Unanswered Questions in Pediatric Pulmonary Hypertension

“Where is the next PH crisis lurking?” – This question may flash past your awareness as you prepare to sit down for the first time during your night shift in the PCICU at “0-dark:30”.

Pulmonary Hypertension (PH) is a recurrent and severe threat to some of our most challenging patients. We have tools that may address PH crises and RV failure that may punctuate their time in the CICU, but evidence-based insights for an optimal approach are missing.

Key questions that do not have answers at present include:

• How to best predict risk for severe pulmonary vasoreactivity with suddenly threatening levels of PVRI in real time?
• How to modulate PVR lability in patients for whom it has been life-threatening without continuous neuromuscular blockade and substantial sedation that may have their own negative impacts on coronary perfusion and cardiac output?
• What are the best pre- and post-operative maintenance drugs for infants and children with PH that will ensure the smoothest possible perioperative course and help kids transition to the optimal developmental trajectory thereafter?

Pediatric PH remains a formidable frontier in 2025 because high mortality and severe morbidities continue to challenge our patients. Unanswered questions like the ones in the list above complicate the care of kids with PH. Little is known about the natural history of their PH, how best to predict outcomes, age-appropriate endpoints for clinical studies, and even optimal care. Clinical trials that address these issues have been few and very challenging to fund and complete. There are several reasons for this. This is a rare disease with several different subtypes, and kids are often quite ill upon initial presentation. MRCTs are challenged by slow recruitment that can compromise the power of the results. Additionally, there is widespread reluctance to test new drugs in kids because they are a vulnerable population.

These are the issues and challenges that motivated the Pediatric Pulmonary Hypertension Network of North America to launch the first investigator-initiated MRCT for kids with PH in North America – the Kids MoD PAH Trial: Mono- vs. Duo-Therapy for Pediatric PAH patients. The Kids Mod PAH study is a research project funded by NHLBI that aims to determine the best initial therapy for children with newly diagnosed pulmonary hypertension. The study compares the effectiveness of one medication (sildenafil) versus a combination of two medications (sildenafil and bosentan) in improving the quality of life and functional class of these children. The study incorporates innovative methods such as actigraphy and quality of life surveys to assess the impact of the therapies on the day-to-day lives and functioning of infants and children with PH. The study faces challenges as both medications are already widely used in the community, making it difficult to enroll children who have already started treatment. The study team aims to provide enhanced care and support to the participants and their families throughout the study. The ultimate goal of this effort is to contribute to improving the care and outcomes for all children with pulmonary hypertension.

To find out more about PPHNet and its task forces on clinical trials, RV failure, and PH practice guidelines, please visit the website.

Thanks so much!