Background: Bronchopulmonary dysplasia (BPD) is a serious complication of prematurity, with multifactorial associations. Associated alveolar diffusion impairment, abnormal vascular remodeling, and pulmonary vascular growth arrest results in pulmonary hypertension (PH) in about 25% of infants with moderate to severe BPD with these infants demonstrating worse physical growth, neurodevelopmental, and survival outcomes, higher rates of tracheostomy, increased use of supplemental oxygen, feeding problems, and frequent hospitalizations. 

Pharmacotherapy targeting the prostacyclin pathway, the nitric oxide pathway, and the endothelin pathway is administered to induce pulmonary vasodilation, decreasing pressure in the right ventricle in attempts to avoid right heart failure. The phosphodiesterase-5 inhibitors (PDE5i) are frequently the first line in contemporary BPD PH therapy, demonstrating improvement in pulmonary vascular resistance and functional class. The FDA has also approved the PDE5i tadalafil for the treatment of PH based on studies that have shown long term tolerance and efficacy in pediatric PH populations. The use of non-selective endothelin A- and B-receptor antagonists (ERAs) like bosentan have also found support in studies such as the FUTURE-1 trial through improvement in hemodynamics and functional status class. 

Progressive disease often necessitates combination therapy, a practice that has been widely adopted in the clinical setting. Meta-analyses and trials on combination therapy compared to monotherapy in adults have previously demonstrated improvement in exercise capacity, hemodynamics, and reduction of risk of clinical worsening and failure.  In the treatment of infants with BPD PH, sildenafil and bosentan, alone and in combination, are frequently used. Evidence has shown that combination therapy is independently associated with improved survival as compared with single-agent therapy. However, there is limited data published and gaps in translation to clinical practice for the use of combination therapy (utilizing multiple drug classes) in PH secondary to BPD. 

This study aims to describe the effects of combination pulmonary vasodilator therapy in children with PH secondary to BPD in comparison with monotherapy on specific echocardiogram parameters. 

Project Design: This retrospective study compares neonates with PH secondary to BPD started in the first year of life on single pulmonary vasodilator therapy with those on combination therapy. Data was obtained by identification of medication orders between 01/2010 to 11/2021 through TheraDoc and Epic Electronic Health Record system for Johns Hopkins All Children’s Hospital. Demographic, therapeutic, and diagnostic data were obtained through chart review and analyzed using mean, fisher’s exact test, and two-tailed paired and unpaired t-tests.   

Monotherapy consists of those on sildenafil, combination therapy consists of those on sildenafil or tadalafil and bosentan, plus or minus a prostacyclin analogue (PCA) (treprostenil). Parameters include right ventricular pressure (RVP), right ventricular dilation (RVD), right ventricular function depression (RVFd), tricuspid regurgitation (TR). Baseline data was from immediately prior to initiation of PH therapy. Subsequent data was obtained after medication addition and steady state dosing reached. Infants without BPD, with complex congenital heart defects, with congenital diaphragmatic hernias, without data, or with therapy started after 365 days were excluded.   

Results: Out of the reviewed population, 17/44 (63%) met inclusion criteria for combination therapy and 21/523 (4%) met inclusion criteria for monotherapy. Qualitative echo parameters were assessed and grouped into binary categories based on severity. There was no significant difference in the baseline distribution of patients among the two categories of severity between the monotherapy group and the combination therapy group. 

For those in the monotherapy only group, those with RVP > ½ systemic decreased by 52% from 90% (n=19) before therapy to 38% (n=8, p=.009) after therapy. The combination group did not see a significant change in RVP until an additional agent was added. In the combination therapy sample, 48% of the patients had decrease in RVP, from 88% (n=15) with RVP > ½ systemic initially decreasing to 40% (n=6, p=.008) with RVP > ½ systemic after combination therapy. 

For those on monotherapy only, the percentage of patients that had more than mild RVD pre-therapy decreased from 33% (n=7) to 0% (n=0, p=.008) after initiation of therapy. 

Conclusion: The development of PH in children with BPD is associated with significant mortality and morbidity. The use of pulmonary vasodilators improves pulmonary artery (PA) pressure and  may help improve outcomes. Some children with significant PH may have an insufficient response to first line monotherapy (traditionally PDE5i) and may require additional agents (such as ERAs or PCAs) to improve PA pressure and RVP. Analysis of baseline data such as gestational age, birth weight, did not demonstrated significant difference between the monotherapy and combination group. There was similarly no significant difference in concurrent therapy in the form of oxygen delivery and medications within the groups pre-therapy and post therapy and across groups pre-therapy and post-therapy. 

The data shows that a significant improvement in RVP can be achieved in many infants with PH secondary to BPD, but it may require multiple agents for a subset of these patients. The baseline distribution of severity scores was not significantly different between those patients that needed only one medication versus those requiring multiple pulmonary vasodilators.  More information  is needed to continue better understanding risk factors for needing multiple PH targeted medications.  

Good progress has been made in the past few decades in treatment of pediatric PH. A limitation to broadly extrapolating this data is the single center retrospective nature of this study. Further multi-institutional or prospective may help add more insights to risk factors and better therapeutic strategies for this challenging disease.