Published onNeonatology Update
Nicolas Bamat, MD, MSCE, is an attending neonatologist in the Division of Neonatology and a core faculty member in the Center for Pediatric Clinical Effectiveness (CPCE). His main research interest is neonatal respiratory failure. In this Q-and-A, we delve into Dr. Bamat’s research on pharmacotherapies for severe bronchopulmonary dysplasia (sBPD). We are proud to share insight into the valuable work and wisdom of this trailblazing member of our team.
Q: What sparked your interest in infants with lung disease?
A: I started doing neonatal lung disease research as a student at the Perelman School of Medicine at the University of Pennsylvania. As I completed my clinical training at Children’s Hospital of Philadelphia, I gravitated toward the Newborn and Infant Chronic Lung Disease Program. It’s a multidisciplinary referral program admitting infants with sBPD from a broad geographic region, resulting in an uncommon concentration of infants with sBPD in one center, and a valuable opportunity for research.
The CLD program admits approximately 70 infants with sBPD yearly and continues to grow in size and reputation. Of the 11 academic neonatologists in the program, I am one of 3 focused primarily on clinical research.
One thing that caught my attention early on is the extent to which these infants are exposed to medications. It’s not surprising. They are a patient population that’s incredibly sick and in the hospital for a very long time. Because of that, they are exposed to a very large number of medications, despite a lack of rigorous study of safe and effective practices.
That was my initial concern. Taking care of these babies clinically and looking at the long list of medications these babies are exposed to, I saw the need for good clinical evidence to support their use and safety. This represents a critical, unmet need to improve the quality of neonatal care. It’s been my focus since about 2016.
Q: What is the most common medication used for managing sBPD?
A: The first project that I did was with my K23 primary mentor, Scott Lorch, MD, MSCE, Director of Clinical and Epidemiological Research and Associate Chief of CHOP’s Division of Neonatology. We used the Pediatric Health Information System, a comparative pediatric database that includes clinical and resource utilization data for inpatient, ambulatory surgery, emergency department and observation unit patient encounters for more than 49 children’s hospitals across the country. We asked a very simple, two-pronged question: How many different medications are children with BPD exposed to, and what are the most common medications?
From that project, we identified the loop diuretic furosemide as the most frequently used medication for managing sBPD.
Q: Why is furosemide given to these infants?
A: Babies with BPD develop pulmonary edema which contributes to their poor gas exchange. The hope is that if we can reduce some of that pulmonary edema, then they’ll have an easier time breathing. There’s a saying that dry lungs are happy lungs. Furosemide is used in an effort to get the lungs dry. While the benefits of furosemide acting in this way are plausible, they remain unproven. Despite the frequent use of furosemide in established BPD, no prospective studies have been published in 30 years. Existing data is from small cohorts of infants with the phenotypically distinct “old” BPD and generalize poorly to contemporary practice. Further, furosemide is associated with various harms.
Q: What are the concerns about furosemide’s use?
A: There are some very fundamental questions about its optimal use that remain unanswered. One of the big gaps that we recognize is a need to better characterize furosemide pharmacology in older infants because their underlying pharmacology is very different than younger preterm infants.
One of the things that’s very challenging for neonatologists is that our patient population is developing very dynamically. There are very few medical specialties that take care of a dynamically developing patient population in this way. With a lot of our therapies, we are literally aiming at a moving target. A 1-week-old extremely preterm infant is very different than one that is at 40 weeks corrected gestational age with established BPD, with respect to their underlying physiology and pharmacology.
In clinical experience and in reading the literature, there is a concept of tolerance to furosemide. If you give the drug to a baby that is naive to the drug, you will have a strong diuretic response with the initial exposure. But over time, that response gets attenuated. The kidney can respond or adapt to the presence of this medication. This is a medication that we use chronically. Some babies might be on it for months, but it might only be having a diuretic effect for a couple of days. So, we are trying to determine how long it has an effect.
Q: What is the focus of your current research?
A: I’m now in the beginning of the second year of my K23 award from the National Institutes of Health. The goals of the research supported by this grant are to determine:
- The pharmacology of furosemide in older infants, i.e., how it gets absorbed, distributed, and eliminated in the body
- If and when tolerance to furosemide sets in
- Whether the insights from this initial research can be used to develop a more informed dosing strategy for furosemide
- If we can support this medication’s use when dosing it in an informed way
Arriving at a definitive answer to these questions is going to take a long time. But my long-term goal is to generate evidence of efficacy and/or harm through multicenter clinical trials.
Dr. Bamat’s Research Firsts
- First prospective study of furosemide in preterm infants with established “new” BPD
- First study to prospectively evaluate the impact of furosemide on respiratory outcomes in infants with BPD on positive pressure ventilation
- First to apply modern statistical techniques such as longitudinal data modeling to the study of furosemide in BPD
- First to apply modern pharmacometric techniques, like volumetric absorptive microsampling and population PK models in severe BPD