Nebulized epinephrine to prevent extubation failure in neonates after short-term intubation: a randomized, double-blind, placebo-controlled trial

Abstract Background Extubation failure remains a major challenge in neonatal intensive care. Post-extubation upper-airway obstruction due to mucosal edema is a potentially reversible contributor. Nebulized epinephrine is frequently used in this context, but randomized evidence supporting prophylactic administration in neonates is limited. Methods In this randomized, double-blind, placebo-controlled trial (level III NICU, Mousavi Hospital, Zanjan, Iran; May–December 2025), we enrolled invasively ventilated neonates meeting standardized readiness criteria for their first planned extubation after < 7 days of intubation, with written informed parental/legal guardian consent. We excluded neonates with contraindications to epinephrine, major congenital or structural upper-airway abnormalities, inherited metabolic/neuromuscular disorders, critical conditions at extubation, or recent epinephrine exposure. Participants were randomized to nebulized L-epinephrine (0.5 mg/kg per dose; 1:1000 solution diluted with saline to 4 mL) or volume-matched saline placebo, delivered via nebulizer over 15 min (oxygen flow 6 L/min) every 12 h for 3 days, with cardiorespiratory monitoring. The primary outcome was extubation failure, defined as reintubation within 72 h; reintubation within 24 h, 48 h and 7 days was assessed as a secondary, time-windowed analysis. Results Ninety-seven neonates were randomized (51 epinephrine; 46 placebo). For the primary endpoint, extubation failure (reintubation within 72 h) did not differ between groups (7/51 [13.7%] vs. 7/46 [15.2%]; risk ratio 0.90, 95% CI 0.34–2.38; absolute risk difference − 1.5%, 95% CI − 15.5% to + 12.5%; p = 1.00), and failure rates were similar at 24 h, 48 h and 7 days; no reintubations occurred between 72 h and 7 days. Post-extubation respiratory distress was numerically lower with epinephrine but not statistically significant (13.7% vs. 21.7%; risk ratio 0.63, 95% CI 0.26–1.52; p = 0.423). Adverse effects were infrequent, with similar tachycardia rates (3.9% vs. 4.3%). The confidence intervals were wide and did not exclude clinically meaningful benefit or harm. Conclusions Scheduled nebulized epinephrine initiated after extubation in neonates ventilated for less than one week did not reduce extubation failure compared with placebo. Given the low event rate and wide confidence intervals, a clinically meaningful effect cannot be excluded. The study regimen was not associated with excess short-term adverse events. Trial registration IRCT20201222049802N5 (https//www.irct.ir). Registered 8 May 2025.