Benefits seen with levosimendan in preterm infants with PH: Study

Safety, efficacy make drug a promising prenatal cardiac therapy candidate

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by Andrea Lobo |

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Treatment with levosimendan — a medication seen to improve cardiac function — was associated with rapid clinical benefits in preterm infants with heart problems and pulmonary hypertension (PH), a study in Germany reports.

The response to treatment was independent of the babies’ birth weight and how far along in the pregnancy the infants were born.

According to the researchers, “the beneficial effects and its safety profile regarding drug-related side effects make levosimendan a promising drug for cardiac therapy in [the] neonatal population.”

The study, “Evaluation of levosimendan as treatment option in a large case-series of preterm infants with cardiac dysfunction and pulmonary hypertension,” was published in the European Journal of Pediatrics.

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Treating preterm infants in critical condition has several challenges, most notably being the newborns’ very low birth weight, lung immaturity, and acute respiratory distress syndrome — a serious lung condition resulting in low blood oxygen. Many health problems are due to the infants’ extremely low gestational age, or how how far along in weeks the pregnancy was, calculated from the time since the mother’s last menstrual period.

Regarding the newborn’s heart, the major targets of intensive care treatment are PH and cardiac dysfunction.

Known PH and cardiac dysfunction risk factors for these babies include complications related to twin pregnancies in which there’s a significant size or weight difference between the two fetuses, low oxygen in the uterus, and lung disorders that lead to lung underdevelopment or structural alterations in blood vessels.

Levosimendan is thought to work by facilitating the heart muscle’s ability to contract and by relaxing blood vessels through effects on smooth muscle cells. It’s been shown to improve cardiac function, and to ease PH severity in both adults and children.

However, data related to the use of levosimendan in preterm babies, or those born before 37 weeks of pregnancy, are still scarce.

Now, researchers sought to evaluate if levosimendan might be a treatment option for preterm babies with cardiac dysfunction and PH. To that end, they retrospectively evaluated 105 preterm babies treated at the neonatal intensive care unit of University Children’s Hospital of Bonn, Germany, between January 2018 and June 2021.

Most babies (73%) were classified as very low birth weight, weighing less than 1,500 grams (3.31 pounds) at birth. Nearly half (48%) were classified as extremely low gestation age newborns — born before 28 weeks of gestational age.

The diagnosis of PH and cardiac dysfunction was based on clinical signs and on an echocardiographic exam, or an ultrasound scan to look at the heart.

At the study’s start (baseline), moderate to severe PH was found in 77% of the infants, and mild PH in 16%.  The rest of the infants did not show signs of PH.

Right ventricle dysfunction was found in about 40% of the group, left ventricle dysfunction in approximately 20%, and dysfunction of both heart ventricles in about 30%. The ventricles are the two lower chambers of the heart; the right ventricle pumps blood to the lungs, whereas the left ventricle pumps it to the rest of the body.

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More than 70% of treated babies respond to levosimendan

Infants with PH were treated with the vasodilator inhaled nitric oxide to reduce pulmonary vascular resistance, the resistance of blood vessels to blood flow. Revatio (sildenafil) was given as a second-line therapy and Tracleer (bosentan) as third-line treatment. Levosimendan was given to those with severe cardiac dysfunction that did not improve with standard therapy.

The treatment with levosimendan was administered by a continuous infusion for 24 hours. In three infants (3%), a bolus — a single, large dose of medicine — with a higher medication dose was given at the start of the infusion. In most babies, the bolus administration was not performed to avoid low blood pressure.

Six infants (6%) received a second levosimendan dose, with a minimum interval of seven days.

More than two-thirds of the preterm babies (71%) responded to levosimendan treatment, defined as echocardiographic improvement after 24 hours and/or decreased PH severity, regardless of gestational age or birth weight.

Our results potentially motivate clinicians to introduce levosimendan as second-line therapy in cases of severe [cardiac dysfunction] and PH in preterm infants without improvement using standard treatment strategies.

In those infants who responded to levosimendan treatment, the incidence of moderate or severe PH significantly decreased at follow-up in about 30%. Moreover, the incidence of left ventricular dysfunction and both ventricles dysfunction significantly decreased from baseline to follow-up in those who responded to the treatment.

The level of arterial lactate decreased significantly between baseline (4.7 mmol/L) to 12 hours (3.6 mmol/L) and 24 hours (3.1 mmol/L) following levosimendan treatment. High blood lactate is a measure of reduced oxygen delivery to the body tissues, and a marker of low amount of blood pumped by the heart.

During the observation period, which lasted a maximum of 48 hours, there was no severe low blood pressure related to levosimendan. On the contrary, blood pressure increased significantly between the baseline and the 48 hours of follow-up.

“We hypothesize that levosimendan can be used without preoccupation of arterial hypotension [low blood pressure] in preterm infants and neonates, but a bolus infusion should be avoided,” the researchers wrote.

However, response to levosimendan was not associated with less in-hospital mortality.

“Our results potentially motivate clinicians to introduce levosimendan as second-line therapy in cases of severe [cardiac dysfunction] and PH in preterm infants without improvement using standard treatment strategies,” the researchers concluded.

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