Drug studies may help change core practices in neonatology
- Copyright © 2005 by the American Academy of Pediatrics
The AAP Committee on Drugs and Section on Clinical Pharmacology and Therapeutics are committed to a long-term effort to have pharmaceutical agents studied in pediatric patients of all ages.
The National Institute for Child Health and Human Development (NICHD) and the Food and Drug Administration (FDA) have joined forces in a Newborn Initiative to “develop an approach for the design and conduct of clinical trials for drugs in defined priority newborn conditions, and to develop a priority list of drugs that require study.” George P. Giacoia, M.D., FAAP, wrote about this effort in AAP News (http://aapnews.aappublications.org/cgi/content/full/24/2/87-a).
As I rounded recently on 48 infants in the neonatal intensive care unit (NICU), I was reminded of the scientific uncertainties of neonatal medicine that underscore the importance of the Newborn Initiative's goals.
In an individual child, the use of a pharmaceutical agent optimally should be guided by adequate information on drug efficacy for the condition being treated as well as a risk-benefit (safety) profile specific to the overall care of the child.
In the NICU, we commonly use drugs before efficacy, safety or basic pharmacokinetic information is available. The “therapeutic imperative” to treat a critical illness drives some of this drug usage. Clinicians struggle to make the best extrapolations from drug usage experience in children and adults, but this does not guarantee a successful or uncomplicated outcome.
Inhaled nitric oxide (iNO) is a proven treatment for term and nearterm infants with certain types of severe respiratory disease. Published studies on iNO therapy in preterm infants have not validated efficacy and have raised the specter of an increase in certain complications, such as intraventricular hemorrhage. Nonetheless, preterm infants in many NICUs receive iNO therapy for acute or chronic respiratory disease. Results of three large U.S. multicenter studies in preterm infants eventually will outline the role of iNO in this population.
Five years ago, any infant who was a spitty feeder, had recurrent gastric residuals or was thought to have feeding-associated bradycardia was likely to have been treated with cisapride—even though evidence of short- or long-term efficacy in neonates was lacking. As soon as safety concerns prompted withdrawal of this drug from general usage, the same symptoms were treated with metoclopramide, another drug with no persuasive efficacy data and significant safety concerns.
Eight of the 48 infants in our NICU were being treated with metoclopramide. Did their symptoms merit therapy with this unproven drug? In the absence of appropriate efficacy and safety data, I would argue that as the symptom severity falls, the incidence of therapeutic nihilism should rise.
The use of dopamine for neonatal hypotension illustrates both the need and the difficulty of the NICHD-FDA initiative to re-evaluate core practices in neonatology. An expert panel of cardiologists unanimously supported a randomized controlled trial of dopamine's use for neonatal hypotension. The impetus for study arose from concerns about whether treatment was always necessary and whether dopamine might increase the risk of long-term neurodevelopmental handicap (via a potential reduction in cerebral perfusion) compared to other inotropes. However, most neonatologists at the conference admitted that such a trial could not be conducted in their NICUs due to a lack of clinical balance.
Recently, two of my 48 babies had been started on dopamine infusions to improve mean blood pressure numbers in the absence of clinical or laboratory evidence of pathology. I may be waiting a long time to know if they would have been more likely to have a better outcome had they not been treated.
A journey of 1,000 miles starts with a single step. Recent legislation (e.g., the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act) and the interest of the NICHD and FDA in neonatal pharmaceutical study promise that as we march into the future, there will be more light than heat generated by neonatal pharmaceutical disputes.
Dr. Hudak is a member of the AAP Committee on Drugs.