Milrinone Plus Sildenafil Improved Outcomes in Newborns With Persistent PH, Compared to Individual Treatments

Using sildenafil and milrinone together proved more effective than either therapy alone in treating newborns with severe persistent pulmonary hypertension (PH), a recent clinical study indicates.

This combo treatment may be used in resource-constrained settings that lack inhaled nitric oxide or extracorporeal membrane oxygenation (ECMO) as therapeutic options.

The study, “Efficacy of Milrinone Plus Sildenafil in the Treatment of Neonates with Persistent Pulmonary Hypertension in Resource‐Limited Settings: Results of a Randomized, Double‐Blind Trial,” was published in the journal Pediatric Drugs.

At birth, the circulatory system undergoes significant changes when transitioning away from relying on the placenta for circulation and oxygen. Severe persistent pulmonary hypertension of the newborn (PPHN) can result when the pulmonary circulation fails to make this transition and the baby may not get enough oxygen.

Although newborns with PPHN should ideally receive either inhaled nitric oxide or ECMO, in which blood is oxygenated in a device outside the body, the high costs of these therapies prevent them from being widely available in developing countries.

Pulmonary vasodilators like sildenafil — sold as Revatio or as a generic alternative in the United States — and milrinone, a heart failure medicine marketed as Primacor, among other brand names, have emerged as effective and less expensive alternatives.

However, as several patients do not respond to these medications alone, researchers from Alexandria University, in Egypt, investigated their effectiveness as a combined therapy.

The investigators conducted a randomized, double-blind trial (Pan African Clinical Trial Registry identifier number PACTR201902691230243) to compare the combined treatment to each medication alone, as measured by improvements in pulmonary artery systolic pressure (PASP) for three months.

Each of the three treatment groups included 2o newborns from 1 to 28 days old with PPHN. These newborns had no statistically significant differences in terms of weight, stage of maturity, and sex.

The sildenafil-only group received oral sildenafil at 0.5 mg/kg every six hours, rising to a maintenance dose of 2 mg/kg every six hours. The milrinone-only group received intravenous milrinone 0.5 micrograms/kg/minute as a continuous infusion. Finally, the combined therapy group received both oral sildenafil and intravenous milrinone.

In addition to PASP measurements, all participants underwent Doppler echocardiography exams at the start of the trial and within 24 hours of starting treatment. Follow-up echocardiography was continued for three months, according to the needs of the individual case, until clinical and echocardiographic improvement or death.

Clinical improvement served as the secondary outcome in this trial.

Results showed that PASP values dropped significantly in the combined therapy group, from day one to day two of treatment, and up to the end of the study.

PASP values remained unchanged in the sildenafil-only group and, although they did drop in the milrinone-only group from day one to day two of treatment, this group did not experience significant changes in PASP from day two through the end of the trial.

The oxygenation index — a measure of the fraction of inspired oxygen and its usage within the body (the lower that index, the better) — also decreased significantly in the combined therapy group.

The combo group also had the lowest mortality rate of the three groups — 15% (three deaths) vs. 25–30% in the other two groups — although this difference was not statistically significant.

“Combined therapy with oral sildenafil and intravenous milrinone had significantly better outcomes than monotherapy with either agent in neonates with PPHN,” the researchers concluded. The team recommended this combined treatment to be used “in resource-constrained settings.”

Nonetheless, “future trials with longer durations and more patients are needed to confirm the benefits and evaluate the neurodevelopmental effects of the different treatment modalities in these patients,” the team added.