Pharmacotherapy for Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Past, Present, and Future

Abstract

Approximately 8–42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies are commonly used to treat BPD-PH, all current use is off-label. Moreover, all current recommendations for the use of any PH-targeted therapy in infants with BPD-PH are based on expert opinion and consensus statements. Randomized Control Trials (RCTs) are needed to determine the efficacy of PH-targeted treatments in premature infants with or at risk of BPD-PH. Prior to performing efficacy RCTs, studies need to be conducted to obtain pharmacokinetic, pharmacodynamic, and safety data for any pharmacotherapy used in this understudied and fragile patient population. This review will discuss current and needed treatment strategies, identify knowledge deficits, and delineate both challenges to be overcome and approaches to be taken to develop effective PH-targeted pharmacotherapies that will improve outcomes for premature infants with or at risk of developing BPD-PH.

Navigating Diagnostic and Treatment Challenges of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia

“…Three broad classes of PH-specific vasodilators are typically utilized by PH specialists in the management of BPD-PH, targeting the nitric oxide pathway, endothelin pathway, and prostacyclin pathway. While none of these agents have been extensively studied in controlled clinical trials in the population affected with BPD-PH [ 88 ], there are numerous cohort studies, case reports, and reviews that attest to their safety, tolerability, and efficacy using standard PH dosing regimens in appropriately selected patients. Newer agents such as those acting on the soluble guanylate activation (i.e., riociguat) or oral prostanoids activators (i.e., selexipag) have limited data within the BPD-PH population.…”

“…Compared to BPD infants without PH, BPD-PH infants have higher rates of needing technology including respiratory support, feeding support, and oxygen therapy and readmissions with illness are not infrequent [ 7 ]. With expectant management, avoidance of illness, and good growth, BPD-PH is generally felt to improve over the course of the first few years of life, allowing for the discontinuation of PH therapies by a median of 4.4 years [ 88 , 99 ]. However, the postdischarge course of a BPD-PH infant requires close follow-up because negative cardiorespiratory outcomes can persist well beyond infancy and even into adulthood [ 7 , 100 , 101 ].…”

Multi-dose enteral L-citrulline administration in premature infants at risk of developing pulmonary hypertension associated with bronchopulmonary dysplasia

“…In 2022, the Pediatric Pulmonary Hypertension Network (PPHNet) noted the remarkable contribution of BPD-PH to the spectrum of pediatric PH and highlighted the need for focused research and randomized clinical trials (RCTs) in this understudied group of patients 11 . To date, no RCTs have been performed to evaluate the e cacy of any PH-targeted pharmacotherapy as a treatment to inhibit or reverse the development of BPD-PH 12 . Per FDA guidance, prior to performing a RCT, pharmacokinetic studies are needed to establish doses to be evaluated for e cacy and safety of any drug in a pediatric population 13 .…”