Nebulized Epinephrine Fails to Prevent Extubation Failure in Newborns, Trial Finds

Every year, thousands of newborns in neonatal intensive care units around the world pass through the same delicate ritual: the removal of an endotracheal tube after a period of invasive mechanical ventilation. The moment of extubation is meant to mark a turning point toward recovery, but for a small yet stubborn fraction of infants it becomes the start of a new crisis. When the tube comes out, the upper airway can swell shut, breathing grows labored, and within hours the baby may need to be intubated all over again. A research team in Iran has now tested one of the most commonly deployed countermeasures against this scenario, and the results, published in BMC Pediatrics, are a sobering reminder of how hard it is to outsmart airway physiology in the smallest patients.

The trial, led by Asghar Marzban and SeyedehFatemeh Mousavi of Zanjan University of Medical Sciences, set out to answer a deceptively simple question: if you give nebulized epinephrine on a fixed schedule after extubation, can you prevent the baby from failing to breathe on their own? Epinephrine, the same adrenaline-derived compound that has saved countless infants from croup, constricts blood vessels in the airway mucosa and is thought to shrink the edema that narrows the passage. It is widely used in neonatal units exactly for this purpose, often as a rescue treatment when stridor appears. But as the authors note, the randomized evidence supporting its prophylactic use in newborns has been thin, and the practice has persisted largely on physiological plausibility and clinical habit rather than on firm trial data.

To settle the question, the investigators designed a randomized, double-blind, placebo-controlled trial at the level III neonatal intensive care unit of Ayatollah Mousavi Hospital in Zanjan, running from May to December 2025. They enrolled invasively ventilated neonates who met standardized readiness criteria for their first planned extubation after less than seven days of intubation, with written informed consent from a parent or legal guardian. Neonates with contraindications to epinephrine, major congenital or structural upper-airway abnormalities, inherited metabolic or neuromuscular disorders, critical conditions at the time of extubation, or recent epinephrine exposure were excluded. The narrow focus on short-term intubation was deliberate: the longer a tube sits in the airway, the more complex the edema and the harder it is to attribute failure to a single reversible cause.

The intervention itself was meticulously standardized. Participants were randomized to receive nebulized L-epinephrine at a dose of 0.5 milligrams per kilogram per dose, drawn from a 1:1000 solution and diluted with saline to a total volume of four milliliters, or a volume-matched saline placebo. The drug was delivered through a nebulizer over fifteen minutes at an oxygen flow of six liters per minute, every twelve hours for three days, with continuous cardiorespiratory monitoring throughout. The primary outcome was extubation failure, defined as the need for reintubation within seventy-two hours. The team also tracked reintubation within twenty-four hours, forty-eight hours, and seven days as secondary, time-windowed analyses, along with post-extubation respiratory distress and adverse effects such as tachycardia.

Ninety-seven neonates were randomized, fifty-one to the epinephrine arm and forty-six to placebo. When the data came in, the primary endpoint showed no difference between the groups. Seven of the fifty-one babies in the epinephrine arm, or 13.7 percent, needed reintubation within seventy-two hours, compared with seven of the forty-six babies, or 15.2 percent, in the placebo arm. The risk ratio was 0.90 with a 95 percent confidence interval of 0.34 to 2.38, and the absolute risk difference was minus 1.5 percent with a confidence interval spanning from minus 15.5 percent to plus 12.5 percent. The p value was 1.00. In plain terms, the scheduled epinephrine regimen did nothing to reduce the likelihood that a baby would fail extubation in the critical first three days.

The time-windowed secondary analyses told the same story. Failure rates were similar at twenty-four hours, forty-eight hours, and seven days, and, notably, no reintubations occurred at all between seventy-two hours and seven days in either arm. Post-extubation respiratory distress was numerically lower with epinephrine, 13.7 percent versus 21.7 percent, but the difference was not statistically significant, with a risk ratio of 0.63 and a confidence interval of 0.26 to 1.52 and a p value of 0.423. Adverse effects were infrequent and balanced between the arms, with tachycardia rates of 3.9 percent in the epinephrine group and 4.3 percent in the placebo group. The regimen, in other words, was not associated with excess short-term harm, but neither did it deliver the benefit that clinicians have long hoped for.

The authors are careful to frame their conclusions within the statistical limits of the study. The confidence intervals were wide and did not exclude clinically meaningful benefit or harm. With only fourteen reintubations across both arms, the trial was powered for a much larger effect than the roughly 14 to 15 percent failure rate actually observed. A risk ratio of 0.90 with a confidence interval reaching down to 0.34 means the data are compatible with anything from a modest reduction to a substantial one, and equally with a modest increase in risk. The low event rate, paradoxically a sign of good neonatal care, makes it statistically harder to detect a true benefit, and the authors explicitly state that a clinically meaningful effect cannot be excluded on the basis of this trial alone.

What does this mean for the neonatal units that have been reaching for the nebulizer after every extubation? The most direct implication is that scheduled nebulized epinephrine, initiated after extubation in neonates ventilated for less than one week, should not be assumed to prevent extubation failure. The trial does not rule out benefit in selected subgroups, such as babies with more severe airway edema or those with specific risk factors for obstruction, and it does not address rescue use of epinephrine once stridor has already appeared. But as a one-size-fits-all prophylactic regimen, the fixed twelve-hourly dosing schedule tested here did not move the needle on the outcome that matters most: keeping the tube out.

The study also highlights a broader truth about neonatal intensive care research. Extubation failure remains a major challenge in the field, and post-extubation upper-airway obstruction due to mucosal edema is a potentially reversible contributor, which is precisely why the epinephrine hypothesis has endured. But the trial demonstrates how easily a plausible mechanism can fail to translate into clinical benefit when tested rigorously. The regimen was safe, with no excess adverse events, which means the negative result is not a story about harm but about the limits of a widely used practice. For clinicians, the message is that the decision to use nebulized epinephrine after extubation should rest on individual clinical judgment rather than on the assumption that a fixed schedule will protect every baby.

For now, the trial stands as a rigorous test of a common practice, registered prospectively in the Iranian Registry of Clinical Trials and approved by the ethics committee of Zanjan University of Medical Sciences. It does not close the book on nebulized epinephrine in neonates, but it does raise the bar for the evidence required before the drug is deployed as routine prophylaxis. As the authors conclude, scheduled nebulized epinephrine initiated after extubation in neonates ventilated for less than one week did not reduce extubation failure compared with placebo, and given the low event rate and wide confidence intervals, a clinically meaningful effect cannot be excluded. In the high-stakes world of the neonatal intensive care unit, where every breath counts and every tube removal is a calculated gamble, that is a finding worth taking seriously.

Subject of Research: Neonatology

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

Article References: Marzban, A., Mousavi, S., Mokhtari, S., Jafari, N., Bagherivand, M., Habibi, S., Esmaeili, F., & Motiei Langroudi, S. M. (2026). Nebulized epinephrine to prevent extubation failure in neonates after short-term intubation: a randomized, double-blind, placebo-controlled trial. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07825-z

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07825-z

Keywords: neonatology, extubation failure, nebulized epinephrine, randomized controlled trial, mechanical ventilation, upper airway obstruction, BMC Pediatrics, Nebulized, epinephrine, prevent, extubation, failure