{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:10:09Z","timestamp":1790770209110,"version":"4.1.0"},"reference-count":47,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"unspecified","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Direction G\u00e9n\u00e9rale de l\u2019Offre de\n                                    Soins","award":["DGOS -\n                                    PHRCI - 2017"],"award-info":[{"award-number":["DGOS -\n                                    PHRCI - 2017"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Apnoea affects 85% of premature infants under 34 weeks of age and\n                            would be an important risk factor for subsequent neuropsychological\n                            disorders. Currently, premature children with life-threatening apnoeas\n                            receive stimulants such as methylxanthines (mainly, caffeine) or\n                            doxapram (an analeptic unlicensed in children under 15). However, these\n                            products have undesirable effects (hyperarousal, irritability, sleep\n                            disorders, tachycardia) and are not always effective because apnoea does\n                            persist in some premature newborns. Previous studies have indicated that\n                            odorant stimulation, a non-invasive intervention, may stimulate the\n                            respiratory rhythm. The objective of the present protocol is to reduce\n                            the occurrence of apnoeic episodes in premature newborns by controlled\n                            odorant stimulation added to current pharmacological\n                            treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>The project is a randomised open-label Latin-square trial with\n                            independent evaluation of the main endpoint. It will include 60 preterm\n                            neonates from two university hospital neonatal intensive care units over\n                            2 years (2021\u20132023). Each newborn will receive no (S0), sham (S1) or\n                            real olfactory stimulation (S2) in random order. During S2, three\n                            distinct odorants (mint, grapefruit and vanilla) will be delivered\n                            successively, in puffs, over 24 hours. Mint and grapefruit odours\n                            stimulate the main and the trigeminal olfactory pathways, whereas\n                            vanilla odour stimulates only the main olfactory pathway. A statistical\n                            analysis will compare the incidence of apnoeic episodes during S1 versus\n                            S2 using a mixed effects Poisson model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>Ethical approval was obtained from the Comit\u00e9 de Protection des\n                            Personnes \u00cele-de-France XI (# 2017-AO13-50-53). The results will be\n                            disseminated through various scientific meetings, specialised\n                            peer-reviewed journals and, whenever possible, posted on appropriate\n                            public websites.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" specific-use=\"clinicaltrial pre-results\" xlink:href=\"NCT02851979\">NCT02851979<\/jats:ext-link>\n                      ; Pre-results.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2020-047141","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T11:22:31Z","timestamp":1667560951000},"page":"e047141","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Protocol of controlled odorant stimulation for reducing apnoeic episodes\n                        in premature newborns: a randomised open-label Latin-square study with\n                        independent evaluation of the main endpoint (PREMODEUR)"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct02851979","registry":"10.18810\/clinical-trials-gov","type":"preResults"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7730-266X","authenticated-orcid":false,"given":"Patricia","family":"Duchamp-Viret","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huu Kim","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Maucort-Boulch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Remontet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurore","family":"Guyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Cividjian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Thevenet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Iwaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Galletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behrouz","family":"Kassai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Cornaton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Plaisant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Claris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Gauthier-Moulinier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,9,13]]},"reference":[{"key":"2022110304314600000_11.9.e047141.1","unstructured":"Jouen F , H\u00e9nocq A . Du nouveau-n\u00e9 Au nourrisson:\n                            Recherche fondamentale et p\u00e9diatrie. Paris PUF,\n                            1991."},{"key":"2022110304314600000_11.9.e047141.2","doi-asserted-by":"publisher","DOI":"10.3390\/bs3010154"},{"key":"2022110304314600000_11.9.e047141.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-9384(97)00187-X"},{"key":"2022110304314600000_11.9.e047141.4","doi-asserted-by":"crossref","first-page":"266","DOI":"10.3109\/00016488509108907","article-title":"Vomeronasal organs and nerves of Jacobson in the human fetus","volume":"99","author":"Nakashima","year":"1985","journal-title":"Acta Otolaryngol"},{"key":"2022110304314600000_11.9.e047141.5","doi-asserted-by":"crossref","unstructured":"Marlier L , Schaal B , Gaugler C , et al . Olfaction\n                            in Premature Human Newborns: Detection and Discrimination Abilities Two\n                            Months Before Gestational Term. In: Marchlewska-Koj A , Lepri JJ ,\n                            M\u00fcller-Schwarze D , eds. Chemical signals in vertebrates 9. Boston, MA:\n                            Springer, 2001.","DOI":"10.1007\/978-1-4615-0671-3_27"},{"key":"2022110304314600000_11.9.e047141.6","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1207\/S15327078IN0301_3","article-title":"Olfactory familiarization and discrimination in preterm and full-term newborns","volume":"3","author":"Goubet","year":"2002","journal-title":"Infancy"},{"key":"2022110304314600000_11.9.e047141.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(78)80307-2"},{"key":"2022110304314600000_11.9.e047141.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2004.04.003"},{"key":"2022110304314600000_11.9.e047141.9","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2004-0865"},{"key":"2022110304314600000_11.9.e047141.10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.arcped.2006.09.006","article-title":"[The olfactory sensitivity of the premature newborn]","volume":"14","author":"Marlier","year":"2007","journal-title":"Arch Pediatr"},{"key":"2022110304314600000_11.9.e047141.11","first-page":"273","article-title":"The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies","volume":"17","author":"Henderson-Smart","year":"1981","journal-title":"Aust Paediatr J"},{"key":"2022110304314600000_11.9.e047141.12","first-page":"CD000074","article-title":"Doxapram treatment for apnea in preterm infants","author":"Henderson-Smart","year":"2004","journal-title":"Cochrane Database Syst Rev"},{"key":"2022110304314600000_11.9.e047141.13","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.5665\/sleep.2192","article-title":"Sleep apnea in early childhood associated with preterm birth but not small for gestational age: a population-based record linkage study","volume":"35","author":"Raynes-Greenow","year":"2012","journal-title":"Sleep"},{"key":"2022110304314600000_11.9.e047141.14","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00825"},{"key":"2022110304314600000_11.9.e047141.15","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jp.7211182"},{"key":"2022110304314600000_11.9.e047141.16","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1542\/peds.55.5.584","article-title":"The xanthine treatment of apnea of prematurity","volume":"55","author":"Lucey","year":"1975","journal-title":"Pediatrics"},{"key":"2022110304314600000_11.9.e047141.17","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(87)80569-3"},{"key":"2022110304314600000_11.9.e047141.18","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/S0022-3476(84)80568-5","article-title":"Doxapram in the treatment of idiopathic apnea of prematurity unresponsive to aminophylline","volume":"104","author":"Alpan","year":"1984","journal-title":"J Pediatr"},{"key":"2022110304314600000_11.9.e047141.19","doi-asserted-by":"publisher","DOI":"10.1136\/adc.59.3.281"},{"key":"2022110304314600000_11.9.e047141.20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/251047","article-title":"Doxapram use for apnoea of prematurity in neonatal intensive care","volume":"2013","author":"Prins","year":"2013","journal-title":"Int J Pediatr"},{"key":"2022110304314600000_11.9.e047141.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2007.03.005"},{"key":"2022110304314600000_11.9.e047141.22","first-page":"227","article-title":"Sleep, sleeplessness, and sleep disruptions in infants and young children","volume":"17","author":"Ferber","year":"1985","journal-title":"Ann Clin Res"},{"key":"2022110304314600000_11.9.e047141.23","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.biopsycho.2009.12.001","article-title":"Arousal response to hypoxia in newborns: insights from animal models","volume":"84","author":"Gallego","year":"2010","journal-title":"Biol Psychol"},{"key":"2022110304314600000_11.9.e047141.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409782102"},{"key":"2022110304314600000_11.9.e047141.25","first-page":"77","article-title":"Influence of repeated exposure to rapidly developing hypoxaemia on the arousal and cardiopulmonary response to rapidly developing hypoxaemia in lambs","volume":"11","author":"Fewell","year":"1989","journal-title":"J Dev Physiol"},{"key":"2022110304314600000_11.9.e047141.26","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-011-1409-6"},{"key":"2022110304314600000_11.9.e047141.27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0803836"},{"key":"2022110304314600000_11.9.e047141.28","doi-asserted-by":"publisher","DOI":"10.1093\/chemse\/bjp079"},{"key":"2022110304314600000_11.9.e047141.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2005.01.058"},{"key":"2022110304314600000_11.9.e047141.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.07.048"},{"key":"2022110304314600000_11.9.e047141.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2007.12.001"},{"key":"2022110304314600000_11.9.e047141.32","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0009464","article-title":"Cardiac muscarinic receptor overexpression in sudden infant death syndrome","volume":"5","author":"Livolsi","year":"2010","journal-title":"PLoS One"},{"key":"2022110304314600000_11.9.e047141.33","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp048194"},{"key":"2022110304314600000_11.9.e047141.34","first-page":"261","article-title":"Olfactory stimulation by vanillin prevents apnea in premature newborn infants","volume":"23","author":"Edraki","year":"2013","journal-title":"Iran J Pediatr"},{"key":"2022110304314600000_11.9.e047141.35","doi-asserted-by":"crossref","DOI":"10.1111\/jjns.12271","article-title":"Impact of the odors of Vanilla extract and breast milk on the frequency of apnea in preterm neonates","volume":"17","author":"Kanbur","year":"2020","journal-title":"Jpn J Nurs Sci"},{"key":"2022110304314600000_11.9.e047141.36","doi-asserted-by":"publisher","DOI":"10.2307\/1132193"},{"key":"2022110304314600000_11.9.e047141.37","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1440-1789.2010.01190.x","article-title":"Developmental alterations of the spinal trigeminal nucleus disclosed by substance P immunohistochemistry in fetal and infant sudden unexplained deaths","volume":"31","author":"Lavezzi","year":"2011","journal-title":"Neuropathology"},{"key":"2022110304314600000_11.9.e047141.38","unstructured":"Diggle SL , Liang PPJ , Zeger KY . Analysis of\n                            longitudinal data. New-York: Oxford Univ Pr,\n                            1994."},{"key":"2022110304314600000_11.9.e047141.39","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060082"},{"key":"2022110304314600000_11.9.e047141.40","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(87)91340-0"},{"key":"2022110304314600000_11.9.e047141.41","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-7634(97)00010-9"},{"key":"2022110304314600000_11.9.e047141.42","doi-asserted-by":"publisher","DOI":"10.1016\/0013-4694(89)90222-8"},{"key":"2022110304314600000_11.9.e047141.43","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0154-12.2012"},{"key":"2022110304314600000_11.9.e047141.44","doi-asserted-by":"publisher","DOI":"10.1177\/0145445501254002"},{"key":"2022110304314600000_11.9.e047141.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.017"},{"key":"2022110304314600000_11.9.e047141.46","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s00405-017-4796-0","article-title":"Olfactory stimulation may promote oral feeding in immature newborn: a randomized controlled trial","volume":"275","author":"Cao Van","year":"2018","journal-title":"Eur Arch Otorhinolaryngol"},{"key":"2022110304314600000_11.9.e047141.47","doi-asserted-by":"publisher","DOI":"10.1254\/jphs.10R05CP"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2020-047141","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T11:22:55Z","timestamp":1667560975000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2020-047141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9]]},"references-count":47,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9,13]]},"published-print":{"date-parts":[[2021,9]]}},"alternative-id":["10.1136\/bmjopen-2020-047141"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2020-047141","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9]]}}}