PEDIATRICS Vol. 122 No. 1 July 2008, pp. e149-e155 (doi:10.1542/peds.2007-3398)
ARTICLE |
Intranasal Budesonide Treatment for Children With Mild Obstructive Sleep Apnea Syndrome
Division of Pediatric Sleep Medicine, Department of Pediatrics, University of Louisville, Louisville, Kentucky
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ABSTRACT |
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OBJECTIVES. Intranasal corticosteroids have been advanced as a nonsurgical therapeutic alternative for pediatric obstructive sleep apnea syndrome, particularly for patients with mild disease, and aims at reducing the size of hypertrophic adenotonsillar tissue.
METHODS. Of 71 possible candidates, 62 children with polysomnographically diagnosed mild obstructive sleep apnea syndrome were recruited onto a double-blind, randomized, crossover trial of intranasal budesonide (32 µg per nostril at bedtime) or placebo for 6 weeks followed by an additional 6-week treatment in the alternative treatment arm after allowing for a 2-week washout period. Polysomnographic assessment and radiographs for assessment of adenoid size were performed after completion of each phase.
RESULTS. There were significant improvements in both polysomnographic measures (sleep latency, slow-wave sleep, and rapid-eye-movement sleep), in the magnitude of respiratory disturbance (apnea/hypopnea index, nadir pulse oxygen saturation), and in adenoid size among the 48 children who completed the treatment phase compared with 32 children who received placebo in their initial arm, with normalization of sleep measures in 54.1% of the treated children. Furthermore, discontinuation of treatment for 8 weeks for 25 children revealed a sustained duration of the initial treatment effect.
CONCLUSIONS. A 6-week treatment with intranasal budesonide effectively reduced the severity of mild obstructive sleep apnea syndrome and the magnitude of the underlying adenoidal hypertrophy, and this effect persisted for at least 8 weeks after cessation of therapy. These findings justify the use of topical steroids as the initial therapeutic option in otherwise healthy children with mild obstructive sleep apnea.
Key Words: adenoid hypertrophy • upper airway resistance syndrome • budesonide • topical steroids • obstructive sleep apnea
Abbreviations: OSAS—obstructive sleep apnea syndrome • AHI—apnea/hypopnea index • T&A—surgical adenotonsillectomy • TST—total sleep time • PSG—polysomnographic • SpO2—pulse oxygen saturation • OAHI—obstructive apnea/hypopnea index • RAI—respiratory arousal index • N/P ratio—adenoidal nasopharyngeal ratio
Obstructive sleep apnea syndrome (OSAS) is a common disorder in the pediatric population. It is characterized by prolonged periods of increased upper airway resistance and partial or complete intermittent obstruction of the upper airway during sleep, which may be accompanied by episodic snoring, episodic oxyhemoglobin desaturations and hypercapnia, and repeated arousals. The prevalence of childhood OSA has been estimated at 2% to 3% of all children,1–8 usually peaking in children between 2 and 8 years of age, and adenotonsillar hypertrophy is by far the major contributor to the pathophysiology of OSAS in children. OSAS in children not only is associated with increased health care costs9 but also can result in a large array of morbidities, such as neurocognitive and behavioral disturbances,10–12 enuresis,13,14 systemic and pulmonary hypertension and endothelial dysfunction,15–18 and somatic growth failure.19
Although a combination of structural and neuromuscular abnormalities contributes to the occurrence of OSAS in children,20 the severity of OSAS is primarily related to the adenoid and tonsillar size,21,22 such that surgical extirpation of these tissues is usually the first line of treatment.23 It is the standard of practice at our institution that children whose apnea/hypopnea index (AHI) in the overnight sleep study exceeds 5 events per hour of sleep should undergo adenotonsillectomy (T&A). This cutoff for T&A has been empirically established as a relative compromise between the need to prevent OSAS-related morbidity and the morbidity and mortality rates associated with T&A surgery; however, different criteria for surgical referral are implemented among the various sleep laboratory centers in the United States and around the world and usually range between an AHI of >2 and >5 per hour of total seep time (TST). As such, there is still considerable debate as to whether therapy is indicated for children with milder OSAS and, if so, which approaches should be considered.
It has now become apparent that nasal and oropharyngeal mucosal inflammation is present in patients with OSAS and may serve as an important determinant in the pathogenesis of sleep-disordered breathing in children.24 In addition, whereas systemic corticosteroids are not useful in the management of pediatric OSAS,25 globally favorable outcomes have been reported in the past decade by several groups of investigators who used intranasal corticosteroids in more severe pediatric OSAS in an attempt to reduce the size of the upper airway lymphoid tissues.26–30 In their vast majority, however, these studies either did not use randomization approaches or did not assess milder OSAS cases that would have not been offered a surgical treatment option in most pediatric sleep centers.
We recently showed that the lymphadenoid tissues of the upper airway of children with OSAS express glucocorticoid receptor 
in high abundance and are therefore likely to respond favorably to therapy with topical steroids.31 Therefore, we hypothesized that administration of intranasal budesonide for 6 weeks using a randomized, double-blind, crossover design would improve sleep-related disturbances in children with mild OSAS and that this effect would be sustained for at least 6 to 8 weeks after discontinuation of this therapy.
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METHODS |
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The study was approved by the University of Louisville Human Research Committee, and informed consent was obtained from the legal caregiver of each child. Children were recruited from all pediatric patients who were referred for evaluation of snoring and who underwent clinical evaluation, lateral neck radiograph, and an overnight sleep study at the Kosair Children's Hospital Sleep Medicine and Apnea Center. Eligible for inclusion in the study were children who were older than 6 years and younger than 12 years, had habitual snoring, and on the initial overnight polysomnographic assessment (PSG-1) fulfilled the criteria for mild OSAS (see the next section). Exclusion criteria were the presence of any of the following: asthma that required chronic preventive therapy; hypersensitivity to budesonide; recent nasal trauma; nasal surgery or nasal septum perforation; current therapy with drugs that interact with budesonide (erythromycin, clarythromycin, ketoconazole, and cimetidine); known immunodeficiency or undergoing immunosuppressant therapy; craniofacial, neuromuscular, syndromic, or defined genetic abnormalities; acute upper respiratory tract infection; systemic corticosteroid therapy; or antibiotic therapy in the 2 weeks before the initiation of the study; and children who already had had T&A in the past 12 months. In addition, children who were receiving long-term oral antihistamine preparations or nonsteroidal nasal decongestants were required to continue using these medications throughout the duration of the study. Patients who were receiving immunotherapy also continued on the same regimen without escalation of dosage and frequency throughout the duration of the study.
Study Design
During the period spanning from April 2004 until May 2006, children who fulfilled the study inclusion criteria on the basis of the PSG-1 findings were recruited by 1 of the authors and assigned by a clinical research coordinator to 1 of 2 treatment groups using a double-blind, randomization, crossover procedure generated using random computer numeral allocation and managed by the same clinical research coordinator who was otherwise not involved in any aspect of the study (Fig 1). The treatment group was started on a-6 week course of intranasal topical budesonide (32 µg per puff per nostril to both nostrils [total dosage of 64 µg]; the control group received once-a-day placebo spray [saline]). Parents were instructed to give the treatment at bedtime. After 6 weeks of either treatment, children underwent a second overnight sleep study (PSG-2) and a lateral neck radiograph (radiograph 2). After a 2-week washout period, children then started a 6-week course with the compound that they were not receiving during the first phase of the study. All of the outcome end points were assessed again on completion of the second 6-week course (PSG-3 and radiograph 3; Fig 1).
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Overnight PSG Evaluation
Children were studied for up to 12 hours in a quiet, darkened room with an ambient temperature of 24°C in the company of 1 of their parents. No drugs were used to induce sleep. The following parameters were measured: chest and abdominal wall movement by inductance plethysmography, heart rate by electrocardiography, air flow was triply monitored with a side-stream end-tidal capnograph that also provided breath-by-breath assessment of end-tidal carbon dioxide levels (BCI SC-300, Menomonee Falls, WI), a nasal pressure cannula, and an oronasal thermistor. Arterial pulse oxygen saturation (SpO2) was assessed by pulse oximetry (Nellcor N 100 [Nellcor Inc, Hayward, CA]), with simultaneous recording of the pulse wave form. The bilateral electro-oculogram, 8 channels of electroencephalogram (2 frontal, 2 occipital, 2 temporal, and 2 central leads), chin and anterior tibial electromyograms, and analog output from a body position sensor were also monitored. All measures were digitized using a commercially available system (Rembrandt [MedCare Diagnostics, Amsterdam, Netherlands]). Tracheal sound was monitored with a microphone sensor, and a digital time-synchronized video recording was performed. The sleep technician followed patient behavior and confirmed sleep position by the infrared camera inside the room. All of the studies were initially scored by a certified technician and were then blindly reviewed by 2 physicians who were experienced in pediatric polysomnography and underwent training in an accredited fellowship program.
Sleep architecture was assessed by standard techniques.32 The proportion of time spent in each sleep stage was expressed as percentage of TST. Central, obstructive, and mixed apneic events were counted. Obstructive apnea was defined as the absence of airflow with continued chest wall and abdominal movement for duration of at least 2 breaths.33,34 Hypopneas were defined as a decrease in oronasal flow of 
50% with a corresponding decrease in SpO2 of 4% and/or arousal.34 The obstructive AHI (OAHI) was defined as the number of apneas and hypopneas per hour of TST. Arousals were defined as recommended by the American Sleep Disorders Association Task Force report35 and included respiratory-related (occurring immediately after an apnea, hypopnea, or snore), technician-induced, and spontaneous arousals. Arousals were expressed as the total number of arousals per hour of sleep time.
The diagnostic criteria for OSAS included an obstructive apnea index >1 per hour of TST, and an obstructive AHI of >2 per hour of TST with a nadir oxygen saturation value of at least <92%.34 The specific criteria for mild OSAS consisted of an AHI of >2 per hour of TST but 
7 per hour of TST or an AHI of 2 per hour of TST but in the presence of a respiratory arousal index (RAI) of 2 per hour of TST and nadir oxygen saturation >85%. Patients with a history of allergic rhinitis were also included when they met the PSG inclusion criteria.
Lateral Film of the Neck
For assessment of airway patency, lateral neck radiographs were performed using standard techniques in the radiology department at Kosair Children's Hospital. The neck was extended, and the patient was instructed to breathe through the nose. The adenoidal/nasopharyngeal ratio was then measured according to the method of Fujioka et al36 by 1 of the investigators (Dr Gozal), who was blinded to the treatment group and PSG findings of the children.
Sample Size Estimate
A minimal sample size of 30 patients per arm in this parallel design study was estimated on the basis of an error of .05, β error of .2, an initial mean AHI of 3 per hour of TST, an SD of 1.0 per hour of TST, and a potential decrease in AHI by 20%, while allowing for a 20% attrition rate. In addition, such number of children would allow for detection of a 30% improvement in adenoid size estimate. This design and target sample size also permitted determination of rebound exacerbation, when >30% of posttherapy baseline, after transition from budesonide to placebo in half of the children (Fig 1).
Data Analysis
Results are presented as means ± SEM, unless stated otherwise. We defined AHI and RAI as primary outcomes and adenoid size estimate as secondary outcome. All numeric data were subjected to statistical analyses using either t tests or 2-way analysis of variance procedures for repeated measures followed by Neuman-Keuls posthoc tests, as appropriate. A 2-tailed P < .05 was considered statistically significant.
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RESULTS |
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A total of 62 children were recruited of 71 potential consecutively identified eligible candidates after screening a total of 97 children, 35 of whom were found ineligible for the study (Fig 1). The reasons for ineligibility were an AHI of >7 per hour of TST (n = 29), receiving inhaled corticosteroids for asthma and allergic rhinitis (n = 4), and T&A in the preceding year (n = 2). Similarly, the reasons for nonparticipation among the 71 eligible children were lack of interest by the child or the family (5 children) and unwillingness to use topical steroids by the parents (4 children). These 9 children did not differ in any aspect from those who elected to participate in the study. Of the 62 participants, 43 completed all phases of the protocol, and 19 children completed the first arm of the protocol and subsequently decided to withdraw. Among the latter, 14 children were in the placebo treatment group and 5 were in the budesonide treatment group. Thus, the relative risk for withdrawal from the study was 2.80 for children who started on placebo compared with those who started with intranasal budesonide (95% confidence interval: 1.15–6.83; P < .02 after Mantel-Haenszel correction). The reason for withdrawal included unwillingness of the child to continue with the nasal spray (7 children), marked improvement and satisfaction with the outcome of the first arm of the study (6 children with 5 being among those receiving intranasal budesonide), and 6 children whose parents decided to pursue T&A (all in the placebo treatment group).
Table 1 shows the similar demographic and initial PSG characteristics of the 43 children who completed all phases of the study and of the 19 children who completed only phase 1 of the experimental protocol. Therapy with antihistaminic medications or immunotherapy for allergic symptoms was recorded for 23 children.
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Treatment with intranasal budesonide for a 6-week period in 48 children with mild OSAS was associated with significant improvements in several PSG abnormalities, namely OAHI, RAI, and nadir SpO2, along with significant changes in some measures that pertain to sleep macroarchitecture, such as sleep latency, and the percentage of TST spent in either slow-wave sleep or rapid-eye-movement sleep (Table 2). In addition, significant reductions in adenoid size occurred with decreases in adenoidal nasopharyngeal ratio (N/P) ratio from 0.71 ± 0.02 before treatment to 0.57 ± 0.02 after 6 weeks of budesonide therapy (P < .0001). Moreover and as shown in Fig 2, 26 (54.1%) children had normalization of their OAHI on the basis of currently accepted criteria (ie, OAHI < 1 per hour of TST).34,37 These findings contrasted with the 32 children in the placebo-treated control group for whom no changes occurred for most of the measurements, except for mild worsening of OAHI (P < .04; Table 2 and Fig 2). Of note, there were no differences in the responses to treatment either for obese versus nonobese children or among children who had a history of allergic symptoms as compared with those who did not report any allergic problems, and there were no discernible differences in the response to therapy according to age. A total of 5 adverse events were reported, namely migraine (n = 2), diarrhea (n = 2), and vomiting and diarrhea (n = 1). Three of these adverse events occurred in the treatment group and 2 in the control group. All events were minor, did not require withdrawal from the study, and were considered as being unrelated to the underlying OSA or to the treatment.
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, OAHI before initiation of treatment; 
, postintervention OAHI. Drop lines permit better identification of individual changes over time. The horizontal line indicates the upper limit of normal OAHI in children.As mentioned, 25 children who were randomly assigned to the initial treatment arm completed the second phase of the protocol and therefore allowed for assessment of whether discontinuation of intranasal budesonide for a period of 8 weeks (2 weeks of washout followed by 6 weeks of placebo) would be accompanied by a rebound in the severity of OSAS. As shown in Table 3, no significant changes emerged during this follow-up period in PSG characteristics, degree of respiratory disturbance, or adenoid size.
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DISCUSSION |
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This study clearly showed that intranasal budesonide administered during a period of 6 weeks to children with mild OSA effectively alleviated the severity of respiratory disturbance, reduced the size of adenoid tissues, and significantly improved, albeit slightly, some components of sleep architecture. Furthermore, discontinuation of the therapy for a period of 8 weeks did not seem to be associated with worsening of sleep or respiratory parameters.
Before discussing the potential implications of our findings, some technical aspects of this study deserve comment. First, we enrolled as part of our study design only patients who had mild symptoms and whose PSG findings were in the very mild range of respiratory disturbance. As such, we could a priori only expect a very limited theoretical range of improvement in either the respiratory abnormalities or the sleep architecture disturbances; therefore, the obvious improvements that resulted from the intervention with intranasal budesonide and their conspicuous absence when placebo was administered emerge as all the more remarkable. Second, we used a double-blind crossover study design that not only permitted objective assessment of the effects of intranasal budesonide but also allowed for determination as to whether such effect is restricted to the duration of therapy or will persist beyond the discontinuation of intranasal budesonide. Third, we included children with mild allergic symptoms and found that the response to therapy did not differ among those with and without those symptoms.
The use of topical steroid therapy in pediatric OSAS is not novel, particularly when considering that surgical extirpation of hypertrophic adenoids and tonsils for OSAS not only is accompanied by an increased risk for potential postoperative complications and emotional distress for the patient and family but also is associated with increased health-related costs; therefore, it is not surprising that nasal corticosteroids have been proposed in recent years for the treatment of children with OSAS. Indeed, Brouillette et al27 examined this issue in patients with moderate-to-severe OSAS before undergoing T&A and found significant improvements in respiratory disturbance after a 6-week treatment with intranasal fluticasone, albeit in the absence of discernible changes in the size of adenoids. Subsequent studies of patients with milder OSAS have suggested a similarly beneficial effect; however, these studies were "open label" in nature, such that the improvements in sleep-related respiratory disturbances that were documented after either 3 or 4 weeks of therapy with nasal budesonide were fraught with the traditional limitations inherent to any interventional study that uses an open-label design.28,29 It is interesting that Alexopoulos et al28 followed their 27-patient cohort for up to 9 months after discontinuation of the treatment, and similar to the findings in our study, these investigators reported a sustained effect for this temporally restricted intervention, although they assessed only for OSAS-related symptoms rather than conducting the more objective overnight sleep studies and radiologic assessments of adenoid size. Notwithstanding, the initial estimates of adenoid size in the study by Alexopoulos et al28 and in that by Brouillette et al27 were remarkably similar to those reported for our cohort (N/P ratios of 0.72, 0.76, and 0.71, respectively). Similarly, these 2 previously published studies reported improvements revolving around 40% to 60% in the severity of OSAS, and such improvement was 54.1% in our study. Thus, although differences in the severity of OSAS, selection criteria, and the overall method make accurate comparisons difficult, the overall outcomes are consistently strikingly similar and support a role for the use of nasal corticosteroids in pediatric OSAS as a first-line option; however, on the basis of the limited currently published evidence, it remains unclear what is the optimal dosage and duration of therapy using intranasal steroids, whether particular patients (eg, younger, nonobese) would be more likely to benefit from this therapeutic option, and whether addition of other anti-inflammatory agents such as leukotriene receptor antagonists38,39 may provide additive or synergistic effects. Furthermore, it is unknown whether early-phase topical steroid therapy will ultimately improve the surgical outcomes of T&A in more severely affected children with OSAS.40 In addition, the absence of discernible differences in the response to intranasal steroid therapy among children with and without allergic rhinitis was somewhat surprising, because we expected improved responses among those with allergic nasal symptoms, particularly considering the important role of the nose in upper airway collapsibility. We should emphasize, however, that such observation may be explained to some extent by the possibility that this study may be underpowered to draw such a conclusion definitively.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We have learned in recent years that even mild cases of OSAS may be associated with significant cognitive, behavioral, and vascular morbidity, with a major impact on quality of life and health care use. On the basis of this compelling body of evidence, this study strongly supports the initiation of intranasal corticosteroid therapy in children with mild OSAS as the first step in the treatment of these children. To somehow paraphrase Dr Marcus in her editorial in 2001 regarding the role of corticosteroids in pediatric OSAS, we believe that the cumulative experience regarding the use of budesonide would endorse "temporarily throwing away the scalpel" for those symptomatic children with mild OSAS.41
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ACKNOWLEDGMENTS |
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This study was supported by an investigator-initiated grant from Astra Zeneca Ltd (to Dr Kheirandish-Gozal). Dr Gozal is supported by National Institutes of Health grants HL-65270, HL-69932, and SCOR 2P50HL60296-06, the Children's Foundation Endowment for Sleep Research, and the Commonwealth of Kentucky Challenge for Excellence Trust Fund.
We thank all of the parents and children who participated in this study for cooperation and are grateful to Dianna O'Neal for assisting in the coordination aspects of the study.
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FOOTNOTES |
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Accepted Jan 9, 2008.
Address correspondence to Leila Kheirandish-Gozal, MD, University of Louisville School of Medicine, Division of Pediatric Sleep Medicine, Department of Pediatrics, Heyburn Building, 331 W. Broadway, Suite 1100, Louisville, KY 40202. E-mail: l0khei01{at}gwise.louisville.edu
This trial has been registered at www.clinicaltrials.gov (identifier NCT00560586).
Financial Disclosure: Dr Kheirandish-Gozal is the recipient of investigator-initiated grants from Astra Zeneca Ltd and Merck Co for studies in pediatric sleep apnea; Dr Gozal is on the National Speaker Bureau of Merck Co and has received honoraria for lectures.
| What's Known on This Subject Intranasal steroids are potentially effective in reducing the severity of moderate-to-severe sleep apnea in children who are slated for adenotonsillectomy; however, the role of this therapy in mild sleep apneic pediatric patients is unknown.
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| What This Study Adds To our knowledge, this is the first randomized, double-blind, controlled trial of intranasal steroids in mild sleep apnea in children for whom assessments were also conducted to determine whether rebound worsening occurs after cessation of therapy.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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