You are on page 1of 8

Olfactory Stimulation Prevents Apnea in Premature Newborns Luc Marlier, Christophe Gaugler and Jean Messer Pediatrics 2005;115;83

DOI: 10.1542/peds.2004-0865

The online version of this article, along with updated information and services, is located on the World Wide Web at:

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2005 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on April 4, 2012

Olfactory Stimulation Prevents Apnea in Premature Newborns

Luc Marlier, PhD*; Christophe Gaugler, MD; and Jean Messer, MD
ABSTRACT. Objective. Methylxanthines and doxapram are currently used to treat apnea of prematurity but are not fully effective and often present undesirable side effects. The present study examines whether exposure to an odor known to modulate the infants respiratory rate could reduce the frequency of apneic spells. Method. Fourteen preterm newborns born at 24 to 28 gestational weeks presenting recurrent apnea despite caffeine and doxapram therapy were exposed to a pleasant odor diffused during 24 hours in the incubator. Efficiency of the olfactory treatment was judged by comparing frequency and severity of apneas occurring during the day of odorization with that observed the day before (baseline) and the day after (posttreatment control). Apnea was defined as any complete cessation of breathing movements for >20 seconds, or less if associated with hypoxia or bradycardia. Results. Concerning all types of apneas, a diminution of 36% was observed and seen in 12 of 14 infants. Apneas without bradycardia were reduced (44%) during the day with odorization, and this diminution affected all the infants. The frequency of apnea with moderate bradycardia (heart rate between 70 and 90 beats per minute) was maintained while the frequency of apnea associated with severe bradycardia (heart rate <70 beats per minute) decreased strongly (45%) and affected all the infants. No side effects were observed. Conclusion. The introduction of a pleasant odor in the incubator is of therapeutic value in the treatment of apneas unresponsive to caffeine and doxapram. Pediatrics 2005;115:8388; premature newborn, apnea, olfaction, incubator, health, neonatal adaptation.
ABBREVIATIONS. RR, respiratory rate; HR, heart rate; Spo2, oxygen saturation; bpm, beats per minute.

ecurrent apnea is common in premature newborns, particularly at early gestational ages. It affects 80% of infants born at 30 weeks of gestation.1 Causal factors include immature neurologic and respiratory systems, reduced hypercapnic and hypoxic responses, and difficulties with central respiratory control.2 These cessations of breathing can lead to hypoxemia and bradycardia,3,4 therefore

From the *Centre National de la Recherche Scientifique, UMR 5170, site of Strasbourg, France; and Centre Hospitalier Regional Universitaire de Hau tepierre, Pediatrie 2, Strasbourg, France. Accepted for publication Jun 21, 2004. doi:10.1542/peds.2004-0865 No conflict of interest declared. Reprint requests to (L.M.) Service de Pediatrie 2, Centre Hospitalier Re gional Universitaire de Hautepierre, Avenue Moliere, F-67098 Strasbourg ` Cedex, France. E-mail: PEDIATRICS (ISSN 0031 4005). Copyright 2005 by the American Academy of Pediatrics.

increasing the risk of cerebral injury as attested by several studies showing noticeable decreases in cerebral blood flow velocity and cerebral oxygenation during apneic episodes.59 Since the 1970s, the first-line treatment for apnea of immaturity has been pharmacological treatment with methylxanthines (theophylline and caffeine), the efficiency of which in preventing apneas has been well documented.1012 Doxapram, an analeptic agent and powerful respiratory stimulant, has been used more recently for controlling apneas unresponsive to methylxanthines alone.1315 However, none of these substances administered alone or in combination seem to be fully effective. Some treated newborns continue to have frequent spells of apnea and may need more vigorous ventilatory techniques such as nasal continuous positive airway pressure or mechanical ventilation.13 Additionally, several undesirable side effects such as hyperactivity, irritability, alteration of sleep organization, tachycardia, metabolic, gastrointestinal, and urinary disorders have been noticed in treated infants.13,1517 Caffeine has also been suspected to reduce cerebral blood flow18 and doxapram to increase blood pressure, thus enhancing the risk of cerebral hemorrhage.14,19 Therefore, there is clearly a need for additional studies for a more effective treatment with fewer side effects. During an investigation on the ability of premature infants to detect and discriminate odors, we observed that the infants respiratory rate (RR) was modulated according to the hedonic value of the odorants. Pleasant odors elicited increasing responses, whereas unpleasant odors elicited decreasing responses.20 Moreover, the power of odors to affect the RR seemed particularly effective during active sleep,21 a sleep state during which apneas are most likely to occur.22,23 We were thus interested in verifying whether the stimulating effect of a pleasant odor could counterbalance (at least partly) the respiratory fall observed during apneic spells. For ethical reasons, we were reluctant to replace the pharmacological treatment applied to premature infants suffering from apnea by an olfactory treatment, the efficiency of which had to be proved. So we decided, as a first step, to examine the effect of odor exposure on apneas unresponsive to the traditional pharmacological substances, thus sparing any intervention on the current treatment. More precisely, we tested whether the introduction of a slight pleasant odor into the incubator was beneficial for infants who continued to suffer from apneic spells while receiving caffeine-plus-doxapram therapy.

PEDIATRICS Vol. 115 No. 1 January 2005 Downloaded from by guest on April 4, 2012

Measurements were conducted on 14 premature newborns (7 females) in the neonatal intensive care unit at the University Hospital at Strasbourg (Alsace, France). All the infants had recurrent central apneas unresponsive to caffeine-plus-doxapram therapy. Caffeine was administered by enteral route (5 mg/kg per day; n 14) and doxapram either by enteral route (30 mg/kg per day; n 10) or continuous intravenous infusion (1230 mg/kg per day; n 4). This pharmacological treatment was maintained for each subject throughout the study. Central apnea was diagnosed only when causes other than immaturity (ie, infections, anemia, hypocalcemia, hypoglycemia, hyperthermia, or hypothermia) were eliminated. Radiography was used to confirm lack of respiratory disorders; echocardiography was used to exclude patent ductus arteriosus; and cranial ultrasounds were used to exclude intraventricular hemorrhage larger than grade 1 and periventricular leukomalacia. Infants were also free of major complications (ie, chromosomal abnormalities, congenital malformations, or cardiovascular or brain disorders). They were not on nasal continuous positive airway pressure, and their clinical status was stable (during at least 48 hours before enrollment). Their gestational ages ranged from 24 to 28 weeks (mean: 26.5 weeks), birth weight ranged from 815 to 1680 g (mean: 1169 g), and postnatal ages ranged from 11 to 33 days (mean: 22.4 days). In accordance with ethical standards, parents were informed and had to give written consent.

tion concerning the introduction of an odor in the incubator was given, but extreme care was taken not to inform the staff about the aim of the study and specifically the focus on apnea. After the end of the olfactory treatment, the odorized pillow was removed, the complete incubator was washed and aired, and a clean pillow was installed. The third day of observation was free of any experimental intervention. The present protocol was approved by the local ethical committee (Alsace no. 1, Agreement no. 02/120).

Classification of Apnea and Data Analysis

According to common acceptation,2,9 central apnea was defined as any complete cessation in breathing movements 20 seconds, or less if associated with hypoxia (blood oxygen saturation 88%) or bradycardia (HR 90 beats per minute [bpm]). Apneic episodes associated with bradycardia were classified into 2 different groups. Apnea with moderate bradycardia was defined as a cessation of breathing followed by a diminution of the HR between 90 and 70 bpm. Apnea was considered as associated with severe bradycardia if the HR fell to 70 bpm. HR, RR, and Spo2 were recorded throughout the study. A paper graph of these 3 signals was obtained (and alarm activated) when HR 90 bpm, RR 20 cpm, or Spo2 88%. The frequency, duration, and degree of severity of the apneic spells were extracted from the printed graphs. A minimal interval of 2 minutes was used to consider 2 apneic spells as independent and to code them as 2 separate events. Two raters (C.G. and J.M.), expert in respiratory data reading and blind during coding, coded separately all the recordings. Interrater reliability of the measurements was computed by calculating the percentage of agreement between the 2 raters for each category of apnea. The correlations in all cases were .92. If a disagreement was noted, each case was reexamined, and a decision was taken together.

Because of great variability of incidence and severity of apneic spells between patients, we used a protocol in which each infant was considered as his or her own control. The study was conducted over 3 consecutive 24-hour periods. Day 1 served to obtain baseline values. Odorization of the incubator was applied during day 2. Finally, to ensure that eventual changes of responses were not caused by rapid maturational processes, a third day of observation without any experimental intervention was considered. During the 3-day survey, infants were lying supine in the incubator (8000 SC, Drager Technology, Lubeck, Germany) under con tinuous monitoring. Heart rate (HR) and RR were recorded by using a Viridia monitor (V24C, Agilent Technologies, Bablingen, Germany). Oxygen saturation (Spo2) was measured by using a pulse oximeter. No specific guidelines concerning the treatment of apnea were given to the caregivers. Following the usual rule, caregivers had to stimulate the infant by gentle tactile stimulation if the resolution of apnea was not spontaneous. If the number of such interventions exceeded 3 per hour, then mechanical ventilatory assistance (continuous positive airway pressure) was provided. Nursing habits and the method and rhythm of feeding were held constant during the complete duration of the study. Temperature (mean SD: 30.4 0.4C), ventilation (7.3 0.7 L/minute), and hygrometry (78.7% 6.5%) of the internal environment of the incubator could change slightly from 1 infant to the other, but care was taken to keep them constant for each subject throughout the study. Six infants benefited from skin-to-skin contact with the mother (duration: 1-1.5 hours per day). In these cases, the mothers were asked to establish this daily contact at the same time window in the course of the day and for approximately the same duration. After a 1-day observation without any experimental intervention (baseline period), the olfactory stimulus was introduced in the incubator. Using a pipette, 15 drops of saturated solution of vanillin (Aldrich, Fallavier, France) were applied on the periphery of the infants pillow (40 60 cm, 100% cotton). The odor of vanillin was chosen because previous studies reported reliable physiologic and facial responses in premature newborns20,24 and because this odorant was appreciated as hedonically pleasant by premature infants of the same gestational age.25 Because the air in the incubator was continuously renewed, pilot tests were conducted to find the best procedure to maintain the intensity of the stimulation as constant as possible over the 24-hour period. Finally, we found that 15 drops at the beginning of the session and a second 15-drop dose 12 hours after the onset of odorization offered the best result. A persistent slight vanillin odor was thus perceptible by adults nose during the stimulation period. Because it was probable that the nursing staff detected the presence of the stimulus, informa-

Statistical Analysis
To verify whether there was a significant change in the frequency of apnea over the 3 days of the study, repeated-measures analysis of variance was computed, where the day of observation constituted the intrasubject factor. If a change was noticed, we tested specifically the hypothesis of a reduction of the number of apnea only during olfactory treatment (day 2 compared with days 1 and 3) by using the statistical method of contrasts.26 If our hypothesis was confirmed, we tested its strength by examining the percentage of the total variance that could be explained by the predicted effect. A high percentage was considered as indicative of a strong impact of the olfactory treatment on the frequency of apnea. Finally, to examine individual responses to odor exposure, the number of infants presenting a reduction of the number of apneas was compared (using the 2 test) with the number of infants who maintained or increased the number of apneas (day 2 compared with day 1). A P value of .05 was considered significant. All statistical treatments were conducted by using SAS/ STAT 8.2 software (SAS Institute, Cary, NC).


All 14 infants enrolled completed the study, and no one needed mechanical ventilatory assistance. Efficiency of olfactory treatment was judged by the frequency and severity of the occurring apneas.
Frequency of Apnea Without Distinction of the Type

When the totality of apneas was considered, a decrease in frequency could be observed during odor exposure. The mean number of events (see Table 1 for SDs) fell from 34.7 (day before odor application) to 22.2 (day with odor application), representing a diminution of 36% (Fig 1). After cessation of odor application, the mean frequency of apnea returned to the baseline value (33.2). The difference between the 3 days of study appeared highly significant (F[2,26] 10.06; P .001). It is more interesting that the predicted effect of a reduction of apneic episodes only during the day of odor application was


OLFACTORY STIMULATION PREVENTS APNEA Downloaded from by guest on April 4, 2012

TABLE 1. Apnea Without Bradycardia After 23 29 18 18 17 91 34 24 10 5 52 81 24 39 18.5 33.2 24.4 17.9 18.8 17.8 17.8 8.6 7.9 7.9 7.0 8.2 7.7 6 21 8 6 14 22 4 6 15 1 13 68 12 54 5 9 8 4 13 28 31 14 6 4 8 68 15 36 8 17 1 3 10 32 3 7 4 2 8 15 5 6 12 14 7 0 3 27 7 5 5 1 13 8 6 0 10 16 7 13 0 19 3 1 3 3 27 2 9 2 4.5 Before During After Before During After Before Apnea With Moderate Bradycardia

Number of Apneic Spells Occurring During the Day Before, the Day of, and the Day After Olfactory Treatment According to the Type of Apnea in the 14 Premature Newborns Apnea With Severe Bradycardia During 2 6 4 12 0 16 1 0 1 0 18 0 3 0 6.0 6.6 After 5 8 3 11 0 21 0 3 1 0 36 2 1 2 9.8

Subject No.

Total No. of Events

Before 17 22 16 14 12 61 11 7 9 1 39 64 16 22


1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean SD

24 54 16 22 24 73 10 14 22 6 48 85 26 62

Downloaded from by guest on April 4, 2012




3 2 5 2 9 18 3 2 3 0 8 56 7 22 10 14.7

13 12 7 3 4 42 3 7 3 1 8 11 8 1 8.8 10.0

confirmed by the statistical method of contrasts (F[1,26] 19.87; P .001). Furthermore, 98.8% of the variance could be explained by the predicted effect. When individual data were considered, it seemed that 12 of 14 infants presented a reduction of the

Fig 1. Mean percent difference in the number of apneic spells occurring during (day 2) and after (day 3) olfactory treatment, compared with baseline (day 1), according to the type of apnea in the 14 premature newborns. *P .05, which indicates a significant difference with baseline.



number of apneic events (Table 1), a proportion that was significantly different from a proportion predicted by chance ( 2 7.14; P .01). Taken together, these results indicate that the presence of vanillin in the incubator reduces significantly the frequency of apneic spells.
Frequency of Apneas Without Bradycardia

43.3 4 cpm; for daily cardiac rate: 148.2 11.9, 146.9 12, and 147.3 12.1 bpm; for days 1, 2, and 3, respectively). Gastrointestinal tolerance seemed unaffected by odor exposure, because neither gastric residuals nor regurgitations were observed. Finally, no behavioral changes such as excitability or increased activity were noted by the nursing staff among the infants during the study.

The number of apneas for 20 seconds, or less if associated with hypoxia but without bradycardia, was particularly affected by odor exposure. A decrease of 44% could be observed (Fig 1). From a mean of 17.9 apneic events recorded the day before odor application, this number fell sharply to 10 during the day with odor application before regaining the initial value (17.8) after the stimulation was removed. This variation was significant (F[2,26] 7.26; P .01) and followed the predicted curve characterized by a significant diminution only during odor exposure (F[1,26] 14.51; P .001). The predicted effect explained 99.9% of the variance. All infants without exception benefited from a reduction of the number of apneic spells during odor exposure (Table 1).
Frequency of Apneas With Moderate Bradycardia

For the frequency of apneas followed by an HR situated between 70 and 90 bpm, no significant difference was noted between the days before, during, or after odor application (8.6, 7.9, and 8.8 during days 1, 2, and 3, respectively; Fig 1). When individual data were considered, mitigated results were also apparent. Only 8 of the 14 infants seemed to derive benefit from olfactory stimulation (Table 1), a proportion that was not significantly different from a proportion given by chance.
Frequency of Apneas With Severe Bradycardia

For the whole group, the baseline mean number of apneas associated with severe bradycardias (HR 70 bpm) was 8.2. During the day on which the incubator was odorized, the frequency of apneas decreased to 4.5, which represents a strong reduction of 45% (Fig 1). The mean recorded was 6.6 during the day after odor application. This variation of the number of apneic events during the 3 days was significant (F[2,26] 5.39; P .01). The hypothesis of a significant diminution of the number of apneas only during the odorized day (compared with days 1 and 3) was confirmed further (F[1,26] 8.87; P .01), and the percentage of variance (82.2%) could be explained in great part by the predicted effect. This effect concerned all the infants except 1, who did not express any severe bradycardia during the 3-day survey (Table 1; 2 10.29; P .001). Thus, odorization of the incubator reduces significantly the number of apnea events associated with severe bradycardia.
Side Effects

No side effects in any of the patients were noticed. Daily weight gain was maintained throughout the study. Daily RRs and cardiac rates appeared stable regardless of whether the incubator was odorized (mean SD for daily RR: 44.4 4.4, 43.3 3.3, and

The present study addressed the question of whether the frequency of apneas unresponsive to caffeine and doxapram can be reduced in premature newborns exposed to a pleasant odor in the incubator. Our results indicate that odor exposure leads to a clear diminution of the incidence of apneas. This reduction reached 44% for apneas without bradycardia and 45% for apneas with severe bradycardia. Inspection of individual data revealed that this decrease was strongly consistent across subjects. Apparently, apneas associated with moderate bradycardia seemed unaffected by odor exposure. However, it can be noticed that a substantial proportion of subjects (8 of 14 [57%]) exhibited a reduction in the number of apneas with moderate bradycardia (in this subgroup, the reduction reached 37%), suggesting that odor exposure could affect this category of apnea as well. Additionally, it is not excluded that the olfactory treatment affects also the severity of bradycardia, so that less severe bradycardia would in consequence increase the amount of moderate bradycardia, or in our case, kept the frequency stable because of probable simultaneous reduction of the number of moderate bradycardia events. This possibility is supported by the fact that the 6 infants who did not lower the frequency of moderate bradycardia expressed concomitantly a strong reduction (51%) of the number of severe bradycardia events. Thus, despite the case of apneas with moderate bradycardia, the results of our study show that the introduction of a pleasant odor in the incubator is of therapeutic value in the treatment of apneas unresponsive to caffeine and doxapram. In recent years, a growing number of studies have emphasized noticeable effects of ambient odors on psychologic2729 and physiologic3032 states in adults. Several studies have also reported physiologic variations during the inhalation of odors in both term24,33,34 and, more recently, premature infants.20,24,35,36 However, the specific relevance of olfaction in positively altering health has been poorly documented.37 In 1 case of temporal lobe epilepsy, an inhibition of seizures by unpleasant odor exposure was reported.38 Similarly, it was observed that epileptic attacks could sometimes be stopped by a strong olfactory stimulus or by the application of ammonia.39 Nevertheless, in these studies, the observed effects are most probably the result of trigeminal and not exclusively olfactory stimulation, and it is likely that patients are more responsive to the irritability than to the smell of the odor. Thus, it remains uncertain whether an exclusive olfactory stimulus can have some role in curing or preventing diseases. The reduction of the number of apnea

OLFACTORY STIMULATION PREVENTS APNEA Downloaded from by guest on April 4, 2012

events during exposure to vanillin, a stimulus known to have no trigeminal component especially at low concentration such as that used in our study, may thus constitute the first evidence of the power of an olfactory stimulus to exert a significant beneficial effect on health. To date, we cannot fully explain the efficacy of vanillin exposure in these cases of relative caffeine and doxapram failure. Here we propose 2 hypotheses, which are not mutually exclusive. First, it is possible that vanillin possesses pharmacological properties and therefore has direct or indirect effects on the respiratory centers. The absorptive capacity of the nasal mucosa has been known for decades.40 Chemical compounds have the possibility to cross the nasal mucosa, enter the bloodstream through microcapillary channels, and finally reach cerebral structures.41 More recently, it was demonstrated that particles or viruses can also be caught by olfactory neuroreceptor cells and carried along the axons to the olfactory bulbs, and from there to more central structures.42 Until now, the possible mechanisms of action of vanillin have not been identified but could be 1 or both of these routes. Interestingly, it has been found that a lower dosage of pharmacological substances is often sufficient when administrated via the olfactory pathway as compared with the intravenous or enteral routes,41 which suggests that the olfactory pathway may constitute a more direct route to the brain centers than other more traditional routes used by physicians, and this should be a route explored further in the future. A second explanation is that the mere presence of a pleasant odor in the environment may help the subject to regulate his psychologic and physiologic states. This possibility is supported by several observations. For example, a reduction in the duration of crying could be obtained swiftly after exposure to maternal or familiar odors in term newborns.4345 Inversely, term infants in a low level of activation before a feed increased their body, head, and mouthing movements with the presentation of milky odors.4648 In the same way, it was suggested that preterm infants who received oral tactile stimulation with a lemon-flavored swab stick tended to restore an appropriate RR after a breathing fall.49 Taken together, these data indicate that the presentation of pleasant or familiar odors (alone or in association with other stimulations) can be of clinical usefulness in subjects presenting adaptive difficulties by helping them to reestablish an appropriate state of activation. In this context, the odorization of the incubator may represent a particular interest for premature infants. First, because studies have attested that premature newborns perform poorly on measures of self-regulation as well as autonomic regulation and even more poorly than term infants.50,51 Second, premature infants spend the first few weeks or months of their lives in an environment that is, by its nature, more stressful (because of overstimulations, frequent handling, painful procedures, separation from the mother)52 than the intrauterine milieu. Pleasant and familiar ambient odors thus may represent an interesting means to facilitate the psychophysiologic ad-

aptation of the premature newborn to its initial environment. Because apneas of prematurity occur mainly during active sleep, it cannot be excluded that ambient odor would be of particular effectiveness on the infants sleep quality. However, because of the absence of clear indicators of sleep/wake states during this first step of study, it was not possible to provide more details on this potential effect. Additional explorations are therefore needed to examine the impact of an odorized environment on sleep organization, and particularly to verify that the benefit observed is not caused by a relative deprivation of active sleep. This study presents several limitations. First, because our patients were chosen selectively because of relative caffeine-plus-doxapram failure, we cannot comment on the overall effectiveness of vanillin in apnea of prematurity. A study is currently being undertaken to verify whether vanillin treatment could be beneficial to a larger sample of subjects. Second, because vanillin was the only stimulus used in our study, the relative contribution of what is specific to vanillin and what is imputable solely to the presence of a pleasant odor in the incubator could not be established. The effect of qualitatively different odorants on incidence of apnea still remains to be analyzed at this point. Finally, the effect of ambient odor on the incidence of apneic spells was investigated only during a 24-hour period. The impact of shorter or longer durations has yet to be examined. The apparent absence of undesirable side effects suggests that olfactory treatment remains within a good margin of safety. All potential side effects, nevertheless, have to be reexamined, particularly if longer periods of odor exposure are considered.

We think that the practice of odorizing incubators with pleasant (for infants) odors should not be discarded a priori. Moreover, it may constitute a valuable help for premature infants who continue to suffer from apneic spells despite caffeine and doxapram therapy. Based on our results, we believe that such a new approach should be explored further.
This research was supported financially by the French Ministere de la Sante (Programme Hospitalier de Recherche Clinique). ` We are particularly grateful to the parents who agreed to take part in the study; the medical staff of the hospital for their patience; Dr Tao Jiang for material help; Dr Dominique Valentin for statistical support; Professor Andre Holley for valuable discus sions about this study; and Drs B. Bradford and S. A. Parke for helpful thoughts and comments on a previous draft.

1. Henderson-Smart DJ. The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies. Aust Paediatr J. 1981; 17:273276 2. Miller MJ, Martin RJ. Apnea of prematurity. Clin Perinatol. 1992;19: 789 808 3. Henderson-Smart DJ, Butcher-Puech MC, Edwards DA. Incidence and mechanism of bradycardia during apnoea in preterm infants. Arch Dis Child. 1986;61:227232

Downloaded from by guest on April 4, 2012



4. Martin RJ, Fanaroff AA. Neonatal apnea, bradycardia, or desaturation: does it matter? J Pediatr. 1998;132:758 759 5. Perlman JM, Volpe JJ. Episodes of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics. 1985;76:333338 6. Livera LN, Spencer SA, Thorniley MS, Wickramasinghe YA, Rolfe P. Effects of hypoxaemia and bradycardia on neonatal cerebral haemodynamics. Arch Dis Child. 1991;66:376 380 7. Ramanathan R, Corwin M, Hunt CE, et al. Cardiorespiratory events recorded on home monitors: comparison of healthy infants with those at increased risk for SIDS. JAMA. 2001;285:2199 2207 8. Payer C, Urlesberger B, Pauger M, Muller W. Apnea associated with hypoxia in preterm infants: impact on cerebral blood volume. Brain Dev. 2003;25:2531 9. Baird TM. Clinical correlates, natural history and outcome of neonatal apnoea. Semin Neonatol. 2004;9:205211 10. Lucey JF. The xanthine treatment of apnea of prematurity. Pediatrics. 1975;55:584 586 11. Bairam A, Boutroy M-J, Badonnel Y, Vert P. Theophylline versus caffeine: comparative effects in treatment of idiopathic apnea in the preterm infant. J Pediatr. 1987;110:636 639 12. Erenberg A, Leff RD, Haack DG, Mosdell KW, Hicks GM, Wynne BA. Caffeine citrate for the treatment of apnea of prematurity: a doubleblind, placebo-controlled study. Pharmacotherapy. 2000;20:644 652 13. Alpan G, Eyal F, Sagi E, Springer C, Patz D, Goder K. Doxapram in the treatment of idiopathic apnea of prematurity unresponsive to aminophylline. J Pediatr. 1984;104:634 637 14. Sagi E, Eyal F, Alpan G, Patz D, Arad I. Idiopathic apnoea of prematurity treated with doxapram and aminophylline. Arch Dis Child. 1984; 59:281283 15. Barrington KJ, Finer NN, Peters KL, Barton J. Physiologic effects of doxapram in idiopathic apnea of prematurity. J Pediatr. 1986;108: 125129 16. Gerhardt T, McCarthy J, Bancalari E. Effect of aminophylline on respiratory center activity and metabolic rate in premature infants with idiopathic apnea. Pediatrics. 1979;63:537542 17. Tay-Uyboco J, Kwiatkowski K, Cates DB, Hasan SU, Rigatto H. Clinical and physiological responses to prolonged nasogastric administration of doxapram for apnea of prematurity. Biol Neonate. 1991;59:190 200 18. Hoecker C, Nelle M, Poeschl J, Beedgen B, Linderkamp O. Caffeine impairs cerebral and intestinal blood flow velocity in preterm infants. Pediatrics. 2002;105:784 787 19. Barrington KJ, Finer NN, Torok-Both G, Jamali F, Coutts RT. Doseresponse relationship of doxapram in the therapy for refractory idiopathic apnea of prematurity. Pediatrics. 1987;80:2227 20. Marlier L, Schaal B, Gaugler C, Messer J. Olfaction in premature human newborns: detection and discrimination abilities two months before gestational term. Chemical Signals Vertebr. 2001;9:205209 21. Marlier L, Gaugler C, Soussignan R, Schaal B, Messer J. Premature newborns differentiate the affective value of odours during sleep. J Matern Fetal Neonatal Med. 2002;11(suppl 1):64 22. Gabriel M, Albani M, Schulte FJ. Apneic spells and sleep states in preterm infants. Pediatrics. 1976;57:142147 23. Lehtonen L, Martin RJ. Ontogeny of sleep and awake states in relation to breathing in preterm infants. Semin Neonatol. 2004;9:229 238 24. Goubet N, Rattaz C, Pierrat V, Alleman E, Bullinger A, Lequien P. Olfactory familiarization and discrimination in preterm and full-term newborns. Infancy. 2002;3:5375 25. Marlier L, Gaugler C, Soussignan R, Schaal B, Messer J. Early discrimination of odour hedonics in preterm newborns [abstract]. Chem Senses. 2003;28:74 26. Keppel G. In: Jenkins JJ, ed. Design and Analysis: A Researchers Handbook. Englewood Cliffs, NJ: Prentice-Hall; 1973 27. Ludvigson HW, Rottman TR. Effects of ambient odors of lavender and cloves on cognition, memory, affect and mood. Chem Senses. 1989;14: 525536 28. Knasko SC, Gilbert AN, Sabini J. Emotional state, physical well-being, and performance in the presence of feigned ambient odor. J Appl Soc Psychol. 1990;20:13451357 29. Knasko SC. Ambient odors effect on creativity, mood, and perceived health. Chem Senses. 1992;17:2735

30. Brauchli P, Ruegg PB, Etzweiler F, Zeier H. Electrocortical and autonomic alteration by administration of a pleasant and an unpleasant odor. Chem Senses. 1995;20:505515 31. Alaoui-Ismali O, Vernet-Maury E, Dittmar A, Delhomme G, Chanel J. Odor hedonics: connection with emotional response estimated by autonomic parameters. Chem Senses. 1997;22:237248 32. Bensafi M, Rouby C, Fraget V, Bertrand B, Vigouroux M, Holley A. Influence of affective and cognitive judgments on autonomic parameters during inhalation of pleasant and unpleasant odors in humans. Neurosci Lett. 2002;319:162166 33. Soussignan R, Schaal B, Marlier L, Jiang T. Facial and autonomic responses to biological and artificial olfactory stimuli in human neonates: re-examining early hedonic discrimination of odors. Physiol Behav. 1997; 62:745758 34. Bartocci M, Winberg J, Ruggiero C, Bergqvist LL, Serra G, Lagercrantz H. Activation of olfactory cortex in newborn infants after odor stimulation: a functional near-infrared spectroscopy study. Pediatr Res. 2000;48:18 23 35. VanReempts PJ, Wouters A, DeCock W, VanAcker KJ. Stress responses to tilting and odor stimulus in preterm neonates after intrauterine conditions associated with chronic stress. Physiol Behav. 1997;61: 419 424 36. Bartocci M, Winberg J, Papendieck G, Mustica T, Serra G, Lagercrantz H. Cerebral hemodynamic response to unpleasant odors in the preterm newborn measured by near-infrared spectroscopy. Pediatr Res. 2001;50: 324 330 37. Martin GN. Olfactory remediation: current evidence and possible applications. Soc Sci Med. 1996;43:6373 38. Ionasescu V. The relations between olfactory and vestibular sensory impulses and temporal lobe epilepsy. Acta Psychiatr Scand. 1961;36: 415 420 39. Efron R. The effect of olfactory stimuli in arresting uncinate fits. Brain. 1956;79:267281 40. Fox AW. Pharmaceutics. In: Fletcher AJ, Edwards LD, Fox AW, Stonier P, eds. Principles and Practice of Pharmaceutical Medicine. London, United Kingdom: Wiley; 2003 41. Pagliaro AM. Administrating drugs to infants, children, and adolescents. In: Pagliaro LA, Pagliaro AM, eds. Problems in Pediatric Drug Therapy. Washington, DC: American Pharmacologists Association; 2002: 1 86 42. Astic L, Saucier D, Coulon P, Lafay F, Flamand A. The CVS strain of rabies virus as transneuronal tracer in the olfactory system of mice. Brain Res. 1993;619:146 156 43. Mellier D, Bezard S, Caston J. Explanatory studies on olfaction-pain intersensory connections [in French]. Enfance. 1997;1/1997:98 111 44. Sullivan RM, Toubas P. Clinical usefulness of maternal odor in newborns: soothing and feeding preparatory responses. Biol Neonate. 1998;74:402 408 45. Goubet N, Rattaz C, Pierrat V, Bullinger A, Lequien P. Olfactory experience mediates response to pain in preterm newborns. Dev Psychobiol. 2003;42:171180 46. Soussignan R, Schaal B, Marlier L. Olfactory alliesthesia in human neonates: prandial state and stimulus familiarity modulate facial and autonomic responses to milk odors. Dev Psychobiol. 1999;35:314 47. Varendi H, Porter RH. Breast odour as the only maternal stimulus elicits crawling towards the odour source. Acta Paediatr. 2001;90:372375 48. Marlier L, Schaal B. Human newborns prefer human milk: conspecific milk odor is attractive without postnatal exposure. Child Dev. 2005; In press 49. Garcia AP, White-Traut R. Preterm infants responses to taste/smell and tactile stimulation during an apneic episode. J Pediatr Nurs. 1993; 8:245252 50. Als H, Duffy F, McAnulty G. Behavioral differences between preterm and full-term newborns as measured with the APIB system scores. Infant Behav Dev. 1988;11:305318 51. Lester B, Boukydis C, La Gasse L. Cardiorespiratory reactivity during the Brazelton Scale in term and preterm infants. J Pediatr Psychol. 1996; 21:771783 52. Graven SN, Bowen FW, Brooten D, et al. The high-risk infant environment. Part 1. The role of the neonatal intensive care unit in the outcome of high-risk infants. J Perinatol. 1992;12:164 172


OLFACTORY STIMULATION PREVENTS APNEA Downloaded from by guest on April 4, 2012

Olfactory Stimulation Prevents Apnea in Premature Newborns Luc Marlier, Christophe Gaugler and Jean Messer Pediatrics 2005;115;83 DOI: 10.1542/peds.2004-0865
Updated Information & Services References including high resolution figures, can be found at: l This article cites 47 articles, 15 of which can be accessed free at: l#ref-list-1 This article has been cited by 8 HighWire-hosted articles: l#related-urls This article, along with others on similar topics, appears in the following collection(s): Premature & Newborn _and_newborn Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: ml Information about ordering reprints can be found online:


Subspecialty Collections

Permissions & Licensing


PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2005 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on April 4, 2012