Protocol of controlled odorant stimulation for reducing apnoeic episodes in premature newborns: a randomised open-label Latin-square study with independent evaluation of the main endpoint (PREMODEUR).

INTRODUCTION: Apnoea affects 85% of premature infants under 34 weeks of age and would be an important risk factor for subsequent neuropsychological disorders. Currently, premature children with life-threatening apnoeas receive stimulants such as methylxanthines (mainly, caffeine) or doxapram (an analeptic unlicensed in children under 15). However, these products have undesirable effects (hyperarousal, irritability, sleep disorders, tachycardia) and are not always effective because apnoea does persist in some premature newborns. Previous studies have indicated that odorant stimulation, a non-invasive intervention, may stimulate the respiratory rhythm. The objective of the present protocol is to reduce the occurrence of apnoeic episodes in premature newborns by controlled odorant stimulation added to current pharmacological treatments.

METHODS AND ANALYSIS: The project is a randomised open-label Latin-square trial with independent evaluation of the main endpoint. It will include 60 preterm neonates from two university hospital neonatal intensive care units over 2 years (2021-2023). Each newborn will receive no (S0), sham (S1) or real olfactory stimulation (S2) in random order. During S2, three distinct odorants (mint, grapefruit and vanilla) will be delivered successively, in puffs, over 24 hours. Mint and grapefruit odours stimulate the main and the trigeminal olfactory pathways, whereas vanilla odour stimulates only the main olfactory pathway. A statistical analysis will compare the incidence of apnoeic episodes during S1 versus S2 using a mixed effects Poisson model.

ETHICS AND DISSEMINATION: Ethical approval was obtained from the Comité de Protection des Personnes Île-de-France XI (# 2017-AO13-50-53). The results will be disseminated through various scientific meetings, specialised peer-reviewed journals and, whenever possible, posted on appropriate public websites.

TRIAL REGISTRATION NUMBER: NCT02851979; Pre-results.