MANUSCRIPT CITATION

Brett J. Manley; C. Omar F. Kamlin; Susan M. Donath; Kate L. Francis; Jeanie L. Y. Cheong; Peter A. Dargaville; Jennifer A. Dawson; Susan E. Jacobs; Pita Birch; Steven M. Resnick; Georg M. Schmölzer; Brenda Law; Risha Bhatia; Katinka P. Bach; Koert de Waal; Javeed N. Travadi; Pieter J. Koorts; Mary J. Berry; Kei Lui; Victor S. Rajadurai; Suresh Chandran; Martin Kluckow; Elza Cloete; Margaret M. Broom; Michael J. Stark; Adrienne Gordon; Vinayak Kodur; Lex W. Doyle; Peter G. Davis; Christopher J. D. McKinlay. Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants The PLUSS Randomized Clinical Trial. JAMA. 2024;332(22):1889-1899. doi:10.1001/jama.2024.17380. PMID 39527075

REVIEWED BY

Dr Sahra Adow, Neonatal registrar
University Hospitals Birmingham NHS Foundation Trust
Email: sahra.adow@nhs.net

Dr Mona Noureldein
Neonatal consultant
University Hospitals Birmingham NHS Foundation Trust
Email: mona.noureldein@nhs.net

TYPE OF INVESTIGATION

Multicentre double blinded, two group, parallel, randomised clinical trial.

QUESTION

In preterm infants born <28 weeks gestation (P), does the use of intratracheal budesonide mixed with surfactant given within 48 hours after birth (I), compared to surfactant alone (C), improve survival free from bronchopulmonary dysplasia (O), at 36 weeks corrected gestational age (T)

METHODS

Design and setting: Multicentre, double-blind, 2-group parallel randomised clinical trial conducted in 21 neonatal units in 4 countries (New Zealand, Australia, Canada and Singapore).
Allocation: Eligible infants were allocated to surfactant plus budesonide or surfactant only. The allocation sequence was computer-generated in a 1:1 ratio using a balanced, random permuted block size. These were stratified by study centre, gestational age, prior surfactant therapy and mode of respiratory support at randomisation.
Blinding: Treating clinicians, investigators, parents or caregivers, and outcome assessors were blinded to the interventions. A 2-person intervention team was convened from on-duty staff who were not involved in the clinical care of the study infant.
Follow-up period: recruitment took place between January 2018 and March 2023. Infants were followed up to 36 weeks postmenstrual age.
Patients:
Inclusion criteria:
1. Infants born less than 28 weeks gestation and less than 48 hours of age who were:
• mechanically ventilated or
• requiring non-invasive respiratory support (including nasal continuous positive airway pressure (CPAP), nasal intermittent positive airway pressure (NIPPV) or nasal high flow with clinical decision to treat with surfactant for respiratory distress syndrome.
2. Infants who had received only one surfactant dose remained eligible. They were assessed 6–12 hours later and enrolled if they met the criteria.
Exclusion criteria:
1. Prior postnatal corticosteroid treatment (any route)
2. Unlikely to survive postnatally or not offered active care
3. Expected transfer to a non-participating NICU within 24 hours
4. Major congenital anomaly affecting respiration (e.g. severe pulmonary hypoplasia)

Intervention: infants were randomised to receive 1 or 2 doses of budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first dose; 100 mg/kg second). The first dose was administered post-randomisation; a second dose was given 6–12 hours later if the criteria were still met. The control group received poractant alfa alone at the same doses.
Primary outcome: Survival without bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age, defined by one or more of the following:
1. Need for mechanical ventilation, CPAP, NIPPV, or nasal high flow ≥2 L/min, regardless of oxygen use.
2. Effective FiO₂ ≥0.30 (via Benaron-Benitz formula) on ambient or nasal prong flow <2 L/min to maintain target saturations.
3. Effective FiO₂ ≤0.30 on flow <2 L/min with failed air reduction trial.
Secondary outcomes: 15 outcomes including survival at 36 weeks postmaturation age and survival with BPD that contributed to the primary outcome and nine prespecified hospital outcomes and adverse events.
Analysis and sample size: A sample size of 1038 infants (519 in each group) was required to provide 90% power to detect an absolute increase in survival free of BPD of 10 , with a 2-tailed α = 0.05. To account for any losses, the trial aimed to recruit 1060 infants (530 infants in each group). Mean differences for continuous outcomes were estimated using linear regression; median differences for skewed data were estimated using quantile regression, both with 95% confidence intervals.

MAIN RESULTS

A total of 1,059 infants were enrolled: 524 received budesonide plus surfactant, and 535 received surfactant alone. Mean gestational age was 25.6 weeks (SD 1.3), mean birth weight 775 g (SD 179), and 586 (55.3%) were male. Survival without BPD occurred in 134 (25.6%) infants in the budesonide group and 121 (22.6%) in the surfactant-only group (adjusted risk difference 2.7%, 95% CI –2.1% to 7.4%). At 36 weeks postmenstrual age, 83.2% in the budesonide group and 80.6% in the control group were alive. Of these, BPD was diagnosed in 69.3% and 71.9%, respectively. Adjusted risk differences: • Survival: 1.4% (95% CI –2.9% to 5.7%). • BPD diagnosis: –2.7% (95% CI –8.4% to 3.1%). CONCLUSION In preterm infants receiving surfactant therapy, the early administration of intratracheal budesonide had little to no effect on survival free of BPD at 36 weeks postmenstrual age.

COMMENTARY

Bronchopulmonary dysplasia (BPD) remains a major cause of morbidity in extremely preterm infants, largely driven by inflammation.(1,2) Corticosteroids, particularly inhaled agents such as budesonide, have been extensively studied for their anti-inflammatory effects and potential to reduce systemic toxicity while targeting pulmonary inflammation.(3–5)

 

The PLUSS trial is the largest to evaluate early intratracheal budesonide mixed with surfactant in this population. Despite its robust design and international collaboration, the trial did not show a statistically significant improvement in survival without BPD.(6) Several factors may account for this neutral result.

 

First, although the trial enrolled more immature infants than earlier studies, the cohort was clinically heterogeneous. A considerable proportion had relatively mild respiratory disease at baseline, with 25% of infants not requiring mechanical ventilation. This heterogeneity may have diluted a potential treatment effect. A post hoc analysis revealed that among infants with a baseline FiO₂ >0.50, those treated with budesonide had higher rates of survival without BPD compared to the control group (adjusted RR: 10.2%; 95% CI: 1.5%–18.8%).(6) This aligns with findings from Yeh et al., who restricted enrolment to infants with FiO₂ ≥0.50, reporting a significant reduction in BPD or death (42.0% vs. 66.0%; RR: 0.58; 95% CI: 0.44–0.77). (7)

 

Additionally, the dosing regimen, limited to one or two doses within the first 48 hours, may have been insufficient. Other studies, including that by Yeh et al., employed up to six doses.(7) Two systematic reviews highlighted substantial variability in budesonide dosing regimens, with some studies extending treatment for up to 14 days.(8,9) While prolonged dosing may enhance anti-inflammatory effects, safety concerns must be carefully considered.

 

The NEUROSIS trial, using inhaled budesonide until oxygen or positive pressure support was no longer needed (or up to 32 weeks’ postmenstrual age), reported improvement in survival without BPD (60.0% vs. 53.7%; RR: 0.86; 95% CI: 0.75–1.00), but a slightly higher mortality in the budesonide group (16.9% vs. 13.6%, RR:1.24; 95% CI, 0.91-1.69).(5) This highlights the potential risks of prolonged inhaled corticosteroid exposure.

 

The PLUSS trial reported no increase in mortality or serious adverse events, aligning with earlier studies.(6,7) However, long-term outcomes remain essential, particularly neurodevelopment, growth, and later respiratory health. The NEUROSIS trial also raised concerns about growth suppression.(5)

 

A recent meta-analysis of eight RCTs (n = 2029) found that intratracheal budesonide with surfactant reduced the risk of BPD and mortality (RR for BPD: 0.72; 95% CI: 0.55–0.94; RR for mortality: 0.73; 95% CI: 0.54–0.99), but did not improve survival without BPD, with significant heterogeneity (I² = 94.4%).(9) Of note, PLUSS was included in this meta-analysis.

 

While the PLUSS trial does not support the routine use of intratracheal budesonide mixed with surfactant in all extremely preterm infants, it suggests possible benefit in high-risk subgroups (e.g. FiO₂ ≥0.50 or severe respiratory distress). Future research should prioritise stratified enrollment targeting the high-risk population, explore optimal dosing regimens and treatment durations, and conduct long-term safety assessments to better delineate the role of budesonide in BPD prevention.

REFERENCES

1. Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Research. 2014 Mar;100(3):145–57.
2. Doyle LW, Ranganathan S, Mainzer RM, Cheong JLY. Relationships of Severity of Bronchopulmonary Dysplasia with Adverse Neurodevelopmental Outcomes and Poor Respiratory Function at 7-8 Years of Age. The Journal of Pediatrics. 2024 Jun;269:114005.
3. Hartling L, Liang Y, Lacaze-Masmonteil T. Chorioamnionitis as a risk factor for bronchopulmonary dysplasia: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2012 Jan;97(1):F8–17.
4. Onland W, Van De Loo M, Offringa M, Van Kaam A. Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Neonatal Group, editor. Cochrane Database of Systematic Reviews [Internet]. 2023 Mar 13 [cited 2025 May 24];2024(2). Available from: http://doi.wiley.com/10.1002/14651858.CD010941.pub3
5. Bassler D, Plavka R, Shinwell ES, Hallman M, Jarreau PH, Carnielli V, et al. Early Inhaled Budesonide for the Prevention of Bronchopulmonary Dysplasia. N Engl J Med. 2015 Oct 15;373(16):1497–506.
6. Manley BJ, Kamlin COF, Donath SM, Francis KL, Cheong JLY, Dargaville PA, et al. Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants: The PLUSS Randomized Clinical Trial. JAMA. 2024 Dec 10;332(22):1889.
7. Yeh TF, Chen CM, Wu SY, Husan Z, Li TC, Hsieh WS, et al. Intratracheal Administration of Budesonide/Surfactant to Prevent Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2016 Jan 1;193(1):86–95.
8. Zhang M, Zhang W, Liao H. Efficacy and safety of different inhaled corticosteroids for bronchopulmonary dysplasia prevention in preterm infants: A systematic review and meta-analysis. Respiratory Medicine and Research. 2024 Jun;85:101096.
9. D’lucas Alves Gomes A, Bulhões E, Costa Do Amaral D, Felipe Matos De Sousa L, Cavalcante Lima Júnior E, Airton Alves Ferreira J, et al. Efficacy of intratracheal budesonide plus surfactant vs. Surfactant alone on bronchopulmonary dysplasia in preterm Infants: A meta-analysis of randomized controlled trials. Paediatric Respiratory Reviews. 2025 Mar;S1526054225000272.