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Changes in serum levels of IGF-1 and in growth following adenotonsillectomy in children
International Journal of Pediatric Otorhinolaryngology (2008) 72, 1065—1069
www.elsevier.com/locate/ijporl
Changes in serum levels of IGF-1 and in growth following adenotonsillectomy in children Jun-Myung Kang *, Hyeon-Jin Auo, Young-Hwa Yoo, Jin-Hee Cho, Byung-Guk Kim Department of Otolaryngology-HNS, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Received 2 January 2008; received in revised form 21 March 2008; accepted 22 March 2008 Available online 5 May 2008
KEYWORDS Children; Adenotonsillectomy; Growth; Adenotonsillar hypertrophy; IGF-1; Sleep disorders
Summary Objective: Adenotonsillar hypertrophy can cause upper airway obstruction and may be associated with growth delay in children. The objective of this study was to evaluate the long-term effects of adenotonsillectomy on height, weight, and body mass index (BMI) in children with sleep-disordered breathing (SDB). Methods: Fifty-two children (mean age 6.2 2.3 years) clinically diagnosed with SDB were enrolled. Children were diagnosed and scheduled for adenotonsillectomy (T&A) based on their responses to the validated, 22-item Sleep Related Breathing Disorder (SRDB) scale and a physical examination that showed adenotonsillar hypertrophy. Weight, height, and BMI were evaluated before and 5 years after T&A. Serum levels of insulin-like growth factor-1 (IGF-1) were measured before and 1 month after T&A. Results: Serum levels of IGF-1 were significantly higher at 1 month after T&A compared to before T&A ( p < 0.001). Thirty children (58%) returned for follow-up testing 5 years later. Their Z scores (standard deviation scores) for weight, height, and BMI of 30 children were significantly higher 5 years after T&A compared to before T&A ( p < 0.01). Conclusion: Children with SDB who undergo adenotonsillectomy show significant, long-term increases in weight, height and BMI, as well as a significant increase in serum levels of IGF-1. # 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction * Corresponding author at: Department of Otolaryngology-HNS, Holy Family Hospital, 2 Sosa-dong, Wonmi-gu, Pucheon, Kyounggi-do 420-717, Republic of Korea. Tel.: +82 32 340 7051; fax: +82 32 340 2764. E-mail address: [email protected] (J.-M. Kang).
Sleep-disordered breathing (SDB) includes primary snoring, upper airway resistant syndrome, obstructive hypoventilation, and obstructive sleep apnea syndrome (OSAS). Chronic upper airway obstruction
0165-5876/$ — see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2008.03.015
1066 attributable to adenotonsillar hypertrophy is the most common cause of SDB in children [1]. Although the prevalence of OSAS in children has been reported to range from 1% to 3%, the prevalence of SDB in children may approach 11% [2]. Because OSAS and primary snoring cannot be distinguished without polysomnography (PSG), the broader term of SDB is more relevant for everyday clinical practice. Unlike OSAS, which is defined in part by a specific apnea—hypopnea index (AHI) based on PSG, SDB may be diagnosed clinically and may not consistently meet PSG criteria for obstructive sleep breathing disorder [3]. Children without clinically significant hypoxia as measured by pulse oximetry but with habitual snoring show poorer academic performance than those who do not snore [4]. Insufficient weight and height gain have been well documented in children with OSAS, and ‘catch up’ growth after adenotonsillectomy has been reported [5—7]. Although the exact cause of the poor growth is unknown, candidates include low caloric intake caused by poor appetite and dysphagia, high energy expenditure due to more difficult breathing during sleep, nocturnal acidosis, and nocturnal hypoxemia [6—9]. Abnormal nocturnal growth hormone (GH) secretion and impaired GH action have also been suggested [10,11]. Nocturnal GH secretion is frequently reduced in clinical conditions involving sleep disorders (e.g. in children with OSAS), and surgical correction of OSAS may restore normal GH secretion [11]. Concentrations of circulating insulin-like growth factor-1 (IGF1) are strongly related to diurnal GH secretion, and they seem to correlate well with physiological changes in GH secretion [12]. Adenotonsillectomy (T&A) is the most common surgical treatment of SDB in children. Previous studies have revealed a significant increase in body weight and height following T&A [13,14]. However, the duration of follow-up in these studies was rather short. The purpose of the present study was to evaluate the long-term effects of T&A on height, weight, and body mass index (BMI) of children with clinically diagnosed SDB, as well as the effect of T&A on serum IGF-1 levels.
2. Methods The study population comprised children referred from primary health care to the Department of Otolaryngology, Head and Neck Surgery at the Catholic University Hospital between 1 March 2001 and 31 December 2002. The children had been referred for treatment because of nighttime snoring, mouth breathing, apneas, or difficult breathing
J.-M. Kang et al. presumably secondary to adenotonsillar hypertrophy. Children were excluded if they had known congenital upper airway anomalies, any underlying disease predisposing to upper airway obstruction, asthma, or allergic rhinitis. Parents completed the validated 22-item Sleep Related Breathing Disorder (SRDB) scale of the Pediatric Sleep Questionnaire [15]. A total 52 of children clinically diagnosed with SDB and scheduled to undergo T&A were enrolled. Children were diagnosed with SDB and scheduled for T&A based on an SRDB score (0.33) and a physical examination documenting hypertrophic tonsils and adenoids. Polysomnography was not routinely performed. The parents of 52 children gave informed consent for them to participate in the study. The institutional ethics committee approved the study protocol. All children were followed-up for measurements of serum IGF-1 1 month postoperatively. The scale used to categorize tonsillar hypertrophy has been described previously by Brodsky et al. [16]: 0, tonsils do not impinge on the airway; 1+, less than 25% airway obstruction; 2+, 25—50% airway obstruction; 3+, 50—75% airway obstruction; 4+, 75% or more airway obstruction. Only the patients with scores of 3+ or 4+ were included in this study. All children were examined using a flexible fiberoptic endoscope to assess the size of the adenoid. Adenoid size was classified during nasal inspiration according to the percentage of nasopharyngeal space obstruction: small, <50%; medium, 50—75%; large, >75%. Adenoid hypertrophy was defined as obstruction of more than 50% of the nasopharyngeal airway [17]. The SRDB scale contains 22-symptom items related to snoring frequency, loud snoring, observed apneas, difficulty breathing during sleep, daytime sleepiness, inattentive or hyperactive behavior, and other pediatric features. Responses are ‘‘yes’’=1, ‘‘no’’=0, and ‘‘don’t know’’=missing. The mean response for non-missing items is the score, which can vary from 0 to1. A score greater than 0.33 suggests a high risk for SDB with reasonable sensitivity and specificity [15]. All children underwent tonsillectomy and adenoidectomy. Dissection tonsillectomy and curettage adenoidectomy were performed under general anesthesia. Eight children with otitis media with effusions underwent ventilation tube insertion. Venous blood samples for measurement of IGF-1 levels were taken preoperatively and 1 month following T&A. The serum was extracted from blood samples, centrifuged and stored frozen at 20 8C. Serum IGF-1 concentrations were measured by a radioimmunoassay (Biosource Europe S.A., Belgium) with a Cobra II r-counter (Packard, U.S.A.) with a sensitivity of 0.4 ng/ml. The pre- and post-opera-
Changes in growth following adenotonsillectomy tive samples from the same individual were analyzed in parallel to exclude the effects of interassay variation. Weight was measured to the nearest 0.1 kg with an electronic scale and height was determined to the nearest 1.0 mm with a Harpendan wall-mounted stadiometer during the preoperative period and at 5 years after T&A. Measurements were taken by a trained technician in the otolaryngology office. Body mass index (BMI, kg/m2) was calculated as to determine the appropriate weight for the height. Weight, height, and BMI values were converted to Z scores (standard deviation scores) using current gender- and age-specific values for the growth parameters L, M and S, as published by the Korean Centers for Disease Control and Prevention [18]. Data were tested for normal distribution (Kolmagorov—Smirnov test) and are presented as mean S.D. Student’s t-tests for paired samples and Pearson correlations were applied to normally distributed data. The nonparametric Mannn—Whitney U test, Wilcoxon signed rank tests, and Spearman rank correlation were used for data showing skewed distributions.
3. Results The mean age of the 52 children at surgery was 6.2 2.3 years (range 2.9—10.8 years). The study included 29 boys (56%) and 23 girls (44%). The degree of tonsillar hypertrophy was between 50% and 75% for 18 children and >75% for 34 children. The degree of nasopharyngeal obstruction caused by adenoid hypertrophy was between 50% and 75% for 15 children and >75% for 37 children. The mean serum levels of IGF-1 in the 52 children increased by 16% after T&A, from 257.4 129.6 ng/ ml before T&A to 298.8 170.6 ng/ml 1 month after ( p < 0.001) (Table 1). In one of the 52 children, the preoperative serum level of IGF-1 was below normal. Postoperatively, these levels increased to values within the normal range. Of the 52 children in the original study cohort, 30 of them (58%) including 17 boys returned for followup testing 5 years later. Their average preoperative SRDB score was 0.40 0.16, and the median score was 0.38. At the 5-year follow-up, the average and Table 1 Serum levels of IGF-1 (ng/ml) before and 1 month after adenotonsillectomy (n = 52) Total Boys Girls
n
Pre-OP
Post-OP
p-Value
52 29 23
257.4 129.6 216.6 87.2 308.8 155.9
298.8 170.6 258.4 133.6 349.7 199.7
<0.001 0.011 0.015
1067 Table 2 The Z scores (SDS) for weight, height, and BMI before and 5 years after adenotonsillectomy (n = 30) n
Pre-OP
Post-OP
p-Value
Weight (SDS) Total 30 Boys 17 Girls 13
0.16 1.1 0.04 1.0 0.29 1.3
0.86 1.4 0.84 1.3 0.97 1.5
<0.001 <0.001 <0.001
Height (SDS) Total 30 Boys 17 Girls 13
0.33 0.9 0.25 0.8 0.49 1.3
0.69 1.1 0.64 1.0 0.75 1.4
0.009 0.003 0.02
BMI (SDS) Total 30 Boys 17 Girls 13
0.28 1.3 0.23 1.4 0.36 1.2
0.84 1.1 0.78 0.9 0.99 1.3
<0.001 <0.001 <0.001
median SRDB scores were 0.14 0.13 and 0.11, respectively. This change in the SRDB scores was significant ( p < 0.001). Comparisons of the 30 returning children and the other 22 who did not participate in follow-up revealed no significant difference in demographics, growth parameters, or SRDB scale. The mean Z score for weight in the 30 children increased significantly from 0.16 1.1 before T&A to 0.86 1.4 at 5 years after T&A ( p < 0.001). No difference was observed in these changes between boys and girls. The mean Z score for height increased significantly from 0.33 0.9 before T&A to 0.69 1.1 at 5 years after T&A ( p < 0.001). In the postoperative period, the Z score for height indicated that boys grew somewhat more than girls ( p < 0.05). A significant increase in the Z score for BMI was also observed at 5 years after T&A ( p < 0.001) (Table 2). The change in the Z scores for weight was significantly correlated with the changes in both the SRDB scores (r = 0.69, p < 0.001) and serum levels of IGF-1 (r = 0.54, p < 0.001). Similarly, the change in the Z scores for height was significantly correlated with the changes in both the SRDB scores (r = 0.43, p < 0.001) and serum levels of IGF-1 (r = 0.38, p < 0.01).
4. Discussion Respiratory disturbance during sleep in children with adenotonsillar hypertrophy is associated with reduced growth and nocturnal GH secretion. This is supported by several studies in adults with OSAS demonstrating an increase in GH levels after treatment with continuous positive airway pressure (CPAP) [19]. In previous studies examining the effects of T&A on growth, weight and height were
1068 measured roughly 1 year after surgery [13,14]. Our study focused on the long-term changes in weight, height and BMI after surgery. A study with a follow-up period of 6—13 months examined the effect of T&A on somatic growth. This study found that the standard deviation scores (SDS) of body weight increased significantly after surgery and height also increased significantly especially in children younger than 5 years [14]. Another study with a follow-up period of 1 year showed significant increase in weight, BMI, and height SDS after T&A [13]. Some studies, however, have reported no significant increase in height SDS or percentile after T&A [7]. In this study, we detected a significant increase in weight, height, and BMI at 5 years after T&A. We also observed significant correlations between the changes in the Z scores for weight and height, and the change in SRDB scores. Adenotonsillectomy is considered to be a firstline therapy for SDB in patients with adenotonsillar hypertrophy. Absolute indications for adenotonsillectomy include adenotonsillar hyperplasia with obstructive sleep apnea, failure to thrive, or abnormal dentofacial growth. Relative indications are adenotonsillar hyperplasia with upper airway obstruction, dysphagia, speech impairment, and halitosis [20]. GH is released phasically during a 24-h cycle, mainly during sleep. The peak GH concentration is associated with the onset of slow-wave sleep (SWS). A previous study showed that the only parameter of sleep architecture that changed after T&A was the duration of SWS, which increased by 5.5% [7]. However, the precise linkage between GH secretion and SWS remains unclear. Nocturnal GH secretion can also occur in the absence of SWS, and approximately one-third of SW periods are not associated with detectable GH secretion [21]. In adults, there is a consistent relationship between SWS and increased GH secretion; the reverse relationship between GH secretion and nocturnal awakenings is also observed [22]. In children with OSAS, the sleep architecture is relatively well preserved. Although these children may show a higher number of arousals during sleep, their sleep fragmentation is not well defined [23]. A study of 36 children with OSAS found that the only parameter of sleep architecture that changed significantly following T&A was the number of arousals per hour of sleep. This suggests that frequent arousals may be associated with impaired GH secretion [24]. The effects of GH on skeletal growth are mediated mainly by stimulation of IGF-1 expression. IGF-1 constitute a family of insulin-like peptide growth factors whose activity is modulated by insulin, nutrition and GH. Deficient growth in the pre-
J.-M. Kang et al. sence of adequate GH secretion may result from decreased IGF-1 production, increased inhibitor levels or changes in target organ responsiveness. GH stimulates the synthesis of IGF-1 in the liver and other target tissues [25]. IGF-1 is considered to be the main mediator of the growth-promoting actions of GH [12]. Some studies have found significantly increased serum levels of IGF-1 and insulin-like growth factor binding protein 3 (IGFBP3) after surgery [26]. Vontetsianos et al. [14] reported that the serum levels of GH and IGF-1 did not significantly increase after surgery. The authors did find, however, that the IGF1/GH ratio increased, perhaps indicating improved secretion of IGF-1 stimulated by GH. In this study, there was a significant, gender-insignificant increase in serum IGF-1 levels after surgery, and significant correlations were observed between changes in serum IGF-1 levels and changes in Z scores for weight and height. PSG is considered to be the gold standard for the evaluation of SDB. However, most otolaryngologists make decisions based on medical history that is suggestive of SDB and on a physical examination demonstrating adenotonsillar hypertrophy. There are several reasons why PSG alone may be insufficient to identify all children with SDB. Children with primary snoring and upper airway resistance syndrome may show a normal respiratory disturbance index on a standard PSG, and children with clinically diagnosed SDB may not consistently meet PSG criteria for an obstructive sleep breathing disorder, even though they may suffer from sleep fragmentation and daytime behavioral morbidity similar to that seen in children with OSAS [27]. Alternative instruments, such as quality-of-life (QOL) measures, may be useful for children who do not need PSG testing. A questionnaire specifically designed for predicting SDB may be a useful complement to conventional screening; such a resource may also help determine candidacy for T&A. Because PSG testing for each child was not feasible in our study, we chose a validated SRDB scale for children presenting a medical history of nocturnal airway obstruction and possible OSAS. The SRDB scale cutoff of 0.33 used in this study to indicate the presence of SDB showed a sensitivity of 85% and a specificity of 87% [15]. The SRDB scale may predict OSAS-related neurobehavioral morbidity and its response to T&A as well as or better than does PSG [28]. However, stratification of children with SDB based on PSG parameters would be helpful for understanding the pathophysiological mechanisms of growth impairment in children with SDB. In conclusion, we found here that the weight, height and BMI of children with SDB significantly
Changes in growth following adenotonsillectomy increased 5 years after T&A relative to their values before T&A. These changes were accompanied by a significant increase in serum levels of IGF-1. These findings suggest that T&A may influence the GH-IGF1 axis by increasing IGF-1 levels, leading to acceleration of growth. We conclude that T&A can help children with SDB to achieve their optimal growth.
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1069 [13] B. Ersoy, A.V. Yuceturk, F. Taneli, V. Urk, B.S. Uyanik, Changes in growth pattern, body composition and biochemical markers of growth after adenotonsillectomy in prepubertal children, Int. J. Pediatr. Otorhinolaryngol. 699 (2005) 1175—1181. [14] H.S. Vontetsianos, S.E. Davris, G.D. Christopoulos, C. DacouVoutetakis, Improved somatic growth following adenoidectomy and tonsillectomy in young children. Possible pathogenetic mechanisms, Hormones 4 (2005) 49—54. [15] R.D. Chervin, K. Hedger, J.E. Dillon, K.J. Pituch, Pediatric sleep questionnaire (PSQ): validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems, Sleep Med. 11 (2000) 21—32. [16] L. Brodsky, L. Moore, J.F. Stanievich, A comparison of tonsillar size and oropharyngeal dimensions in children with obstructive adenotonsillar hypertrophy, Int. J. Pediatr. Otorhinolaryngol. 13 (1987) 149—156. [17] P.J. Wormald, C.A. Prescott, Adenoids: comparison of radiological assessment methods with clinical and endoscopic findings, J. Laryngol. Otol. 106 (4) (1992) 342—344. [18] Korea centers for disease control and prevention, Child growth charts, 2007, available from: http://www.cdc.go.kr. [19] B.G. Cooper, J.E. White, L.A. Ashworth, K.G. Alberti, G.J. Gibson, Hormonal and metabolic profiles in subjects with obstructive sleep apnea syndrome and the acute effects of nasal continuous positive airway pressure (CPAP) treatment, Sleep 183 (1995) 172—179. [20] H.D. David, S. Christopher, Indications for tonsillectomy and adenoidectomy, Laryngoscope 112 (2002) 6—10. [21] E. Van Cauter, M. Kerkhofs, A. Caufriez, A. Van Onderbergen, M.O. Thorner, G. Copinschi, A quantitative estimation of growth hormone secretion in normal man: reproducibility and relation to sleep and time of day, J. Clin. Endocrinol. Metab. 746 (1992) 1441—1450. [22] E. Van Cauter, L. Plat, G. Copinschi, Interrelations between sleep and the somatotropic axis, Sleep 216 (1998) 553— 566. [23] D.Y. Goh, P. Galster, C.L. Marcus, Sleep architecture and respiratory disturbances in children with obstructive sleep apnea, Am. J. Respir. Crit. Care Med. 1622 (2000) 682—686. [24] A. Tal, A. Bar, A. Leiberman, A. Tarasiuk, Sleep characteristics following adenotonsillectomy in children with obstructive sleep apnea syndrome, Chest 1243 (2003) 948—953. [25] P. Tapanainen, M. Knip, Evaluation of growth hormone secretion and treatment, Ann. Med. 24 (1992) 237—247. [26] M.D. Yilmaz, A.S. Hosal, H. Oguz, N. Yordam, S. Kaya, The effects of tonsillectomy and adenoidectomy on serum IGF-I and IGFBP3 levels in children, Laryngoscope 112 (2002) 922— 925. [27] R. Downey, R.M. Perkin, J. MacQuarrie, Upper airway resistance syndrome: sick, symptomatic but underrecognized, Sleep 167 (1993) 620—623. [28] R.D. Chervin, R.A. Weatherly, S.L. Garetz, D.L. Ruzicka, B.J. Giordani, E.K. Hodges, et al., Pediatric sleep questionnaire: prediction of sleep apnea and outcomes, Arch. Otolaryngol. Head Neck Surg. 1333 (2007) 216—222.
Available online at www.sciencedirect.com
www.elsevier.com/locate/ijporl
Changes in serum levels of IGF-1 and in growth following adenotonsillectomy in children Jun-Myung Kang *, Hyeon-Jin Auo, Young-Hwa Yoo, Jin-Hee Cho, Byung-Guk Kim Department of Otolaryngology-HNS, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Received 2 January 2008; received in revised form 21 March 2008; accepted 22 March 2008 Available online 5 May 2008
KEYWORDS Children; Adenotonsillectomy; Growth; Adenotonsillar hypertrophy; IGF-1; Sleep disorders
Summary Objective: Adenotonsillar hypertrophy can cause upper airway obstruction and may be associated with growth delay in children. The objective of this study was to evaluate the long-term effects of adenotonsillectomy on height, weight, and body mass index (BMI) in children with sleep-disordered breathing (SDB). Methods: Fifty-two children (mean age 6.2 2.3 years) clinically diagnosed with SDB were enrolled. Children were diagnosed and scheduled for adenotonsillectomy (T&A) based on their responses to the validated, 22-item Sleep Related Breathing Disorder (SRDB) scale and a physical examination that showed adenotonsillar hypertrophy. Weight, height, and BMI were evaluated before and 5 years after T&A. Serum levels of insulin-like growth factor-1 (IGF-1) were measured before and 1 month after T&A. Results: Serum levels of IGF-1 were significantly higher at 1 month after T&A compared to before T&A ( p < 0.001). Thirty children (58%) returned for follow-up testing 5 years later. Their Z scores (standard deviation scores) for weight, height, and BMI of 30 children were significantly higher 5 years after T&A compared to before T&A ( p < 0.01). Conclusion: Children with SDB who undergo adenotonsillectomy show significant, long-term increases in weight, height and BMI, as well as a significant increase in serum levels of IGF-1. # 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction * Corresponding author at: Department of Otolaryngology-HNS, Holy Family Hospital, 2 Sosa-dong, Wonmi-gu, Pucheon, Kyounggi-do 420-717, Republic of Korea. Tel.: +82 32 340 7051; fax: +82 32 340 2764. E-mail address: [email protected] (J.-M. Kang).
Sleep-disordered breathing (SDB) includes primary snoring, upper airway resistant syndrome, obstructive hypoventilation, and obstructive sleep apnea syndrome (OSAS). Chronic upper airway obstruction
0165-5876/$ — see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2008.03.015
1066 attributable to adenotonsillar hypertrophy is the most common cause of SDB in children [1]. Although the prevalence of OSAS in children has been reported to range from 1% to 3%, the prevalence of SDB in children may approach 11% [2]. Because OSAS and primary snoring cannot be distinguished without polysomnography (PSG), the broader term of SDB is more relevant for everyday clinical practice. Unlike OSAS, which is defined in part by a specific apnea—hypopnea index (AHI) based on PSG, SDB may be diagnosed clinically and may not consistently meet PSG criteria for obstructive sleep breathing disorder [3]. Children without clinically significant hypoxia as measured by pulse oximetry but with habitual snoring show poorer academic performance than those who do not snore [4]. Insufficient weight and height gain have been well documented in children with OSAS, and ‘catch up’ growth after adenotonsillectomy has been reported [5—7]. Although the exact cause of the poor growth is unknown, candidates include low caloric intake caused by poor appetite and dysphagia, high energy expenditure due to more difficult breathing during sleep, nocturnal acidosis, and nocturnal hypoxemia [6—9]. Abnormal nocturnal growth hormone (GH) secretion and impaired GH action have also been suggested [10,11]. Nocturnal GH secretion is frequently reduced in clinical conditions involving sleep disorders (e.g. in children with OSAS), and surgical correction of OSAS may restore normal GH secretion [11]. Concentrations of circulating insulin-like growth factor-1 (IGF1) are strongly related to diurnal GH secretion, and they seem to correlate well with physiological changes in GH secretion [12]. Adenotonsillectomy (T&A) is the most common surgical treatment of SDB in children. Previous studies have revealed a significant increase in body weight and height following T&A [13,14]. However, the duration of follow-up in these studies was rather short. The purpose of the present study was to evaluate the long-term effects of T&A on height, weight, and body mass index (BMI) of children with clinically diagnosed SDB, as well as the effect of T&A on serum IGF-1 levels.
2. Methods The study population comprised children referred from primary health care to the Department of Otolaryngology, Head and Neck Surgery at the Catholic University Hospital between 1 March 2001 and 31 December 2002. The children had been referred for treatment because of nighttime snoring, mouth breathing, apneas, or difficult breathing
J.-M. Kang et al. presumably secondary to adenotonsillar hypertrophy. Children were excluded if they had known congenital upper airway anomalies, any underlying disease predisposing to upper airway obstruction, asthma, or allergic rhinitis. Parents completed the validated 22-item Sleep Related Breathing Disorder (SRDB) scale of the Pediatric Sleep Questionnaire [15]. A total 52 of children clinically diagnosed with SDB and scheduled to undergo T&A were enrolled. Children were diagnosed with SDB and scheduled for T&A based on an SRDB score (0.33) and a physical examination documenting hypertrophic tonsils and adenoids. Polysomnography was not routinely performed. The parents of 52 children gave informed consent for them to participate in the study. The institutional ethics committee approved the study protocol. All children were followed-up for measurements of serum IGF-1 1 month postoperatively. The scale used to categorize tonsillar hypertrophy has been described previously by Brodsky et al. [16]: 0, tonsils do not impinge on the airway; 1+, less than 25% airway obstruction; 2+, 25—50% airway obstruction; 3+, 50—75% airway obstruction; 4+, 75% or more airway obstruction. Only the patients with scores of 3+ or 4+ were included in this study. All children were examined using a flexible fiberoptic endoscope to assess the size of the adenoid. Adenoid size was classified during nasal inspiration according to the percentage of nasopharyngeal space obstruction: small, <50%; medium, 50—75%; large, >75%. Adenoid hypertrophy was defined as obstruction of more than 50% of the nasopharyngeal airway [17]. The SRDB scale contains 22-symptom items related to snoring frequency, loud snoring, observed apneas, difficulty breathing during sleep, daytime sleepiness, inattentive or hyperactive behavior, and other pediatric features. Responses are ‘‘yes’’=1, ‘‘no’’=0, and ‘‘don’t know’’=missing. The mean response for non-missing items is the score, which can vary from 0 to1. A score greater than 0.33 suggests a high risk for SDB with reasonable sensitivity and specificity [15]. All children underwent tonsillectomy and adenoidectomy. Dissection tonsillectomy and curettage adenoidectomy were performed under general anesthesia. Eight children with otitis media with effusions underwent ventilation tube insertion. Venous blood samples for measurement of IGF-1 levels were taken preoperatively and 1 month following T&A. The serum was extracted from blood samples, centrifuged and stored frozen at 20 8C. Serum IGF-1 concentrations were measured by a radioimmunoassay (Biosource Europe S.A., Belgium) with a Cobra II r-counter (Packard, U.S.A.) with a sensitivity of 0.4 ng/ml. The pre- and post-opera-
Changes in growth following adenotonsillectomy tive samples from the same individual were analyzed in parallel to exclude the effects of interassay variation. Weight was measured to the nearest 0.1 kg with an electronic scale and height was determined to the nearest 1.0 mm with a Harpendan wall-mounted stadiometer during the preoperative period and at 5 years after T&A. Measurements were taken by a trained technician in the otolaryngology office. Body mass index (BMI, kg/m2) was calculated as to determine the appropriate weight for the height. Weight, height, and BMI values were converted to Z scores (standard deviation scores) using current gender- and age-specific values for the growth parameters L, M and S, as published by the Korean Centers for Disease Control and Prevention [18]. Data were tested for normal distribution (Kolmagorov—Smirnov test) and are presented as mean S.D. Student’s t-tests for paired samples and Pearson correlations were applied to normally distributed data. The nonparametric Mannn—Whitney U test, Wilcoxon signed rank tests, and Spearman rank correlation were used for data showing skewed distributions.
3. Results The mean age of the 52 children at surgery was 6.2 2.3 years (range 2.9—10.8 years). The study included 29 boys (56%) and 23 girls (44%). The degree of tonsillar hypertrophy was between 50% and 75% for 18 children and >75% for 34 children. The degree of nasopharyngeal obstruction caused by adenoid hypertrophy was between 50% and 75% for 15 children and >75% for 37 children. The mean serum levels of IGF-1 in the 52 children increased by 16% after T&A, from 257.4 129.6 ng/ ml before T&A to 298.8 170.6 ng/ml 1 month after ( p < 0.001) (Table 1). In one of the 52 children, the preoperative serum level of IGF-1 was below normal. Postoperatively, these levels increased to values within the normal range. Of the 52 children in the original study cohort, 30 of them (58%) including 17 boys returned for followup testing 5 years later. Their average preoperative SRDB score was 0.40 0.16, and the median score was 0.38. At the 5-year follow-up, the average and Table 1 Serum levels of IGF-1 (ng/ml) before and 1 month after adenotonsillectomy (n = 52) Total Boys Girls
n
Pre-OP
Post-OP
p-Value
52 29 23
257.4 129.6 216.6 87.2 308.8 155.9
298.8 170.6 258.4 133.6 349.7 199.7
<0.001 0.011 0.015
1067 Table 2 The Z scores (SDS) for weight, height, and BMI before and 5 years after adenotonsillectomy (n = 30) n
Pre-OP
Post-OP
p-Value
Weight (SDS) Total 30 Boys 17 Girls 13
0.16 1.1 0.04 1.0 0.29 1.3
0.86 1.4 0.84 1.3 0.97 1.5
<0.001 <0.001 <0.001
Height (SDS) Total 30 Boys 17 Girls 13
0.33 0.9 0.25 0.8 0.49 1.3
0.69 1.1 0.64 1.0 0.75 1.4
0.009 0.003 0.02
BMI (SDS) Total 30 Boys 17 Girls 13
0.28 1.3 0.23 1.4 0.36 1.2
0.84 1.1 0.78 0.9 0.99 1.3
<0.001 <0.001 <0.001
median SRDB scores were 0.14 0.13 and 0.11, respectively. This change in the SRDB scores was significant ( p < 0.001). Comparisons of the 30 returning children and the other 22 who did not participate in follow-up revealed no significant difference in demographics, growth parameters, or SRDB scale. The mean Z score for weight in the 30 children increased significantly from 0.16 1.1 before T&A to 0.86 1.4 at 5 years after T&A ( p < 0.001). No difference was observed in these changes between boys and girls. The mean Z score for height increased significantly from 0.33 0.9 before T&A to 0.69 1.1 at 5 years after T&A ( p < 0.001). In the postoperative period, the Z score for height indicated that boys grew somewhat more than girls ( p < 0.05). A significant increase in the Z score for BMI was also observed at 5 years after T&A ( p < 0.001) (Table 2). The change in the Z scores for weight was significantly correlated with the changes in both the SRDB scores (r = 0.69, p < 0.001) and serum levels of IGF-1 (r = 0.54, p < 0.001). Similarly, the change in the Z scores for height was significantly correlated with the changes in both the SRDB scores (r = 0.43, p < 0.001) and serum levels of IGF-1 (r = 0.38, p < 0.01).
4. Discussion Respiratory disturbance during sleep in children with adenotonsillar hypertrophy is associated with reduced growth and nocturnal GH secretion. This is supported by several studies in adults with OSAS demonstrating an increase in GH levels after treatment with continuous positive airway pressure (CPAP) [19]. In previous studies examining the effects of T&A on growth, weight and height were
1068 measured roughly 1 year after surgery [13,14]. Our study focused on the long-term changes in weight, height and BMI after surgery. A study with a follow-up period of 6—13 months examined the effect of T&A on somatic growth. This study found that the standard deviation scores (SDS) of body weight increased significantly after surgery and height also increased significantly especially in children younger than 5 years [14]. Another study with a follow-up period of 1 year showed significant increase in weight, BMI, and height SDS after T&A [13]. Some studies, however, have reported no significant increase in height SDS or percentile after T&A [7]. In this study, we detected a significant increase in weight, height, and BMI at 5 years after T&A. We also observed significant correlations between the changes in the Z scores for weight and height, and the change in SRDB scores. Adenotonsillectomy is considered to be a firstline therapy for SDB in patients with adenotonsillar hypertrophy. Absolute indications for adenotonsillectomy include adenotonsillar hyperplasia with obstructive sleep apnea, failure to thrive, or abnormal dentofacial growth. Relative indications are adenotonsillar hyperplasia with upper airway obstruction, dysphagia, speech impairment, and halitosis [20]. GH is released phasically during a 24-h cycle, mainly during sleep. The peak GH concentration is associated with the onset of slow-wave sleep (SWS). A previous study showed that the only parameter of sleep architecture that changed after T&A was the duration of SWS, which increased by 5.5% [7]. However, the precise linkage between GH secretion and SWS remains unclear. Nocturnal GH secretion can also occur in the absence of SWS, and approximately one-third of SW periods are not associated with detectable GH secretion [21]. In adults, there is a consistent relationship between SWS and increased GH secretion; the reverse relationship between GH secretion and nocturnal awakenings is also observed [22]. In children with OSAS, the sleep architecture is relatively well preserved. Although these children may show a higher number of arousals during sleep, their sleep fragmentation is not well defined [23]. A study of 36 children with OSAS found that the only parameter of sleep architecture that changed significantly following T&A was the number of arousals per hour of sleep. This suggests that frequent arousals may be associated with impaired GH secretion [24]. The effects of GH on skeletal growth are mediated mainly by stimulation of IGF-1 expression. IGF-1 constitute a family of insulin-like peptide growth factors whose activity is modulated by insulin, nutrition and GH. Deficient growth in the pre-
J.-M. Kang et al. sence of adequate GH secretion may result from decreased IGF-1 production, increased inhibitor levels or changes in target organ responsiveness. GH stimulates the synthesis of IGF-1 in the liver and other target tissues [25]. IGF-1 is considered to be the main mediator of the growth-promoting actions of GH [12]. Some studies have found significantly increased serum levels of IGF-1 and insulin-like growth factor binding protein 3 (IGFBP3) after surgery [26]. Vontetsianos et al. [14] reported that the serum levels of GH and IGF-1 did not significantly increase after surgery. The authors did find, however, that the IGF1/GH ratio increased, perhaps indicating improved secretion of IGF-1 stimulated by GH. In this study, there was a significant, gender-insignificant increase in serum IGF-1 levels after surgery, and significant correlations were observed between changes in serum IGF-1 levels and changes in Z scores for weight and height. PSG is considered to be the gold standard for the evaluation of SDB. However, most otolaryngologists make decisions based on medical history that is suggestive of SDB and on a physical examination demonstrating adenotonsillar hypertrophy. There are several reasons why PSG alone may be insufficient to identify all children with SDB. Children with primary snoring and upper airway resistance syndrome may show a normal respiratory disturbance index on a standard PSG, and children with clinically diagnosed SDB may not consistently meet PSG criteria for an obstructive sleep breathing disorder, even though they may suffer from sleep fragmentation and daytime behavioral morbidity similar to that seen in children with OSAS [27]. Alternative instruments, such as quality-of-life (QOL) measures, may be useful for children who do not need PSG testing. A questionnaire specifically designed for predicting SDB may be a useful complement to conventional screening; such a resource may also help determine candidacy for T&A. Because PSG testing for each child was not feasible in our study, we chose a validated SRDB scale for children presenting a medical history of nocturnal airway obstruction and possible OSAS. The SRDB scale cutoff of 0.33 used in this study to indicate the presence of SDB showed a sensitivity of 85% and a specificity of 87% [15]. The SRDB scale may predict OSAS-related neurobehavioral morbidity and its response to T&A as well as or better than does PSG [28]. However, stratification of children with SDB based on PSG parameters would be helpful for understanding the pathophysiological mechanisms of growth impairment in children with SDB. In conclusion, we found here that the weight, height and BMI of children with SDB significantly
Changes in growth following adenotonsillectomy increased 5 years after T&A relative to their values before T&A. These changes were accompanied by a significant increase in serum levels of IGF-1. These findings suggest that T&A may influence the GH-IGF1 axis by increasing IGF-1 levels, leading to acceleration of growth. We conclude that T&A can help children with SDB to achieve their optimal growth.
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