NEW YORK (Reuters Health) – Treating extremely premature neonates in respiratory distress with inhaled nitric oxide is not associated with less in-hospital mortality, researchers say.
Inhaled nitric oxide (iNO) is increasingly prescribed off-label to affected neonates during the first week of life, despite guidance from the National Institutes of Health and the American Academy of Pediatrics discouraging its use, according to Dr. William Carey of Mayo Clinic in Rochester, Minnesota, and colleagues.
To investigate further, the team analyzed data from the Pediatrix Medical Group Clinical Data Warehouse on singletons born at 22 to 29 weeks’ gestation from 2004 to 2014. Those who required mechanical ventilation for respiratory distress syndrome were included; those with any kind of anomaly were not.
Using “rigorous statistical methods,” the team matched each patient who received iNO during the first week of life (case patient) to a neonate who had not received iNO before the case patient’s iNO initiation age. Neonates “were similar in gestational age, birth weight, degree of illness” and other “important, relevant clinical characteristics,” Dr. Carey told Reuters Health in an email.
As reported online February 9 in Pediatrics, among 37,909 neonates in the study sample, 993 (2.6%) received iNO. The two matched cohorts each contained 971 patients.
In the iNO group, 348 died in the hospital at a median age of six days; the remaining 623 were discharged after a median 89 days. Among the matched referents, 325 neonates died at a median age of six days and 646 were discharged after a median stay of 88 days.
A total of 171 of the matched referents received iNO therapy at a median age of two days.
No significant association was observed between iNO exposure and mortality (HR, 1.08; 95% confidence interval, 0.94-1.25). Exposure to iNO also was not associated with necrotizing enterocolitis, retinopathy of prematurity requiring treatment, chronic lung disease, or periventricular leukomalacia.
“Simply put, we found that iNO treatment during the first week of life did not improve outcomes for extremely premature babies,” Dr. Carey stressed. “Even when we looked at the subgroup of babies who were diagnosed with pulmonary hypertension – a condition for which iNO is clearly effective in term and late-preterm babies – we found no benefit.”
“What surprised us, though, was that early iNO treatment was associated with untoward outcomes (higher mortality) in patients who were not diagnosed with pulmonary hypertension,” he said. “This is important, as iNO has been described as ‘safe’ for use in this population, while efficacy has not been proven.”
“Another important point is that we knew only whether a baby received iNO,” he noted. “We couldn’t know the dose, the duration of use, how dosing changed over time, etc. Some might consider this a limitation of our study, but I would disagree.”
“I truly believe that neonatologists prescribe iNO with the best intentions and in very desperate situations – and I suspect they do so presupposing that the drug is safe,” Dr. Carey said. “Our findings suggest that we need to rethink our off-label use of iNO in the NICU, and I am hopeful that they will inform future guidance from our professional societies.”
Dr. Roger Soll of University of Vermont Medical Center in Burlington, author of a related editorial, told Reuters Health, “The apparent lack of evidence for efficacy in the preterm population has not stopped clinicians from using iNO.”
“This is brought out not only in the (current study),” he noted, “but in data from the Vermont Oxford Network – of which I am president – which is a collaboration of over 1,000 NICUs dedicated to improving the care of newborn infants and their families.”
“Although a majority of units never use iNO in very low birth weight infants,” he added, “over 25% of units (do use it) in over 12% of (those) infants.
“Part of the appeal of iNO,” he said, “is how effective it is in term infants with persistent pulmonary hypertension, and the strong biologic rationale that this could potentially work in preterm infants as well.”
“However,” he observed, “meta-analyses of randomized trials of iNO, both in a population of at-risk preterm infants as well as preterm infants with severe hypoxemic respiratory failure, demonstrate little benefit from therapy.”
“Yet, as a clinician,” he continued, “we have all seen the individual child who appears to respond to therapy.”
“Perhaps the response merely reflects a surrogate: improved oxygenation that does not translate into improvement in important clinical outcomes,” he suggested.
“However, many believe that there is a subset of preterm infants with persistent pulmonary hypertension in whom this intervention might be lifesaving. This clearly propels practice,” Dr. Soll concluded.
SOURCES: http://bit.ly/2EQTd5F and http://bit.ly/2Exr7Pl
Pediatrics 2018.
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