MANUSCRIPT CITATION

Doyle LW, Carse E, Adams A, Ranganathan S, Opie G, and Cheong J. Ventilation in extremely preterm infants and respiratory function at 8 years. NEJM 2017; 377(4): 329-337. PMID 28745986.

REVIEWED BY

Lauren Beard, MD Neonatal-Perinatal Fellow University of Colorado, Aurora, CO Lauren.Beard@ucdenver.edu

Clyde J. Wright, MD
Associate Professor
University of Colorado, Aurora, CO Clyde.Wright@ucdenver.edu

TYPE OF INVESTIGATION

Treatment

QUESTION

To compare the respiratory function at 8 years of age in light of prospectively collected perinatal data in survivors of extremely preterm birth (<28 weeks of gestation) born in three different periods – 1991-92, 1997 and 2005.

METHODS

• Design: This data was collected as part of a prospective cohort study.
• Follow-up: Infants from three distinct epochs, 1991-1991, 1997, and 2005 were followed prospectively and reassessed at 8 years of age.
• Setting: All infants admitted in a neonatal intensive care unit (NICU) in Victoria, Australia were eligible for the cohorts examined in this study.
• Population studied: All infants less than 28 weeks and less than 1000g admitted to a NICU in Victoria Australia during the aforementioned time periods.
• Outcomes: Pulmonary function as assessed by spirometry testing in accordance with American Thoracic Society guidelines, with measures of interest including FEV1, FVC, and FEF25-75.
• Analysis: The primary comparison of interest was between the 2005 cohort and the two preceding cohorts (1991-1992 and 1997). Initial comparisons were performed unadjusted and then subsequently, the authors controlled for perinatal variables, use of exogenous surfactants, and post-natal glucocorticoid use. For the pulmonary function data, adjustment for age and height was additionally performed. Linear and logistic regression models were fitted with generalized estimating equations and mean differences or odds ratios were calculated when appropriate.
• Patient follow-up: Approximately 2-6% of the neonates from all three of the time periods were excluded due to lethal anomalies. Of the remaining infants, in the 1991-1992 cohort 47.4% died prior to 8 years of age as compared to 30% and 37% in the 1997 and 2005 cohorts respectively. Of those who survived to 8 years of age 83%, 74%, and 72% returned for follow-up and underwent pulmonary function testing from the 1991-1992, 1997, and 2005 cohorts respectively.

MAIN RESULTS

In ELBW surviving to 8 years, percent predicted FEV1 was significantly lower in 2005 as compared to 1991-1992. Furthermore, the percent predicted FEV1:FVC was lower for the 2005 cohort as compared to both earlier cohorts. No significant difference was noted for FVC or FEF25-75% between groups.

Important differences in perinatal characteristics between cohorts were noted. The 2005 cohort received a higher rate of antenatal steroids and had significantly higher rate of exogenous surfactant administration as compared to the 1991-1992 cohort. Despite this, the mean and median duration of any assisted ventilation was longer for the 2005 cohort compared to the 1991-1992 cohort. A significant increase in the duration of nasal CPAP and oxygen dependence at 36 weeks was observed in the 2005 cohort.

CONCLUSION

The authors conclude that among the most immature neonatal survivors, long-term respiratory function was not improved in the 2005 as compared to the 1991-1992 cohort. This observation was noted despite the increased use of noninvasive ventilation in routine neonatal care between these time periods.

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COMMENTARY

Bronchopulmonary dysplasia (BPD) remains common and the incidence in rising, likel due to increased survival of the tiniest infants (1). The search continues for respiratory care practices that minimize lung injury. A recent meta-analysis demonstrated that routine use of non-invasive ventilation, with or without surfactant (via LISA or INSURE), reduces BPD (2). Importantly, in an era of widespread non-invasive ventilation use, the long-term data on pulmonary outcomes is lacking.

Doyle et al reported long-term follow-up of ELGANs (<28 weeks of gestation) from three epochs (1991-92, 1997, and 2005). Across epochs, infants were well matched in gestational age, birth weight, and gender, while the rates of antenatal glucocorticoid administration, exogenous surfactant administration, and CPAP use increased, and postnatal steroid administration and mechanical ventilation exposure decreased. Secondary to decreased utilization of mechanical ventilation, one might hypothesize that babies born in the 2005 epoch would have improved lung function compared to earlier epochs.

Perhaps surprisingly, rates of BPD were highest in the 2005 epoch. Similarly, measures of pulmonary function obtained at 8 years of age showed that FEV1 and FEV1:FVC were most abnormal in 2005. The authors speculate: “perhaps the assumption that nasal CPAP is less invasive and less injurious to the lung than endotracheal ventilation was incorrect.”

The study is impressive in scope and follow-up. The perinatal clinical data is relevant, measures of lung function are appropriate, and statistical analyses robust. Maybe, as the authors suggest, we should be more selective in which neonates we support with CPAP; CPAP may not be “one size fits all.”

However, there are other potential explanations for these findings. Survival increased over time, which raises the possibility that some babies that survived with lung disease in 2005 would have died in earlier epochs. This differential mortality is not accounted for in the statistical modeling and may be better addressed through a composite outcome incorporating survival. Furthermore, adjusted analyses suggested no confounding effect of decreased postnatal steroid administration. However, whether dexamethasone versus hydrocortisone use evolved during this time is unknown. It is reasonable to hypothesize that more dexamethasone was used in earlier epochs, and more hydrocortisone in later epochs. As dexamethasone is more effective in preventing BPD (3), an analysis considering the type of steroid administered may reveal confounding. Additionally, the use of caffeine and vitamin A was likely dynamic across epochs.

Many clinicians are struggling to reconcile this data with the protective effect of non-invasive ventilation on “short-term” BPD outcomes. Importantly, even in 2005, these babies were ventilated for a mean of 20 days (median 10 days, IQR 2.5-23.5), which is significantly longer than reported in current studies evaluating LISA (4). Similarly, this is longer than a baby currently admitted to the NICU likely experiences. Whether today’s babies will continue to demonstrate a deterioration of lung function compared to earlier epochs is unknown. What is clear is that continued rigorous follow-up as performed by Doyle and colleagues is imperative if we are to continue improving the care that we provide to the highest risk premature neonates.

REFERENCES

1. 1. Stoll BJ, Hansen NI, Bell EF, Walsh MC, Carlo WA, Shankaran S et al. Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012. JAMA 2015; 314(10):1039–13.
   2. Isayama T, Iwami H, McDonald S, Beyene J. Association of noninvasive ventilation strategies with mortality and bronchopulmonary dysplasia among preterm infants. JAMA 2016; 316(6): 611-614.
   3. Watterberg KL. Policy statement — postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 2010; 126(4): 800-808.
   4. Kribs A, Roll C, Göpel W, Wieg C, Groneck P, Laux R et al. Nonintubated surfactant application vs conventional therapy in extremely preterm infants: A randomized clinical trial. JAMA Pediatr 2015; 169(8): 723-728.