardiographic exam.…”

“…The choice of vasoactive drugs (classified as inotropes [dobutamine], inodilators [milrinone, levosimendan], vasopressors [norepinephrine, vasopressin], and beta blockers [propranolol, landiolol]) and drugs for PH treatment (iNO, intravenous/oral sildenafil, inhaled prostacyclin, bosentan) was made according to clinical and echocardiographic findings in the specific neonate, as described previously by our research group [25,27]. In terms of a need for beta blockade (for myocardial hypertrophy [MH] or selective HR control), neonates were treated with propranolol when oral administration was preferred and with landiolol intravenously when rapid intravenous beta blockade was necessary in the first DOL.…”

“…Potential candidates for drug treatments for PH management include inhaled nitric oxide (iNO), phosphodiesterase-3 (PDE-3) inhibitors (milrinone), phosphodiesterase-5 (PDE-5) inhibitors (intravenous or oral sildenafil), and endothelin-receptor 1 (ET-1) antagonists (bosentan), as well as new candidates such as the calcium sensitizer levosimendan, along with the possibility of selective heart rate (HR) control using intravenous agents (ivabradine, landiolol). The pharmacological and clinical effects of these drugs have been evaluated in preterm and term infants and described in previous studies [21][22][23][24][25][26][27]. Nevertheless, data regarding PH treatment in complicated MC twin pregnancies are not available.…”

An Update on Pharmacologic Management of Neonatal Hypotension: When, Why, and Which Medication

“…The authors also suggested that LEVO may have advantages over MIL in terms of the dosing regimen [36,182]. Ten years later, a large case-series study of preterm infants (n = 105, GA < 37 weeks) with severe cardiac dysfunction and pulmonary hypertension demonstrated that LEVO treatment was associated with a rapid improvement in hemodynamic derangement [184]. Relevant systematic reviews have reported controversial results.…”