Do Systemic Corticosteroids Effectively Treat Obstructive Sleep Apnea Secondary to Adenotonsillar Hypertrophy?

The Laryngoscope Lippincott-Raven Publishers, Philadelphia 0 1997 The American Laryngological, Rhinological and Otological Society, Inc

Do Systemic Corticosteroids Effectively Treat Obstructive Sleep Apnea Secondary to Adenotonsillar Hypertrophy? Saleh A. Al-Ghamdi, MD; John J. Manoukian, MD; Angela Morielli, RRT; Kamaldine Oudjhane, MD; Francine M. Ducharme, MD; Robert T. Brouillette, MD

To determine if pediatric obstructive sleep apnea syndrome (OSAS) caused by adenotonsillar hypertrophy (ATH) could be treated by a short course of systemic corticosteroids, we conducted an openlabel pilot study in which standardized assessments of symptomatology, OSAS severity, and adenotonsillar size were performed before and after a 5-day course of oral prednisone, 1.1 0.1 (+ SE) mgkg per day. Outcome measures included symptom severity, adenotonsillar size, and polysomnographic measures of OSAS. Selection criteria included age from 1 to 12 years, ATH, symptomatology suggesting OSAS, an apneahypopnea index ( M I ) 2 3/hour, and intent to perform adenotonsillectomy. Only one of nine children showed enough improvement to avoid adenotonsillectomy. Symptomatology did not improve after corticosteroid treatment but did after removal of tonsils and adenoids. Polysomnographic indices of OSAS severity did not improve after corticosteroid treatment. After corticosteroids, tonsillar size decreased in only two patients, adenoidal size was only marginally reduced, and the size of the nasopharyngeal airway was not significantly increased. These results s u g gest that a short course of prednisone is ineffective in treating pediatric OSAS caused by ATH. Laryngoscope, 107:1382-1387,1997

INTRODUCTION In children, obstructive sleep apnea syndrome (OSAS) is most commonly associated with adenoFrom the Departments of Pediatrics (F.M.D.,R.T.B.), Otolaryngology Respiratory Therapy (A.M.),and Radiology (K.O.),McGill UniversityMontrea1 Children’s Hospital, Montreal, Quebec, Canada. Supported by The Hospital for Sick Children Foundation, EAssociation Pulmonaire du Quebec, and Jeremy Rill Centre for Sudden Infant Death Syndrome and Respiratory Control Disorders. Editor’s Note: This Manuscript was accepted for publication March 11, 1997. Send Reprint Requests to Robert T. Brouillette MD, Montreal Children’s Hospital, 2300 Tupper Street, Room C-920, Montreal, Quebec, Canada H3H 1P3. (s.A.A., J.J.M.),

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tonsillar hypertrophy (ATHI.122 This chronic sleeprelated airway obstruction results in sleep disturbance and repetitive asphyxia that can cause behavioral and developmental abnormalities, growth failure, and cor pulmonale.2~3Pediatric OSAS is usually treated surgically by tonsillectomy and/or adenoidectomy; however, such surgical therapy is expensive and sometimes is associated with serious complications such as posttonsillectomy bleeding.4-6 Corticosteroids,by their lympholytic and anti-inflammatory effects, have been used to relieve upper airway obstruction secondary to adenotonsillar hypertrophy in infectious mononucleosis.7-12 Similarly, some, but not all, investigators have reported that corticosteroids can be used t o treat otitis media with effusion.13-17 Investigators have suggested that corticosteroids might increase middle ear drainage by decreasing edema or by reducing lymphoid tissue near the eustachian tube opening. We have been unable to find any previous study in the medical literature that evaluated a short course of systemic corticosteroids as a possible treatment for OSAS secondary to ATH. We therefore undertook a prospective, open-label, pilot study to determine if a 5-day course of oral prednisone would reduce adenotonsillar hypertrophy, and minimize the clinical signs and physiological abnormalities of OSAS. Clinical, radiologic, and polysomnographic evaluations before and after corticosteroid treatment allowed each subject to serve as his own control. We reasoned that, if our results suggested an important treatment effect, then a larger, double-blinded, randomized controlled study would be justified.

SUBJECTS A N D METHODS Subjects From November 1994 to July 1995 the sleep laboratory at the Montreal Children’s Hospital evaluated 56 chil-

Al-Ghamdi et al.:Corticosteroidsfor Obstructive Sleep Apnea

dren for possible OSAS. Ten children were found who had adenotonsillar hypertrophy and polysomnographically proven OSAS and met the following inclusion and exclusion criteria. Inclusion criteria comprised the following: 1. age, 1 to 12 years; 2. tonsillar hypertrophy, 2+ or greater, andor adenoidal hypertrophy (adenoidlnasopharyngeal ratio >0.5);18Je3. history of obstructive sleep apnea suspected on the basis of three or more of the following signs of OSAS:20 a) loud snoring (more than 3 nights per week); b) difficulty breathing (more than 3 nights per week);c) obstructive sleep apnea witnessed by the parents; d) parents who were moderately or very worried about the child‘s breathing during sleep; and e) restless sleep (more than 3 nights per week) andor frequent awakenings (twice o r more per night); 4. mixed and obstructive apneahypopnea index 23 established by home po1ysomnography;zl and 5. the participating otolaryngologist (J.J.M., s.A.A.) had recommended surgical removal of tonsils and/or adenoids.

Radiologic assessment of adenoidal and nasopharyngeal airway sizes. Before and after prednisone treatment, a lateral neck radiograph was taken as described previously for adenotonsillar hypertrophy measurement in children with OSAS.18 The study radiologist (K.o.) read both the pretreatment and posttreatment radiographs and made measurements of the adenoid to nasopharyngeal ratio and the diameter of the nasopharyngeal airway a t its narrowest point.18Jg

The exclusion criteria and numbers of subjects excluded (n),if any, were as follows: 1. craniofacial abnormalities; 2. genetic abnormalities including Down’s syndrome; 3. neurologic disease (n = 1);4. exposure to varicella; 5. acute infection including acute tonsillopharyngitis and/or acute otitis (n = 3); 6. use of inhaled or systemic corticosteroids within the past 3 months; 7. need for emergency surgery based on life-threatening OSAS (n = 3); 8. obesity (n = 2); 9. unavailability of staff (n = 1);10. language barrier (n = 1);and 11. lived too far from hospital (n = 1).Five parents refused participation in the study.

Polysomnography. Before and after prednisone treatment, each child underwent home polysomnography to document the severity of obstructive sleep apnea and to evaluate the response to prednisone treatment. The portable recording system comprised cardiorespiratory and video recordings and was designed to quantitate the essential diagnostic elements of OSAS: obstructive, mixed, and central apnea; hypopnea; hemoglobin desaturation; sleep versus wakefulness; sleep position; snoring; and sleep disturbance. Details of our recording and analysis procedures are documented el~ewhere.21~23-25

Of the 10 children initially recruited into the study, one was eliminated from the final analysis because of a computer failure on the poststeroid recording night and because she was subsequently found to have a unilateral diaphragmatic paralysis, probably of congenital origin. However, her clinical course was similar to the other subjects, i.e., failure to improve with prednisone treatment but improvement after adenotonsillectomy.

In the home, equipment was set up by a technician a t the child’s usual bedtime and picked up the following morning. The cardiorespiratory recording consisted of an ECG, pulse rate, SaOz, pulse waveform, and thoracic and abdominal excursions and their sum obtained from a respiratory inductive plethysmograph. The signals were recorded on a portable computer, and later transferred to a computerized polysomnograph in the sleep laboratory. Obstructive apnea was defined as a n 80% or greater decrease in amplitude on the respiratory inductive plethysmography summation channel of at least 3-seconds in duration; hypopnea was defined as a 50% to 80% decrease in amplitude of the summation channel accompanied by a decrease in saturation of 4% or more.21 Audiovisual recordings were made under infrared lighting and provided complementary information about snoring and the subjects’ movement and position. Videotape recordings were time-matched to the cardiorespiratory recordings and analyzed on a computerized movement detection system (Sleepvision@,Martinex, Montreal, Quebec).23

Experimental Protocol Each subject served as his or her own control by being evaluated before and after a 5-day course of oral prednisone, approximately 1mgkg given once daily. Both the pretreatment and posttreatment evaluations included a detailed questionnaire, a physical examination by the otolaryngologist, a lateral neck radiograph for adenoidal size, and a polysomnographic recording of sleep and breathing. Parents and the study otolaryngologists decided after prednisone treatment whether to proceed with surgical removal of the tonsils and adenoids. A final questionnaire was completed by parents at least 6 weeks after surgery.

Specific Measurement Techniques Questionnaire.The questionnaire (available upon request) used for this project is one based on our previous studies20 and asks a wide battery of questions relating to signs and symptoms of OSAS as well as other general health questions. The questionnaire was administered by the sleep laboratory technician before and after prednisone treatment and at least 6 weeks after adenotonsillectomy. A symptom score (OSAS score) derived from responses to questions about snoring, difficulty breathing, and obstructive apnea was calculated and used to assess clinical response to prednisone treatment and to adenotonsillectomy.20 Laryngoscope 107: October 1997

Clinical assessment of tonsillar size. The study otolaryngologist performed a physical examination. Tonsillar size before and after treatment was graded from 0 to 4+.22 The grading was based on the proportion of the distance between the anterior tonsillar pillars that was taken up by the tonsillar tissue: 0, tonsils not extending beyond the pillars; 1+,0% to 25%; 2+, 25% to 50%; 3+, 50% to 75%; and 4+,75% to 100%.

Statistics. Results were expressed as the mean k standard error. To assess treatment effectiveness, the paired t-test and Wilcoxon signed rank test were used for normally and non-normally distributed data, respectively. Analysis of variance was used to compare OSAS scores at the three assessment times. Power calculations were performed to estimate the possibility of missing a significant treatment effect. Informed consent and approval. This project was approved by the Montreal Children’s Hospital/ McGill University Research Institute and the Institutional Review Board of the Montreal Children’s Hospital. Informed consent was obtained from parents of each subject a t the time that the patient was recruited into the study. Al-Ghamdi et al.: Corticosteroids for Obstructive Sleep Apnea

1383

T

\

BASELl N E

POST PREDNISONE

\t

POST T & A

Fig. 1. The obstructive sleep apnea syndrome (OSAS) score was similar before and after prednisone but decreased markedly in the eight of nine children who had surgical removal of tonsils and/or adenoids. A lower OSAS score indicates symptomatic improvement of OSAS, i.e., less snoring, less difficulty breathing at night, and/or less apnea.

RESULTS All nine subjects completed the 5-day prednisone treatment. Age averaged 4.4 -c 1 years; there were six girls. The dose received averaged 1.1 .c 0.1 mgikgld.

BAS ELIN E

POST PREDNISONE

No complications or side effects were noted. Prednisone treatment was begun 16 .c 5.6 days after the baseline polysomnography; the posttreatment polysomnography was performed 1.4 2 0.6 days after completion of the 5-day prednisone regime. Clinical symptomatology did not improve after prednisone treatment but did after surgical removal of the tonsils and/or adenoids. Eight of nine children required surgical removal of the tonsils and adenoids. The OSAS score was not significantly different after prednisone but decreased markedly in the eight children who had surgery: 1.8 2 0.7 versus 1.5 .c 0.7 versus -2.7 -t 0.6, P c 0.01 (Fig. 1). There were no consistent and clinically significant changes in tonsillar, adenoidal, or nasopharyngeal airway sizes after prednisone treatment. Eight of nine children had tonsillar hypertrophy, 2+ or greater. Tonsillar size decreased after prednisone treatment in only two patients and was unchanged in seven. The adenoid to nasopharyngeal ratio, an estimate of adenoidal size, decreased slightly in seven subjects, increased in one, and was unchanged in one; the mean adenoid to nasopharyngeal ratio was marginally reduced after treatment: 0.69 .c 0.03 versus 0.63 -c 0.03, P = 0.05 (Fig. 2A). However, the minimal nasopharyngeal airway size increased in six subjects, decreased in two, and was unchanged in one. Mean values for minimal nasopharyngeal airway size were not significantly different before and after treatment, 1.9 +- 0.8 versus 2.1 2 0.9 mm, P = 0.74 (Fig. 2B).

BASELl N E

B

POST PREDNISONE

Fig. 2. A. The adenoidlnasopharyngeal ratio, a radiographic estimate of adenoidal size, was minimally reduced after a 5-day course of prednisone: 0.69 i 0.03versus 0.63 i 0.03, P = 0.05. B. The minimal nasopharyngeal airway size was not significantly different after a 5-day course of prednisone: 1.9 i 0.8versus 2.1 i 0.9 mm, P = 0.74.

Laryngoscope 107: October 1997 1384

Al-Ghamdi et al.: Corticosteroids for Obstructive Sleep Apnea

~

TABLE I. Polysomnographic Indices Before and After Prednisone Treatment'. Measurement

Before Treatment

After Treatment

Difference

P value

9.9 f 2.4 5.9 f 3.5 19 f 5.8

4 f 3.6 1.5 i 1.3 5.2 f 4.4

0.29 0.27 0.27

18.1 f 1.7

15.9 f 1.9

19 f 1.6 89 f 5.2 96 f 0.4 91 f 2.6

18.7 f 1.3 90.3 f 5.3 97 i 0.4 93.9 f 1.4

2.2 f 2.2 0.3 f 0.6 -1.3 i 2.6 -1.2 f 0.1 -2.7 f 3.5

0.35 0.61 0.62 0.01 0.73

13.9 f 5.1 7.4 4.4 24.4 f 7.6

Apnedhypopnea index (n/hr) Desaturation index (n/hr) Percentage of sleep time with paradoxical movement of chest and abdomen MovemenVarousal index (n/hr)

*

Respiratory rate (breathslmin) Heart rate (beatshin) SaOn (%) Sleep efficiency ("10) 'All values shown as mean i SE.

Polysomnographic indices of OSAS severity did not improve after corticosteroid treatment (Table I). The apnedhypopnea index was not significantly different (Fig. 3), nor were other measures of the breathing disturbance, such as desaturation index or the percentage of sleep time spent with paradoxical movement of the chest and abdomen, a measure of partial airway obstruction. Hemoglobin saturation increased by 1%to 2%in each of the nine subjects, a statistically significant, but clinically insignificant, finding. Sleep efficiency was high before and after treatment in these children with moderately severe OSAS.21>24The frequency with which brief arousals interrupted sleep remained high after prednisone treatment.25

2

i

a.

\

0

I

1 1

BASELINE

POST PREDNISONE

Fig. 3. The apnedhypopnea index was similar before and after prednisone treatment. The child with the highest apneafhypopnea index showed the largest drop in the apnedhypopnea index after prednisone but still required surgical removal of tonsils and adenoids.

Laryngoscope 107: October 1997

DISCUSSION We found an oral prednisone dose of 1mgkg per day for 5 days to be ineffective in the treatment of OSAS secondary to adenotonsillar hypertrophy. The treatment regime did not improve clinical symptomatology due to OSAS, did not reduce adenotonsillar hypertrophy significantly, and did not reduce the sleep-related airway obstruction as assessed polysomnographically. Possible explanations for the apparent failure of a short course of oral prednisone include insufficient dose or duration of treatment, poor compliance, resistance of chronically hypertrophied tonsils and adenoids to the lympholytic and/or anti-inflammatory effects of corticosteroids, subject selection, or rebound after treatment withdrawal. Systemic corticosteroid doses equivalent to prednisone, 1mg/kg per day, have been used to treat acute asthmatic exacerbations, croup, and persistent middle ear effusions; larger doses are sometimes used to reduce tonsillar hypertrophy during mononucleosis, to treat bronchopulmonary dysplasia, or to minimize laryngeal inflammation. It is possible that a larger prednisone dose would be effective in children with OSAS and ATH. The treatment duration of 5 days was chosen because it is nearly free of side effects and does not cause a prolonged depression of the hypothalamic-pituitaryadrenal axis.26 Although a longer course of corticosteroids might be effective in reducing adenotonsillar hypertrophy, our judgment was that the potential side effects of a longer course of systemic corticosteroids would prohibit usefulness in most children. Although compliance was not assessed objectively with blood or urine corticosteroid testing, we believe that parents accurately reported that all children took the corticosteroids; these were sick children for whom the parents had sought treatment. We selected subjects with moderately severe OSAS. Conceivably, patients with mild OSAS27 would respond better but the benefitirisk ratio would then need careful consideration. It is unlikely that the subjects responded to Al-Ghamdi et al.: Corticosteroids for Obstructive Sleep Apnea

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treatment and then deteriorated after treatment was discontinued because the posttreatment evaluation was performed just a few days after completing the prednisone course. Although the etiology of adenotonsillar hypertrophy in children remains poorly understood, some recent data suggest that chronic bacterial infection may play a role. Of our nine subjects, three had just finished a course of antibiotics or were taking antibiotics during the study, five had a history of frequent upper respiratory infection, and three had repetitive episodes of otitis media. Core cultures of tonsils removed for tonsillar hypertrophy, as well as those removed for current tonsillitis causing airway obstruction, have shown large numbers of bacteria.22>2-3 Brodsky et al.29 found that tonsillar size was directly proportional to bacterial density expressed as colony forming units per gram of tonsil. Most authors have found a high frequency of Haemophilus influenzae in the core of enlarged adenoids and ton~ils.28~29J34 Other organisms possibly causing adenotonsillar hypertrophy include Staphylococcus aureus, group A p hemolytic streptococci, and anaerobes.2292a34 Therefore, clinical trials of antibiotics effective against these organisms, possibly in conjunction with a short course of high-dose corticosteroid, could potentially reduce adenotonsillar hypertrophy, lessen the severity of OSAS, and decrease the need for surgery. Recently, Demain and Goetz35 reported that topical nasal beclomethasone reduced adenoidal hypertrophy and nasal airway obstruction in a doubleblind, placebo-controlled study. They reported a significant reduction in the adenoid size and in the mean obstructive symptoms score. It took 2 months of treatment to achieve a 17% reduction in the adenoidchoanal ratio, corresponding to 5 1%improvement in mean obstructive symptom score; it took 26 months to achieve 29%reduction in the adenoid choanal ratio, corresponding to 82% improvement in symptoms. They only studied children 5 years and older, they did not assess tonsillar size, and they did not use polysomnography to document OSAS and its response to treatment. Nevertheless, use of topical nasal corticosteroids would appear to be a most promising medical treatment for adenoidal hypertrophy, possibly allowing some children with OSAS to avoid surgery. Topical nasal steroids have been found effective in treating allergic rhinitis, another cause of sleep-related airway obstructive.3638 Additionally, for prolonged use, inhaled andor topical corticosteroids have a much higher benefit to risk ratio than systemic corticosteroids.39 Our finding that adenoidal size was slightly smaller after prednisone treatment might support a clinical trial in which a short course of oral corticosteroids was followed by a longer course of nasal corticosteroids. It is important to acknowledge the limitations of our study. The number of patients evaluated was Laryngoscope 107: October 1997 1386

small and we did not have an untreated control group. Calculations were therefore performed to determine the sample size needed for a randomized, controlled study comparing corticosteroids with placebo. Assuming that 11%(one in nine) of symptomatic children spontaneously improve and that corticosteroids would benefit 33%, 64 subjects per group would be needed for an 80% chance of finding an effect significant at the 0.05 level.

CONCLUSION Our results suggest that a short course of systemic corticosteroids is not a n effective treatment for pediatric obstructive sleep apnea syndrome secondary to adenotonsillar hypertrophy. The results do not suggest that a larger, double-blind, placebo-controlled trial is warranted. However, other medical treatments should be investigated as an alternative to adenotonsillectomy for pediatric obstructive sleep apnea syndrome. ACKNOWLEDGMENT The authors thank Sylvia Laden and Rina Luciano for technical assistance, and Rosanna Barrafato for preparation of the manuscript. BIBLIOGRAPHY 1.Gulleminault C, Eldridge FL, Simmons FB, Dement WC. Sleep

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