EBNEO Commentary: Intratracheal Budesonide Mixed With Surfactant for Extremely Preterm Infants. The PLUSS Randomized Clinical Trial

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 Randomised Clinical Trial. JAMA. 2024; 332(22): 1889–1899. https://doi.org/10.1001/jama.2024.17380. 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 h, 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. URL link: https://ebneo.org/ebneo-commentary-budesonide-with-surfactant-for-ept?preview=true. Sahra Adow: writing – original draft, writing – review and editing. Mona Noureldein: supervision, writing – review and editing. The authors declare no conflicts of interest. The data that support the findings of this study are openly available in [6].