Increased use of less invasive ventilation for extremely preterm newborns did not reduce infants’ oxygen dependence at 36 weeks’ gestational age, nor translate into improved lung function 8 years later, found a study published online July 27 in the New England Journal of Medicine.
Contrary to their hypothesis, “there were higher rates of oxygen dependence at 36 weeks of age and more airflow obstruction at 8 years of age in the most recent period we reviewed,” Lex W. Doyle, MD, from the Royal Women’s Hospital and the University of Melbourne in Australia, and colleagues write.
“Perhaps the assumption that nasal [continuous positive airway pressure (CPAP)] is less invasive and less injurious to the lung than endotracheal ventilation was incorrect,” the authors surmise. “Another possibility is that nasal CPAP is being overused. Over time, the threshold for commencing nasal CPAP has decreased substantially,” they note, and “physicians’ threshold for tolerating apnea has probably decreased over time, making some infants subject to prolonged periods of nasal CPAP.”
The researchers sought to understand short-term and long-term outcomes of treating children with these less invasive ventilation methods, which they expected would result in improved respiratory outcomes. The ventilation methods used included intermittent positive-pressure ventilation and high-frequency oscillatory ventilation, both of which were delivered through an endotracheal tube, and nasal CPAP.
The researchers analyzed prospectively collected data including expiratory airflow assessed at age 8 years for three cohorts of surviving children born from 22 to 27 weeks’ gestation in Victoria, Australia, during 1991 to 1992 (n = 225), 1997 (n = 151), and 2005 (n = 170).
In the 1991 to 1992, 1997, and 2005 cohorts, 53%, 70%, and 63% of the infants survived to age 8 years; of those, 183, 112, and 123 underwent lung function tests at age 8 years, respectively.
Postnatal prescriptions for glucocorticoids were less common among children born in 2005 than the earlier cohorts, but treatment rates for prenatal glucocorticoids and exogenous surfactant increased from each cohort to the next. In addition, “[t]he mean durations of all assisted ventilation rose substantially over time, primarily because of a large increase in the mean duration of nasal CPAP given the declining duration of endotracheal ventilation,” the researchers write.
After adjustment for perinatal variables, children in the 2005 cohort had greater average durations of assisted ventilation and nasal CPAP than those born during the earlier periods. They also had greater oxygen dependence at 36 weeks, but the association was only significant for comparison with children born during 1997 (adjusted odds ratio, 2.67; 95% confidence interval, 1.60 – 4.46; P < 0.001). Average oxygen therapy duration was also higher in the 2005 group than in the 1997 group.
Lung Function Worse Than Expected at Age 8 Years
For all three cohorts, children’s z scores from forced expiratory volume assessments at 8 years were lower than expected (for all variables), and an improvement that occurred between the first two cohorts then reversed in the 2005 cohort.
Wheezing rates during the year before the 8-year-old assessment were similar across all three groups, ranging from 23% to 26%. Although geographic homogeneity of the infants was a strength of the study, not all surviving children could undergo lung function assessments as a result of their disabilities. The findings may also not be generalizable.
The authors discuss several possible reasons for the findings, including less prescribing of postnatal glucocorticoids between 1997 and 2005, but adjusting for these differences did not change any conclusions.
“We speculate that prolonged periods of oximetry may be partly responsible for the increasing rate of oxygen dependence observed in 2005 and that this trend may translate into worse lung function when children reach the age at which they will attend school,” the authors offer as another consideration. “The problem with the continuous monitoring of oxygen saturation in infants breathing ambient air is that the fraction of inspired oxygen can only be increased, not decreased.”
They suggest that extra oxygen exposure in infants without “substantial lung disease may cause pulmonary oxygen toxicity, which may impair lung growth. We speculate that such a scenario may have contributed to the prolonged oxygen dependence and worse lung function at 8 years of age that we observed in the current study.”
Less Is Not Always More, Editorialists Say
Michael D. Schreiber, MD, and Jeremy D. Marks, MD, PhD, from the University of Chicago, Illinois, discuss the potential implications of the study’s findings, including the association between higher bronchopulmonary dysplasia rates and greater noninvasive nasal CPAP and supplemental oxygen use in 2005 relative to earlier years, in an accompanying editorial.
The 1991 to 1992 and 2005 cohorts cannot be directly compared because the “lower survival rate and shorter courses of mechanical ventilation used in 1991 through 1992 suggest that those babies at highest risk for bronchopulmonary dysplasia did not survive long enough for it to develop,” they write. But 1997 and 2005 survival rates were similar, as were average gestational ages and rates of antenatal glucocorticoid treatment.
“It appears, then, that the modern tendency to use nasal CPAP and prolonged oxygen therapy and to avoid postnatal glucocorticoids, at least in Australia, has been associated with increased bronchopulmonary dysplasia before discharge from the neonatal intensive care unit and worse lung function 8 years later,” Dr Schreiber and Dr Marks write.
They also address the authors’ supposition that overuse of noninvasive respiratory support may contribute to the findings, noting the potential dilemma of responding to “repeated, brief drops in oxygen saturation in the absence of clinically significant bradycardia” when data on long-term neurodevelopment outcomes are lacking.
“However, in the absence of definitive prospective studies of the effects of treating such episodes — studies that will probably never be conducted — it will be very difficult for neonatologists to tolerate any desaturation episodes without increasing supplemental oxygen,” the editorialists explain. “Nonetheless, the present study provides the evidence that our modern use of prolonged, noninvasive support and oxygen therapy is associated with unanticipated adverse outcomes.”
The reduced forced expiratory volume scores seen among the children born in 2005, however, fell within the normal range for age, sex, and height, they point out.
“Nonetheless, it behooves neonatologists to critically appraise the indications for noninvasive ventilation in every preterm infant,” Dr Schreiber and Dr Marks write. “Furthermore, the data reported by Doyle and colleagues suggest that we should not rush to embrace newer, noninvasive approaches to respiratory support in the belief that less is always more.”
The research was funded by the National Health and Medical Research Council of Australia and the Victorian Government’s Operational Infrastructure Support Program. The authors have disclosed no relevant financial relationships. Dr Schreiber reports receiving grants from Mallinckrodt, and Dr Marks reports holding equity interest in Renacyte BioMolecular Technologies and chairing the scientific advisory board of Maroon Biotech Corporation.
N Engl J Med. 2017;377:329-337, 386-388.
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