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In extremely preterm infants receiving surfactant, early intratracheal budesonide had little to no effect on survival free of bronchopulmonary dysplasia (BPD), a randomized clinical trial found.

Among 1,059 infants, survival without BPD occurred in 25.6% of infants who received budesonide and surfactant and 22.6% of infants who received only surfactant (adjusted risk difference 2.7%, 95% CI −2.1% to 7.4%), according to Brett Manley, PhD, of The Royal Women's Hospital in Parkville, Australia, and colleagues.

At 36 weeks' postmenstrual age, 83.2% of infants were alive in the group that received budesonide and surfactant, of whom 69.3% were diagnosed with BPD; 80.6% were alive in the surfactant-only group, of whom 71.9% were diagnosed with BPD, they reported . For survival, the adjusted risk difference was 1.4% (95% CI −2.9% to 5.7%), and for BPD diagnosis, it was −2.7% (95% CI −8.4% to 3.1%).

"In this multicenter, double-blind randomized clinical trial in extremely preterm infants, we found no clear evidence that intratracheal budesonide mixed with surfactant, compared with surfactant only, increased the likelihood of survival free of BPD," they wrote. "However, a small clinical benefit cannot be entirely excluded, given the positive findings in previous trials and the fact that the point estimate for the primary outcome of survival free of BPD favored the budesonide and surfactant group."

Manley and colleagues were referring to two randomized clinical trials with a total sample size of 381 infants that reported 0.25 mg/kg of intratracheal budesonide mixed with surfactant versus surfactant only was linked to more than a one-third reduced risk in the combined outcome of death or BPD. "Neurodevelopmental impairment at 2 to 3 years of age was also potentially reduced in one of these trials," they said.

Some centers have introduced intratracheal budesonide into routine care based on these findings. Still, "a large pragmatic trial to assess the effectiveness of this therapy across a broader group of extremely preterm infants has been needed to guide international practice, including the smallest and highest-risk infants and those receiving noninvasive respiratory support," they added.

"Whilst disappointing to many of us who were hoping the intervention would improve important short-term outcomes for our most challenging [neonatal intensive care unit] patients, it is important that as a neonatal community we do not roll out new promising treatments without high-level evidence of benefit and safety," Manley told 番茄社区 in an email.

, Erik Jensen, MD, of Stanford University in California, called the findings of the trial a "sobering result."

"Confirmation of the large treatment effects observed in earlier and smaller trials of intratracheal budesonide would have been a breakthrough in the long-standing effort to substantively reduce the rates of BPD in extremely preterm infants," Jensen wrote. "This result also provides another reminder of the importance of large multicenter trials in neonatology to define the risks and benefits of incompletely tested interventions and to understand the generalizability of results obtained from initial, smaller studies."

Among 15 secondary outcomes -- including the two components of the primary outcome (survival at 36 weeks and BPD among survivors), and nine predefined safety outcomes (adverse events) -- there were no clinically important differences in the risk of these outcomes between the budesonide and surfactant and the surfactant-only group, Manley and colleagues reported. "Notably, intratracheal budesonide did not reduce the duration of mechanical ventilation or hospitalization or the need for postnatal systemic corticosteroids or home oxygen," they wrote.

A post hoc subgroup analysis to assess the influence of baseline fraction of inspired oxygen (FIO2) on the intervention effect found that, among 226 infants receiving FIO2 at 0.50 or greater immediately prior to the first trial intervention, those who received budesonide and surfactant had higher survival without BPD than the surfactant-only group (adjusted risk difference 10.2%, 95% CI 1.5%-18.8%). This effect was not seen in 418 infants receiving FIO2 at less than 0.50 (adjusted risk difference 0.4%, 95% CI −5.1% to 5.8%). But the term for interaction between the intervention and baseline FIO2 was not significant.

"Results from ongoing trials will help to clarify if intratracheal budesonide therapy has any clinical utility," the study authors wrote. "We did not observe any serious adverse effects from intratracheal budesonide administration."

The PLUSS randomized clinical trial was conducted in 21 neonatal units in four countries (Australia, New Zealand, Canada, and Singapore), and enrolled infants born at less than 28 weeks' gestation and less than 48 hours old who were mechanically ventilated or who were receiving noninvasive respiratory support and had a clinical decision to treat with surfactant. Infants were recruited from January 2018 to March 2023, and the last participant was discharged from the hospital in August of last year.

Ultimately, 524 infants received budesonide and surfactant and 535 received only surfactant. Infants had a mean gestational age of 25.6 weeks and a mean birth weight of 775 g. Slightly more than half were male, and almost all had been exposed to antenatal corticosteroids.

Limitations of the trial included that infants were eligible for inclusion even if they had previously been treated with surfactant. They also added that, "the dose of budesonide was based on previous preclinical and clinical trials that reported benefit, but it is possible that the individual doses or cumulative dose of budesonide were insufficient to achieve a therapeutic effect in the high-risk population studied."

Results of the PLUSS trial, "suggest that intratracheal budesonide mixed with surfactant should not become a routine therapy for extremely preterm infants at this time," Manley said. "The results of other studies, and of longer-term follow-up of surviving infants enrolled in PLUSS at 2 years [PLUSS2] will be important."

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