MedicalResearch: What is the background for this study?
Dr. Ellsworth: Inhaled Nitric Oxide (iNO) is a drug that has FDA approval for use in neonates >34 weeks gestational age. It is used for severe respiratory failure secondary to pulmonary hypertension. However, it has been previously shown that neonatologists have been using this medication off-label and especially in the most premature neonates. Over the last 10 years there have been multiple large studies trying to determine a clinical use (ie long term benefit) for iNO in preterm neonates (patients where there is no FDA approval for iNO use currently). Despite evidence of short term benefit (improved clinical stability) use of this drug has not been shown to improve long-term outcomes (death and chronic lung disease) in premature neonates. As a result of these findings the National Institute of Child Health and Human Development (NICHD) released a consensus guideline in 2011 indicated that available evidence did not support the routine use of iNO in preterm neonates and discouraged this use of this expensive therapy in preterm neonates. Similarly, in 2014 the American Academy of Pediatrics issued a similar statement with similar recommendations.
In 2014 a group of NICUs (collectively called the Neonatal Research Network) associated with the NICHD published a report showing that the use of Inhaled Nitric Oxide in preterm infants (ie off-label) decreased following the report in 2011.
However, I did not feel that these NICUs were representative of the United States alone as the Neonatal Research Network consists of only a handful of NICUs (~15) and is directly associated with the NICHD. As a result I wanted to get a better idea of Inhaled Nitric Oxide use in a population based study to see if the trends were similar (ie use of iNO has been decreasing) on a much larger, more representative scale. (Editorial comment: My anecdotal experience was that rates of iNO use off-label have not decreased in preterm neonates since the 2011 report).
MedicalResearch: What are the main findings?
Dr. Ellsworth: Between 2009 and 2013, the rate of iNO utilization in 23 – 29 week neonates increased from 5.03% to 6.19%, a relative increase of 23% (CI 8-40%; p = 0.003). Of all neonates who received iNO therapy in 2013, nearly half were <34 weeks’ gestation (off label) with these infants accounting for more than half of all first exposure iNO days each year of the study period.
Of note, this data was also validated with data from the Vermont Oxford Network (VON) during the same years. Between 2009 and 2013, for the 79,434 infants 23 to 29 weeks cared for at the 703 hospitals in the United States participating in the Vermont Oxford Network, the rate of iNO utilization increased from 6.7 to 6.9 percent. (This data was added into the discussion of our paper).
We estimated that off-label use in the United States generated a cost of $19.6 million in 2013 alone.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Ellsworth: Despite professional guidance from the NICHD to discourage off-label Inhaled Nitric Oxide use, neonatologists in many NICUs throughout the United States continue to use this medication in the most premature of neonates.
I think it is important for neonatologists to be aware that our data of increasing off label iNO use is, independent of any clinical consequences, potentially placing a significant economic burden on the care of the critically ill neonate in the United States. The uncertainty in future pricing models and insurance reimbursement practices of this costly, and in a majority of cases, off label therapy is something every neonatologist should be aware of and should guide discussions among clinicians on how iNO use should best be managed in their individual NICU settings.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Ellsworth: Over the last few years there has been an uptick in published case series and small trials of alternative therapies for respiratory failure, often due to pulmonary hypertension, in preterm neonates. These therapies (milrinone , vasopressin, sildenafil, prostacyclins) are being shown to provide short term clinical benefits to a similar degree and in the same clinical situations where Inhaled Nitric Oxide is currently being used off label as first-line therapy. Hopefully the findings of our study will encourage investigators to dedicate research efforts and resources to further studying these alternative, and in most cases much more economical, therapies to determine their safety and long term consequences. An approach similar to what was undertaken to study iNO in preterm neonates may enable us to find more suitable alternatives to the vexing clinical situations that often prompt off label prescription of Inhaled Nitric Oxide in NICUs today.
MedicalResearch.com Interview with: Marc Ellsworth, M.D (2015). Inhaled Nitric Oxide Still Used Off-Label In Preterm Infants