Automated intermittent olfactory stimulation to reduce apnea in preterm infants: results of the PREMODEUR randomized clinical trial.

UNLABELLED: Apnea of prematurity is a frequent clinical complication in very preterm infants. Olfactory stimulation has been proposed as a complementary nonpharmacological strategy to reduce apnea episodes, although previous studies have shown methodological limitations. The PREMODEUR study aimed to evaluate the efficacy of automated intermittent olfactory stimulation using three distinct odorants (mint, grapefruit, and vanilla) in reducing central apnea in preterm infants. This randomized Latin-square crossover trial included 15 preterm infants born before 33 weeks of gestation with respiratory instability (≥ 3 pathological apneas/day). Infants were exposed to three 24-h conditions: no stimulation (S0), sham stimulation with nonodorized air (S1), and olfactory stimulation (S2). The primary endpoint was the incidence rate of central apnea episodes, analyzed using a mixed-effects Poisson model. The primary analysis showed no significant difference between S1 and S2 (IRR = 1.04, 95% confidence interval [0.85-1.28]; p = 0.689). An exploratory post hoc sensitivity analysis excluding one influential participant (01-004) yielded a lower apnea incidence under S2 (IRR = 0.76, 95% confidence interval [0.60-0.97]; p = 0.0254). Because this finding depended on excluding a single participant, it should be interpreted with caution. CONCLUSION: Automated intermittent olfactory stimulation did not significantly reduce apnea incidence in the primary analysis. Given the limited sample size, a modest treatment effect cannot be excluded; however, the exploratory post hoc analysis does not provide confirmatory evidence of efficacy. These findings may help inform the design of larger, adequately powered trials with earlier recruitment and predefined subgroup analyses. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02851979. Prospectively registered on 2 August 2016. WHAT IS KNOWN: • Olfactory stimulation, particularly with vanilla, has been proposed to reduce apnea in preterm infants, but previous studies were limited by small sample sizes, heterogeneous protocols, continuous exposure, and limited use of sham controls. WHAT IS NEW: • PREMODEUR shows that automated intermittent olfactory stimulation with sham-controlled objective monitoring is feasible in neonatal intensive care, with no adverse events observed. The neutral primary finding, together with the sensitivity of exploratory analyses to individual variability, may inform the design of future adequately powered trials.