Odors to Insufflate Life

Study Overview
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Brief Summary
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Apneas concern about 85% of premature newborns (NB) born after less than 34 weeks of pregnancy. They are considered as an important risk factor for subsequent neuropsychological deficiency. Current pharmacological treatments are not very effective, and have side effects (agitation, irritability, sleep disorders, tachycardia). Some studies suggest that in NBs with apneas resisting to drugs, a permanent odorisation with a drop of vanillin on the incubator's pillow might reduce the frequency of apneas. This latin square design study will test a controlled olfactory stimulation method, i.e. an olfactometer which controls the odor duration, intensity, and sequence using three different odors, to reduce apneic episodes measured using 24-registration of heart and respiratory rates.

Official Title
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PREMODEUR. Odors to Insufflate Life. Implementation of a Controlled Olfactory Sensorial Method to Decrease Apneas in Premature Newborns. Proof of Concept Study. Latin-square Open Study With Blind Evaluation of Primary Outcome.

Conditions
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Premature Newborns With Gestational Age 28 to 33 Weeks

Intervention / Treatment
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* Other: Olfactory stimulations


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newborns from a single or multiple pregnancy Newborns hospitalized in the Lyon East or Saint-Etienne neonatology services, of both sexes, born before 33 weeks of amenorrhea and after at least 6 days of life, without respiratory disease beside premature birth. Newborns must present at least 3 bradycardia during 3 days, or presenting apneas at observation. Newborns will be randomized if they present at least 3 apnea episodes per 24 hour monitored by RECAN for 3 consecutive days prior to randomization. Written informed consents obtained from the newborns parents or legal representatives Exclusion Criteria: Severe congenital malformation History of allergic reaction to smell stimulation (cough, sneeze, watery eyes, breathing pauses) No social insurance

Ages Eligible for Study
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Minimum Age: 6 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S0 - S1 - S2<br>S0 = no stimulation; washout; S1 = vehicle; washout; S2 = olfactory stimulation | Other: Olfactory stimulations<br>* Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.<br>|
| Experimental: S0 - S2 - S1<br>S0 = no stimulation; washout; S2 = olfactory stimulation; washout; S1 = vehicle | Other: Olfactory stimulations<br>* Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.<br>|
| Experimental: S1 - S0 - S2<br>S1 = vehicle; washout; S0 = no stimulation; washout; S2 = olfactory stimulation | Other: Olfactory stimulations<br>* Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.<br>|
| Experimental: S1 - S2 -S0<br>S1 = vehicle; washout; S2 = olfactory stimulation; washout; S0 = no stimulation | Other: Olfactory stimulations<br>* Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.<br>|
| Experimental: S2 - S0 - S1<br>S2 = olfactory stimulation; washout; S0 = no stimulation; washout; S1 = vehicle | Other: Olfactory stimulations<br>* Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.<br>|
| Experimental: S2 - S1 - S0<br>S2 = olfactory stimulation; washout; S1 = vehicle; washout S0 = no stimulation | Other: Olfactory stimulations<br>* Odors are disseminated using a portable fragrance device, a prototype developed by a research unit, CNRS UMR5292. The device is outside the incubator, the only part inside is a disposable Teflon tube. The odor flux stimulates distally the NBs' nostrils. Odoriferous compounds are placed in glass tubes. This allows the olfactometer to deliver three distinct odors (to avoid habituation) in a random scheme: spearmint odor, vanilla odor, and grapefruit odor (chemicals registered by Chemical Abstracts Service), while controlling for intensity (amount of compound), duration, and odor sequence. For the vehicle period, the glass tubes remain empty. Stimulations occur every 5 minutes, for 5 seconds, they are mixed in medical gas to avoid infection. There are three 24-hour periods, and two 24-hour wash out periods, followed by a maximum of 3 days of surveillance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of respiratory pauses between S1 and S2 | variation of the number of apnea episodes per 24hours -registered on the continuous heart / respiratory monitoring device, defined as a total cessation of breathing superior to 20 seconds (single apnea) or ≤ 20 seconds with decreased heart rate <80 beats / min) - between olfactory stimulation (S2) and placebo stimulation (S1). | per 24hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| difference of the number of apnea episodes between S1 and S2 | difference of the number of apnea episodes between S1 and S2 adjusted on the order of stimulations, gestational age, concomitant treatments likely to interfere with breathing and their dosage | per 24hours | 
| difference of the number of apnea episodes between S0 and S2 | difference in the number of apnea episodes between olfactory stimulation (S2) and no stimulation (S0) | per 24hours | 
| adverse events |  | up to day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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premature newborns, apneas prevention, olfactory stimulation, latin square design