Inhaled Epinephrine for Extubation in Preterm Newborns: A Double-Blind, Randomized Trial

Abstract

Background: Timely extubation of intubated neonates from mechanical ventilation (MV) is ideal; however, the risk of reintubation remains a subject of debate. Objectives: The objective of this study is to evaluate whether inhaled epinephrine can prevent reintubation following extubation in preterm newborns. Methods: A two-arm, double-blind, placebo-controlled, single-center randomized trial was conducted in the Neonatal Intensive Care Unit (NICU) of Shariati Hospital, Tehran, Iran, between 2021 and 2023. Eligible neonates included those with a gestational age ≤ 34 weeks, birth weight ≤ n1700 g, and MV for more than three days. Exclusion criteria were chronic pulmonary, cardiac, or neurologic disease; genetic or syndromic disorders; culture-positive sepsis; unstable blood pressure for gestational age; or tachycardia > 180 beats per minute during nebulization. Enrolled infants were randomly assigned, using block randomization and sealed envelopes, to receive either inhaled L-epinephrine or distilled water, with blinding preserved by using identical syringes. The intervention group received inhaled L-epinephrine (1:10,000) at 0.5 mL/kg via nebulizer every three hours on the first day, and subsequently every six and eight hours over a 72-hour period. All patients received standard post-extubation noninvasive positive pressure ventilation (NIPPV). The primary outcome was reintubation within 48 hours; secondary outcomes included the fraction of inspired oxygen (FiO2) required at 24 hours after extubation and the partial pressure of carbon dioxide (PCO2) at six hours. Multivariable regression was employed to assess the effects of demographic and clinical factors, adjusting for potential confounders. Results: Sixty newborns were enrolled; six did not receive the allocated intervention and died. Among the remaining 54 newborns, gestational ages were 31.3 ± 2.3 and 30.6 ± 2.3 weeks for the intervention and control groups, respectively (P = 0.414). The mean weight of neonates was 1443.3 ± 210.1 g in the intervention group and 1330.6 ± 326.2 g in the control group (P = 0.138). The frequency of reintubation was 5 (18.5%) in the intervention group and 9 (33.3%) in the control group (P = 0.214). Multivariable binary logistic regression indicated that inhaled epinephrine was not significantly associated with reintubation. The intervention group had a mean FiO2 of 24.2 ± 3.4%, significantly lower than the control group (33.5 ± 5.3%, P < 0.001). After adjusting for birth weight, gestational age, and duration of intubation in multivariable linear regression, FiO2 remained significantly lower in the intervention group, with an average reduction of 10.71% [95% confidence interval (CI) = -12.97 to -8.45, P < 0.001]. Conclusions: Although there was no statistically significant difference in reintubation rates between the groups, the intervention group required a significantly lower FiO2 via noninvasive ventilation after extubation, highlighting the potential to reduce severe complications associated with high oxygenation in preterm neonates.