Inhaled nitric oxide for preterm infants: a systematic review

Since the introduction of surfactant therapy, mortality rates for preterm infants have decreased significantly. However, occasionally infants do not experience adequate improvement in oxygenation after surfactant treatment and other complications of prematurity continue to cause substantial long-term disability. The exploration of new therapeutic options is therefore mandatory. In term neonates with hypoxic respiratory failure, inhaled nitric oxide (iNO) therapy decreases the requirement for extracorporeal membrane oxygenation without decreasing mortality rates. For this reason iNO therapy may be seen as an approach to reduce the use of mechanical ventilation and the associated lung injury, that may lead to bronchopulmonary displasia (BPD) in preterm infants; on the other hand, NO has both prooxidant and antioxidant activities that can lead to worsening of lung injury.
In order to investigate the potential benefits of iNO therapy on developing lungs, Barrington and Finer conducted a systematic review to determine whether, in preterm infants with respiratory disease, treatment with iNO improves oxygenation and reduces the rates of death, BPD, intracranial hemorrhage or other serious brain injury, and adverse long-term neurodevelopmental outcomes.
This systematic review utilized keyword-based queries in the most important biomedical databases, such as Medline, Embase, Healthstar, and the Cochrane Central Register of Controlled Trials and covering 1985-2006. Abstracts of the Pediatric Academic Societies were also searched.
In total, 11 randomized, controlled trials of iNO therapy for preterm infants were found. The trials were grouped into 3 categories according to the entry criteria, that is, entry in the first 3 days of life on the basis of oxygenation criteria (early rescue), enrollment after 3 days on the basis of elevated risk of bronchopulmonary dysplasia, and routine use for intubated preterm infants. Overall, early rescue treatment did not seem to affect mortality or BPD rates and routine use for intubated preterm infants showed a barely significant reduction in the incidence of the combined outcome of death or BPD (relative risk [RR]: 0.91 [95% confidence limits (CLs): 0.84, 0.99]). Later treatment based on the risk of BPD showed no significant effect on this outcome. Regarding other effects, early rescue treatment showed a trend toward increased incidence of severe intracranial hemorrhage, whereas routine use for intubated preterm infants seemed to show a reduction in the incidence of either severe intracranial hemorrhage or periventricular leukomalacia (RR: 0.70 [95% CLs: 0.53, 0.91]).
The authors concluded that the use of iNO as rescue therapy for very ill preterm infants undergoing ventilation does not seem to be effective and may increase severe intracranial hemorrhage. Later use of inhaled nitric oxide to prevent BPD does not seem to be effective. Early routine use of inhaled nitric oxide for mildly sick preterm infants seems to decrease the risk of serious brain injury and may improve rates of survival without BPD.

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