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Inhaled nitric oxide for preemies: Little to no benefit on death, BPD
Cole FS. Pediatrics.
2011;doi:10.1542/peds.2010-3507.
Donohue PK. Pediatrics.
2011;doi:10.1542/peds.2010-3428.
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Inhaled nitric oxide seemed only of little benefit in improving survival, pulmonary outcomes or neurodevelopmental outcomes, according to the results of a meta-analysis and accompanying NIH consensus development statement published online.
“Taken as a whole, the available evidence does not support use of inhaled nitric oxide in early-routine, early-rescue, or later-rescue regimens in the care of premature infants of less than 34 weeks’ gestation who require respiratory support,” wrote the NIH consensus panel, led by F. Sessions Cole, MD, of St. Louis Children’s Hospital.
The panel’s recommendations were based in part on a meta-analysis of 14 clinical trials involving premature infants, led by Pamela K. Donohue, ScD, and colleagues from the department of pediatrics at The Johns Hopkins Hospital.
The researchers said mortality rates in the neonatal ICU were not different between infants treated with inhaled nitric oxide compared with controls (RR=0.97; 95% CI, 0.82-1.15). Bronchopulmonary dysplasia (BPD) rates were similar between treated and untreated patients at 36 weeks, as well (RR=0.93; 95% CI, 0.86-1.003).
The researchers noted a 7% lower composite risk for death or BPD at 36 weeks (RR=0.93 vs. controls; 95% CI, 0.87-0.99), but they said results should be interpreted cautiously. There were no significant advantages with inhaled nitric oxide in neurological outcomes such as cerebral palsy, neurodevelopment impairment or cognitive impairment.
The panel said, however, although the benefits have not been shown, there are some clinical situations, such as hypoplasia or pulmonary hypertension, in which nitric oxide may provide benefit, and further data are needed. Both groups wrote that this treatment should be conducted under tightly controlled clinical circumstances and should be discussed with families regarding benefits and risks.
“There is currently no evidence to support the use of inhaled nitric oxide in preterm infants with respiratory failure outside the context of rigorously conducted randomized clinical trials,” Donohue and colleagues concluded.
Multiple studies have demonstrated the benefits of inhaled nitric oxide in term and near term infants with pulmonary hypertension. A logical next step in the development of this therapy was to examine the potential effects of inhaled nitric oxide in preterm infants. This is especially true in view of basic science and animal studies indicating that inhaled nitric oxide reduces lung inflammation and promotes lung growth, factors that are critically important in the pathogenesis of BPD. While some studies in preterm infants suggest that inhaled nitric oxide may reduce evidence of lung injury and improve clinical pulmonary status, most data do not support a major role for this therapy. This meta-analysis examined almost 3,400 infants enrolled in several countries randomized to receive inhaled nitric oxide or placebo and should have provided definitive evidence of any benefits associated with this therapy if it existed. However, the great difficulty in interpreting this statistical approach is that most studies enrolled different patient populations and had vastly different treatment protocols. For instance, while many studies administered inhaled nitric oxide directly into the lung over relatively short time frames (hours to days) and demonstrated no advantages in outcome, others continued the treatment over much longer time periods (weeks to months) through nasal CPAP or a nasal cannulae even after infants were extubated and did demonstrate improved outcome. Although the exact amount of inhaled nitric oxide reaching the distal lung through these non-invasive techniques is unknown, it is possible that low dose inhaled nitric oxide over prolonged periods of time could be beneficial. The development of new technologies to administer inhaled nitric oxide to newborn infants may re-ignite the debate in this high risk population.
New therapeutic approaches to prevent lung injury in preterm infants are urgently needed. With millions of dollars spent on trials examining potential benefits of inhaled nitric oxide in preterm infants, it is quite disappointing that no specific approach could be adopted to significantly improve outcome. It is appropriate for the NIH to convene a consensus conference to review the large amount of data and to withhold widespread support for this treatment in this population at the present time. Hopefully, this will not deter other investigators and companies from continuing to develop new therapeutic strategies to improve the pulmonary outcome of high risk preterm infants.
—Jonathan M Davis, MD
Chief of Newborn
Medicine, The Floating Hospital for Children at Tufts Medical Center
Professor of Pediatrics, Tufts University School of Medicine
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