Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure

Inhaled nitric oxide (iNO) may attenuate the pathophysiology of respiratory distress syndrome and bronchopulmonary dysplasia (BPD) in pre-term infants. The recent NICHD (National Institute of Child Health and Human Development) trial of iNO in preterm infants did not show a difference in the primary outcome of BPD or death between the control and the iNO groups. However, a post hoc analysis indicated that iNO may benefit some populations (e.g. preterm infants with birth weight >1000 g) but may worsen outcome in other ones (e.g., preterms with birth weight <1000 g, on conventional ventilation). In order to design new studies, it is important to determine and identify clinical variables associated with a worse outcome. Previous small studies have indicated that a lack of initial response was predictive of death. In the NICHD study, the degree of response was arbitrarily defined in these studies, and it is possible that a different magnitude of response may be associated with improved survival and a decreased incidence of BPD. Classification and Regression Tree (CART) analysis is a statistical method that develops intuitive diagrams for identification of risk factors or similar patterns of data. It may be useful for initial data exploration and can be complementary to standard logistic regression.
On these bases, some American researchers have conducted a secondary analysis of data from the NICHD, using both logistic regression and CART analysis. The aim was to determine if the magnitude of initial improvement in PaO2 in response to iNO predicts death and/or BPD and to identify other variables that predict death and/or BPD.
Results indicated that death and/or BPD was not associated with the magnitude of response in PaO2 to iNO, indicating that the initial response to iNO in premature infants with severe respiratory failure may not be an appropriate indicator of whether treatment should be continued. However, death and/or BPD was associated with several factors, such as lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index and outborn status. In particular, infants with birth weight >1072 g were less likely to develop death and/or BPD (53% death/BPD vs 83% for =1072 g). In infants >1072 g, an Oxygen Index (OI) of 20 or more predicted worse outcome (77 vs 35% for OI of <20). For infants =1072 g, FiO2 of 90% or more predicted worse outcome (92 vs 77% with FiO2 <90). Infants with FiO2 of 90% or more receiving two or more doses of surfactant had a worse outcome (97 vs 78%).
This secondary analysis of the NICHD data, using both logistic regression and CART models, identified variables and the optimal cut points of the variables that are associated with death and/or physiologic BPD in premature infants with severe respiratory failure. These models may prove useful in assessment of prognosis as well as in stratification of infants for future clinical trials. Interestingly, the magnitude of initial response to iNO as used in the NICHD trial did not correlate with the outcome. Future studies are required to identify short-term indicators of response to iNO, if any, that may be associated with long-term benefit and can be used to adjust iNO dosing and duration.

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