Manuscript Citation

McEvoy CT, MacDonald KD, Go MA, Milner K, Harris J, Schilling D, Olson M, Tiller C, Slaven JE, Bjerregaard J, Vu A, Martin A, Mamidi R, Schelonka RL, Morris CD, Tepper RS. Extended Continuous Positive Airway Pressure in Preterm Infants Increases Lung Growth at 6 Months: A Randomized Controlled Trial. Am J Respir Crit Care Med. 2025 Feb 20. doi: 10.1164/rccm.202411-2169OC. Epub ahead of print. PMID: 39977011

Reviewed By

Mackenzie Parker, MD
University of Colorado School of Medicine
mackenzie.parker@childrenscolorado.org

Kathleen Hannan, MD
University of Colorado School of Medicine
kathleen.hannan@childrenscolorado.org

Type of Investigation

Treatment

Question

In stable preterm infants born at >24 and <32 weeks gestation age who required CPAP for >24 hours for clinical care (P), does two weeks of extended CPAP (eCPAP) (I) versus CPAP discontinuation to room air at point of achieving respiratory stability (C) increase lung growth, measured by alveolar volume, at 6 months corrected age (OT).

Methods

Design: Single center randomized controlled trial

Allocation and Stratification: Eligible infants were neonates born at >24 and <32 weeks gestational age that required >24 hours of CPAP for clinical care, either as initial respiratory support or respiratory support after extubation from invasive ventilation. If infants met CPAP respiratory stability criteria* for >12 hours at <35 weeks postmenstrual age (PMA), families were approached for informed consent. Allocation was performed using a permuted block randomization, stratified by delivery GA (<29 and >29 weeks). Qualifying twin pairs were allocated to the same treatment block by randomization of the first twin.

*CPAP respiratory stability criteria include: CPAP of 5 cm H2O, 21% FiO2, respiratory rate <70 breaths/minute, retractions score < 1, fewer than 3 apnea/bradycardia/desaturation events per hour, average SpO2 > 86% for 90% of the time in past 24 hours, tolerating time off CPAP for routine cares, and not being treated for patent ductus arteriosus or sepsis.

Blinding: Blinding the treatment allocation was not possible during the treatment period in the NICU, however, all assessors of infant outcomes from NICU discharge through 12 months of age were blind to treatment allocation in the NICU. The statistician was also blinded to allocation.

Follow-up period: Lung function testing was performed outpatient at 6 months corrected age. In addition, respiratory questionnaires were administered monthly from NICU discharge through 12 months corrected age.

Setting: Oregon Health & Science University level IV NICU, a 46-bed unit that admits approximately 650 infants per year.

Patients: Eligible infants were born between 24 and 32 weeks GA and required >24 hours of CPAP for clinical care. Infants were excluded for congenital malformations, IUGR, LGA, inability of the research team to communicate with parents/guardian, triplets, complex maternal medical history, transferred to another facility, or did not achieve respiratory stability criteria on CPAP at <35 weeks PMA.

Intervention: CPAP was administered via a bubble CPAP system with Hudson nasal prongs with chinstrap applied. At the study center, all infants are maintained on CPAP until “CPAP respiratory stability criteria” (see above) are met. After stability criteria met, a measurement of functional residual capacity (FRC) was taken in all infants. The intervention (eCPAP) group was then maintained on CPAP of 5 cm H2O for 14 days after respiratory stability criteria was achieved whereas the control (dCPAP) group transitioned from CPAP to room air after achieving respiratory stability. Clinical stability of each infant was monitored daily by the research team. Infants allocated to dCPAP were placed back on CPAP for signs of respiratory distress and infants allocated to eCPAP were taken off of CPAP if significant nasal breakdown or abdominal distension occurred. FRC measurements were repeated at the end of the two weeks for both groups.

Outcomes

Primary outcome: Alveolar volume (VA), measured by single breath hold technique, at 6 months corrected age.

Secondary outcomes: Lung diffusion capacity to carbon monoxide (DL) and forced expiratory flow (FEF) at 6 months corrected age. An additional exploratory outcome assessed parental recorded occurrence of wheeze up to 12 months corrected age.

Analysis and Sample Size: Based on a hypothesized 12% increase in VA in eCPAP vs dCPAP, a sample size of 34 patients per group was needed to yield 80% power. The research team aimed to allocate 100 infants in the NICU to account for loss to follow up at six months. A total of 276 infants were screened for eligibility. 168 failed screening (see Figure 1) and 100 infants were enrolled with 54 infants allocated to eCPAP and 46 to dCPAP. Mean (SD) PMA and weight at time of treatment allocation was 32.4 (0.9) weeks and 1,579 (258) g in the eCPAP group compared to 32.4 (0.8) weeks and 1,582 (243) grams in the dCPAP group. Pulmonary function testing measurements were obtained in 93 of 98 eligible infants at 6 months corrected age (95% of eligible infants). Analysis was based on intention to treat with a secondary per protocol analysis.

Patient follow-up: 100% – no participants withdrew consent or were lost to follow up.

Main Results: Both groups had similar FRC at study allocation, while infants allocated to the eCPAP group had significantly higher FRC at the end of the 2 week treatment period. Infants randomized to eCPAP had statistically significant increases in VA, DL, and FEF at 6 months corrected age. There was not a significant difference in parental reported occurrence of wheeze between the two groups. There were no serious adverse events related to the study intervention.

Conclusion

For stable preterm infants in the NICU, extended use of CPAP stimulated lung growth that persisted after NICU discharge.

Commentary

Bronchopulmonary dysplasia (BPD) is a common and challenging complication of preterm birth. Despite advances in the use of antenatal steroids, surfactant, and lung protective ventilation, rates of BPD are stable or even increasing(1). Ongoing research into improving respiratory outcomes in preterm infants is essential. In this context, McEvoy et al. investigate whether extended CPAP (eCPAP) beyond respiratory stability enhances lung growth and reduces long-term respiratory issues.

 

First described in the 1970s and gaining popularity in the 2000s, the use of CPAP in the NICU is well established, with early use consistently shown to decrease rates of BPD compared to invasive ventilation by avoiding ventilator-induced lung injury while maintaining FRC, stabilizing the compliant chest wall of infants, and accelerating lung tissue growth(2–4). Early CPAP administration is the standard of care in preterm infants. However, the optimal timing to discontinue CPAP in the stable preterm infant remains unclear(5).

 

McEvoy et al. address this gap with a trial comparing two weeks of eCPAP to standard discontinuation after achieving respiratory stability. In keeping with the author’s hypothesis, pulmonary function testing revealed greater lung growth in the eCPAP group. The study’s strengths include its randomized design with blinded outpatient follow up and remarkably high participant retention. Measurement of lung function at six months corrected age, rather than shortly after CPAP discontinuation, likely represents a true increase in lung growth. This study also supports recently published findings that eCPAP use does not prolong hospitalization(6).

 

However, several limitations in addition to those presented by the authors warrant consideration. While the authors report that there was no difference between the groups in terms of timing of oral feeds or age at discharge, we question whether additional potential adverse effects of eCPAP could be experienced, notably effects on developmental therapy participation, family bonding, or long-term neurodevelopment(7). Additionally, there are limits to the generalizability of this study’s findings. As noted in the discussion, infants with more severe respiratory disease were excluded, including those born <24 weeks GA and those not stable on CPAP by 35 weeks PMA. Only 12% of participants were born <29 weeks, limiting applicability to the highest-risk group for BPD and its associated complications. Given the high health care utilization of infants born at <24 weeks and those with more severe BPD(8,9), investigating potential therapies to improve their lung health remains prudent. Further, while this study compared eCPAP to room air, many institutions wean from CPAP to high flow or low flow nasal cannula, which offer varying amounts of respiratory support. Whether these alternatives offer similar benefits for lung growth remains unknown.

 

In conclusion, the study supports eCPAP as a safe, nonpharmacologic approach to promoting lung growth in preterm infants. Further research should explore the optimal duration of CPAP therapy, evaluate its use in more severely ill infants, and compare it with other common weaning strategies. Longitudinal follow-up of this cohort would give exciting insight into whether extended CPAP can improve long term respiratory health into childhood and adulthood.

References

1. Jensen EA, Edwards EM, Greenberg LT, Soll RF, Ehret DEY, Horbar JD. Severity of Bronchopulmonary Dysplasia Among Very Preterm Infants in the United States. Pediatrics [Internet]. 2021 Jul;148(1). Available from: http://dx.doi.org/10.1542/peds.2020-030007
2. Ramaswamy VV, Devi R, Kumar G. Non-invasive ventilation in neonates: a review of current literature. Front Pediatr. 2023 Nov 28;11:1248836.
3. Foglia EE, Jensen EA, Kirpalani H. Delivery room interventions to prevent bronchopulmonary dysplasia in extremely preterm infants. J Perinatol. 2017 Nov;37(11):1171–9.
4. Morley CJ, Davis PG, Doyle LW, Brion LP, Hascoet JM, Carlin JB. Nasal CPAP or intubation at birth for very preterm infants. N Engl J Med. 2008 Feb 14;358(7):700–8.
5. Bamat N, Jensen EA, Kirpalani H. Duration of continuous positive airway pressure in premature infants. Semin Fetal Neonatal Med. 2016 Jun 3;21(3):189–95.
6. Massarelli C, Weintraub A, Bush D, Ratner V, Juliano C. Duration of continuous positive airway pressure: associations with length of stay and oral feeding patterns in a level IV neonatal intensive care unit. J Perinatol [Internet]. 2025 Feb 11 [cited 2025 Apr 11]; Available from: http://dx.doi.org/10.1038/s41372-025-02221-4
7. Antinmaa J, Salonen J, Jääskeläinen SK, Kaljonen A, Lapinleimu H. Continuous positive airway pressure treatment may negatively affect auditory maturation in preterm infants. Acta Paediatr. 2021 Nov;110(11):2976–83.
8. Bell EF, Hintz SR, Hansen NI, Bann CM, Wyckoff MH, DeMauro SB, et al. Mortality, in-hospital morbidity, care practices, and 2-year outcomes for extremely preterm infants in the US, 2013-2018. JAMA. 2022 Jan 18;327(3):248–63.
9. Kurihara C, Zhang L, Mikhael M. Newer bronchopulmonary dysplasia definitions and prediction of health economics impacts in very preterm infants. Pediatr Pulmonol. 2021 Feb;56(2):409–17.