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The n e w e ng l a n d j o u r na l of m e dic i n e original article A Randomized Trial of Adenotonsillectomy for Childhood Sleep Apnea Carole L. Marcus, M.B., B.Ch., Reneé H.
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  srcinal article The   new england journal of    medicine n engl j med 368;25  nejm.org june 20 , 2013 2366 A Randomized Trial of Adenotonsillectomy for Childhood Sleep Apnea Carole L. Marcus, M.B., B.Ch., Reneé H. Moore, Ph.D., Carol L. Rosen, M.D., Bruno Giordani, Ph.D., Susan L. Garetz, M.D., H. Gerry Taylor, Ph.D., Ron B. Mitchell, M.D., Raouf Amin, M.D., Eliot S. Katz, M.D., Raanan Arens, M.D., Shalini Paruthi, M.D., Hiren Muzumdar, M.D., David Gozal, M.D., Nina Hattiangadi Thomas, Ph.D., Janice Ware, Ph.D., Dean Beebe, Ph.D., Karen Snyder, M.S., Lisa Elden, M.D., Robert C. Sprecher, M.D., Paul Willging, M.D., Dwight Jones, M.D., John P. Bent, M.D., Timothy Hoban, M.D., Ronald D. Chervin, M.D., Susan S. Ellenberg, Ph.D., and Susan Redline, M.D., M.P.H., for the Childhood Adenotonsillectomy Trial (CHAT) The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Redline at Brigham and Women’s Hos-pital, 221 Longwood Ave., Boston, MA 02115, or at sredline@partners.org.This article was published on May 21, 2013, at NEJM.org. N Engl J Med 2013;368:2366-76.DOI: 10.1056/NEJMoa1215881 Copyright © 2013 Massachusetts Medical Society. ABSTRACT BACKGROUND Adenotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and polysomnographic findings has not been rigorously eval-uated. We hypothesized that, in children with the obstructive sleep apnea syndrome  without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as com-pared with watchful waiting with supportive care, would result in improved outcomes. METHODS We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Poly-somnographic, cognitive, behavioral, and health outcomes were assessed at base-line and at 7 months. RESULTS The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean [±SD] improvement, 7.1±13.9 in the early-adenotonsillectomy group and 5.1±13.4 in the watchful-waiting group; P = 0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. Normalization of polysomnographic findings was observed in a larger pro-portion of children in the early-adenotonsillectomy group than in the watchful- waiting group (79% vs. 46%). CONCLUSIONS As compared with a strategy of watchful waiting, surgical treatment for the obstruc-tive sleep apnea syndrome in school-age children did not significantly improve atten-tion or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and poly-somnographic findings, thus providing evidence of beneficial effects of early adeno-tonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT00560859.) The New England Journal of Medicine Downloaded from nejm.org on August 15, 2017. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.  Adenotonsillectomy for Childhood Sleep Apnea n engl j med 368;25  nejm.org june 20 , 2013 2367 T he childhood obstructive sleep   ap- nea syndrome is associated with numer-ous adverse health outcomes, including cognitive and behavioral deficits. 1  The most commonly identified risk factor for the child-hood obstructive sleep apnea syndrome is adeno-tonsillar hypertrophy. Thus, the primary treat-ment is adenotonsillectomy, which accounts for more than 500,000 procedures annually in the United States alone. 2  Nevertheless, there has been no controlled study evaluating the benefits and risks of adenotonsillectomy, as compared  with watchful waiting, for the management of the obstructive sleep apnea syndrome.The Childhood Adenotonsillectomy Trial (CHAT)  was designed to evaluate the efficacy of early adenotonsillectomy versus watchful waiting with supportive care, with respect to cognitive, behav-ioral, quality-of-life, and sleep factors at 7 months of follow-up, in children with the obstructive sleep apnea syndrome. Our primary outcome  was a neurobehavioral measure of attention and executive function, a domain that has been shown to be sensitive to intermittent hypoxemia related to the obstructive sleep apnea syndrome. 3  Given the prevalence of this syndrome among black children and obese children, 4,5  we also evaluated whether the relative efficacy of the treatment differed according to race, weight, or baseline severity of the syndrome. METHODS STUDY DESIGN AND PATIENTS We conducted this multicenter, single-blind, ran-domized, controlled trial at seven academic sleep centers. Methodologic details have been published previously  6  and are provided in the full protocol and in the Supplementary Appendix (available  with the full text of this article at NEJM.org). Eligible children were 5 to 9 years of age, had the obstructive sleep apnea syndrome  without prolonged oxyhemoglobin desatura-tion, and were considered to be suitable candi-dates for adenotonsillectomy. The obstructive sleep apnea syndrome was defined as an ob-structive apnea– hypopnea index (AHI) score of 2 or more events per hour or an obstructive apnea index (OAI) score of 1 or more events per hour. 7-10  Children with an AHI score of more than 30 events per hour, an OAI score of more than 20 events per hour, or arterial oxyhemo-globin saturation of less than 90% for 2% or more of the total sleep time were not eligible, owing to the severity of the polysomnographic findings. Exclusion criteria included recurrent tonsillitis, a z score based on the body-mass index (the weight in kilograms divided by the square of the height in meters) of 3 or more, and medication for attention deficit–hyperactivity dis-order (ADHD).Children were randomly assigned to early adenotonsillectomy (surgery within 4 weeks after randomization) or a strategy of watchful waiting. At the baseline visit, children with coexisting conditions that could exacerbate the obstructive sleep apnea syndrome (e.g., allergies and poorly controlled asthma) were referred for treatment as needed. STUDY OVERSIGHT The study was approved by the institutional re- view board at each participating site. Written in-formed consent was obtained from caregivers, and assent from children who were 7 years of age or older. An independent data and safety moni-toring board reviewed interim data on safety and study quality. An external medical monitor adjudicated treatment failures, defined as chang-es in clinical status requiring a change in the as-signed therapy. 6  All the authors vouch for the completeness and accuracy of the data and the fidelity of the study to the protocol (available at NEJM.org). There was no commercial support for this study. ASSESSMENTS Children underwent standardized polysomno-graphic testing with scoring at a centralized sleep reading center, cognitive and behavioral testing, and other clinical and laboratory evalu-ations at baseline and 7 months after randomiza-tion. 6  At both examinations, caregivers were asked to complete survey instruments, and teachers were mailed behavioral assessments (see the Supple-mentary Appendix). OUTCOMES The primary study outcome was the change in the attention and executive-function score on the Developmental Neuropsychological Assessment (NEPSY; scores range from 50 to 150, with 100 representing the population mean and higher scores indicating better functioning). 11  This test has well-established psychometric properties 11  and comprises three tasks (tower building, visual The New England Journal of Medicine Downloaded from nejm.org on August 15, 2017. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.  The   new england journal of    medicine n engl j med 368;25  nejm.org june 20 , 2013 2368 attention, and auditory attention) performed un-der the supervision of a psychometrist. Other outcomes included caregiver and teach-er ratings of behavior (Conners’ Rating Scale Revised: Long Version Global Index, comprising Restless–Impulsive and Emotional   Lability fac-tor sets [caregiver-rated T scores range from 38 to 90, and teacher-rated T scores range from 40 to 90, with higher scores indicating worse func-tioning]), 12  and the Behavior Rating Inventory of Executive Function [BRIEF] Global Executive Composite T score, comprising summary mea-sures of behavioral regulation and metacognition [caregiver-rated scores range from 28 to 101, and teacher-rated scores range from 37 to 131,  with higher scores indicating worse function-ing]) 13 ; symptoms of the obstructive sleep apnea syndrome, as assessed by means of the Pediatric Sleep Questionnaire sleep-related breathing dis-order scale (PSQ-SRBD), in which scores range from 0 to 1, with higher scores indicating greater severity  14 ; sleepiness, as assessed with the use of the Epworth Sleepiness Scale modified for chil-dren, in which scores range from 0 to 24, with higher scores indicating greater daytime sleepi-ness 15 ; global quality of life (caregiver-rated total score from the Pediatric Quality of Life Inven-tory [PedsQL], in which scores range from 0 to 100, with higher scores indicating better quality of life) 16 ; disease-specific quality of life (total score on the 18-item Obstructive Sleep Apnea-18 assessment tool, in which scores range from 18 to 126, with higher scores indicating worse qual-ity of life) 17 ; generalized intellectual functioning (General Conceptual Ability score from the Dif-ferential Ability Scales-II [DAS], in which scores range from 30 to 170, with higher scores indicat-ing better functioning) 18 ; and polysomnographic indexes. STATISTICAL ANALYSIS We calculated that with a sample of 400 children, randomly assigned in a 1:1 ratio to early adeno-tonsillectomy or a strategy of watchful waiting, the study would have 90% power to detect an ef-fect size of 0.32 or more (on the basis of an esti-mate from one previous study  19 ) for the primary outcome.  We planned to enroll 460 children to compensate for withdrawal from the study. Chil-dren who crossed over to the other treatment  were included in their assigned study groups for the primary analysis, consistent with the intention-to-treat principle. Primary and secondary outcomes were evalu-ated with the use of an analysis of covariance  with adjustment for the stratification factors of age, race, weight status, and study site. Addi-tional prespecified analyses included adjust-ments for other factors and restrictions to certain subgroups (see the Supplementary Appendix). Models evaluating possible effect modification of treatment according to race, obesity status, AHI score, and age were tested by including terms for interactions between the two groups and by the effect of each of these factors on each of the study outcomes. A sensitivity analysis was performed with the use of multiple imputation to assess the effect of missing values on the primary outcome. 20 RESULTS STUDY OVERVIEW Figure 1 shows the enrollment and randomiza-tion of the participants. From January 2008 through September 2011, a total of 464 children underwent randomization. Follow-up visits were conducted for 400 children (86%), with 397 chil-dren having measurements of attention and ex-ecutive function on the NEPSY that could be evaluated. A comparison of children who com-pleted the study and those who did not showed a significant difference only with respect to race; black children were less likely to complete the study (P   =   0.04), but this trend was evident in both study groups. Baseline characteristics are shown according to study group ( Tables 1 and 2 , and Table S1 in the Supplementary Appendix). Baseline demo-graphic and clinical characteristics were gener-ally well balanced between the study groups, and cognitive and behavioral scores were close to population means. Nearly half the par-ticipants were overweight or obese. A similar number of children in each group used nasal glucocorticoids (19 children in the early-adeno-tonsillectomy group and 8 in the watchful- waiting group) or montelukast (7 in the early-adenotonsillectomy group and 8 in the  watchful-waiting group) for allergic rhinitis or asthma; the data were the same at baseline and at 7 months of follow-up. The New England Journal of Medicine Downloaded from nejm.org on August 15, 2017. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.  Adenotonsillectomy for Childhood Sleep Apnea n engl j med 368;25  nejm.org june 20 , 2013 2369 STUDY OUTCOMES The baseline attention and executive function score on the NEPSY was close to the population mean of 100 in both groups. Average scores in-creased in both groups; the difference between the groups favored early adenotonsillectomy but  was not significant (P = 0.16). A sensitivity analy-sis to assess the possible effect of missing data  yielded results that were essentially identical to those presented in Table 2. There was a significantly greater improvement on the caregiver-reported Conners’ Rating Scale among children randomly assigned to early adeno-tonsillectomy than among those assigned to  watchful waiting. Teacher-reported data for this measure, which were available for 212 children, also showed significantly greater improvement in the early-adenotonsillectomy group. The caregiver-reported BRIEF score was lower (indicating an improvement) in the early-adenotonsillectomy group, with a small increase in score in the  watchful-waiting group; the teacher-reported ver-sion, which was available for 207 children, showed changes that paralleled the caregiver data but were not significantly different between the groups.Symptoms of the obstructive sleep apnea syndrome were measured with the use of the PSQ-SRBD and the Epworth Sleepiness Scale, and generic and disease-specific measures of quality of life were assessed by means of the PedsQL and OSA-18, respectively. All these in-struments showed a significantly greater reduc-tion in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. The DAS score did not change significantly in either study group (data not shown).The AHI score improved in both groups but significantly more so in the early-adenotonsil-lectomy group. Similar results were observed for the oxygen desaturation index (the number of times per hour of sleep that the blood oxygen 453 Underwent randomizationat included sites10,519 Children were referred for screening7613 By chart review2684 By clinical referral200 By flyers, brochures, or media22 By other means9072 Were excluded6095 Were ineligible1382 Were not interested1595 Had other reasons1244 Completed polysomnographicscreening650 Were excluded607 Had normal results(OAI <1 or AHI <2)43 Had results that weretoo severe594 Were eligible on the basisof polysomnographic screening464 Underwent randomization11 Were excluded owing tosite withdrawal1447 Were eligible on the basisof prescreening226 Were assigned to early adeno-tonsillectomy210 Received assigned intervention16 Did not receive assigned inter-vention8 Declined to undergo surgery8 Had unknown informationregarding surgery227 Were assigned to watchful waiting211 Received assigned intervention16 Did not receive assigned inter-vention owing to undergoingearly surgery196 Were included in follow-up through 7 mo23 Were lost to follow-up7 Withdrew204 Were included in follow-up through 7 mo12 Were lost to follow-up11 Withdrew194 Were included in primary outcomeanalysis2 Were excluded owing to examinererror203 Were included in primary outcomeanalysis1 Was excluded owing to incompleteNEPSY evaluation130 Were excluded owing to failure to meet other inclusion criteria Figure 1. Study Enrollment and Randomization. A total of 464 children underwent randomization, with 226 children assigned to early adenotonsillectomy and 227 to a strategy of watchful waiting with supportive care. A total of 194 children in the early-adenotonsillectomy group and 203 in the watchful-waiting group were in-cluded in the analysis of the primary outcome, the at-tention and executive-function score on the Develop-mental Neuropsychological Assessment (NEPSY). The New England Journal of Medicine Downloaded from nejm.org on August 15, 2017. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved.
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