Adenoidectomy and Adenotonsillectomy for Recurrent Acute Otitis Media

Transcription

1 ORIGINAL CONTRIBUTION Adenoidectomy and for Recurrent Acute Otitis Media Parallel Randomized Clinical Trials in Children Not Previously Treated With Tympanostomy Tubes Jack L. Paradise, MD Charles D. Bluestone, MD D. Kathleen Colborn, BS Beverly S. Bernard, RN, BS Clyde G. Smith, MS Howard E. Rockette, PhD Marcia Kurs-Lasky, MS ADENOIDECTOMY AND ADENOtonsillectomy (T&A) are the most commonly performed major surgical operations among US children; in 1994 an estimated US children younger than 15 years underwent adenoidectomy, and an estimated underwent T&A. 1 In many, if not most, of the children undergoing adenoidectomy and in many of the children undergoing T&A, the primary or secondary surgical diagnosis has been otitis media. 2 Based on early recommendations 3-5 and also on more recent studies, 6-9 adenoidectomy has generally been considered the component of tonsil and adenoid surgery that is efficacious in reducing the occurrence of otitis media. textbooks of pediatrics 10,11 and otolaryngology 12,13 as well as current guidelines of the American Academy of Otolaryngology Head and Neck Surgery 14 recommend adenoidectomy, but not tonsillectomy, for this purpose. Nonetheless, many practicing otolaryngologists recommend T&A for children with persis- For editorial comment see p 987. Context Adenoidectomy and adenotonsillectomy are commonly performed in US children to reduce the occurrence of persistent or recurrent otitis media, but evidence supporting the efficacy of the operations is limited. Objectives To test the efficacy of adenoidectomy and adenotonsillectomy in children with persistent or recurrent otitis media who had not previously undergone tube placement and to compare the relative efficacy of adenoidectomy alone vs adenotonsillectomy in such children. Design Two parallel randomized clinical trials. Setting and Participants A total of 461 children aged 3 to 15 years were enrolled at Children s Hospital of Pittsburgh, Pa, between April 1980 and April Four hundred ten children were observed for up to 3 years. Interventions Children without recurrent throat infection or tonsillar hypertrophy (304 enrolled; 266 followed up) were randomized to either an adenoidectomy, adenotonsillectomy, or control group; children who had such conditions (157 enrolled; 144 followed up) were randomized to an adenotonsillectomy or control group. Main Outcome Measures Occurrence rate of episodes of acute otitis media by treatment group and estimated proportion of time with otitis media. Results In both trials, most subjects were eligible because of recurrent acute otitis media, with or without persistent otitis media with effusion. A total of 47 children assigned to surgical treatment groups had no surgery. The efficacy of surgery in both trials was modest and limited mainly to the first follow-up year. The largest differences in that year were found in the 3-way trial between the adenotonsillectomy group and the control group: mean annual rate of episodes of acute otitis media, 1.4 vs 2.1 (P.001); and mean estimated percentage of time with otitis media, 18.6% vs 29.9% (difference, 11.3%; 95% confidence interval, 4.4%-18.2%; P =.002). Perioperative and postoperative complications or other adverse events occurred not infrequently, especially among subjects undergoing adenotonsillectomy (14.6%). Conclusions Our study showed limited and short-term efficacy of both adenoidectomy and adenotonsillectomy; given the risks, morbidity, and costs of these procedures, these data suggest that neither operation should ordinarily be considered as a first surgical intervention in children whose only indication is recurrent acute otitis media. JAMA. 1999;282: Author Affiliations: Departments of Pediatrics (Dr Paradise and Mss Colborn and Bernard), Otolaryngology (Dr Bluestone), and Audiology (Mr Smith), Children s Hospital of Pittsburgh, Pittsburgh, Pa; Departments of Pediatrics (Dr Paradise and Ms Bernard) and Otolaryngology (Drs Paradise and Bluestone and Mr Smith), School of Medicine, and Department of Biostatistics, Graduate School of Public Health (Dr Rockette and Ms Kurs-Lasky), University of Pittsburgh. Corresponding Author and Reprints: Jack L. Paradise, MD, Children s Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA ( jpar@ pitt.edu) American Medical Association. All rights reserved. JAMA, September 8, 1999 Vol 282, No

2 tent and/or recurrent otitis media, and among children undergoing surgery in whom the primary surgical diagnosis was recorded as otitis media, T&A frequently has been the operation performed. 2 Notwithstanding the widespread performance of adenoid-tonsil surgery to reduce the occurrence of otitis media, the efficacy of such surgery under various clinical circumstances has remained in doubt, largely because most reported clinical trials have important limitations Previously we reported results of clinical trials of adenoidectomy in a group of children we considered severely affected because they had undergone tympanostomy tube placement for persistent and/or recurrent otitis media and, after tubal extrusion, had again developed otitis media. 17 However, those trials did not address either the efficacy of adenoidectomy in children with persistent or recurrent otitis media who had not previously undergone tube placement or the relative efficacy in such children of adenoidectomy compared with T&A. We conducted 2 parallel randomized clinical trials to address these issues. METHODS Two parallel, randomized controlled trials were conducted at the Children s Hospital of Pittsburgh, Pittsburgh, Pa, from April 1980 to April 1994 as an extension of a previously instituted study of indications for tonsillectomy and adenoidectomy. 16,18,19 The study was approved annually by the hospital s Human Rights Committee. Subjects were recruited from among hospital outpatients and children referred by community practitioners or directly by parents. Details have previously been reported regarding initial evaluation of subjects, study exclusion criteria (children with overt or submucous palatal clefts were specifically excluded), and procedures regarding informed consent and surgery. 16,17,19,20 To be eligible for the present trials, children were required to be age 3 to 15 years, not have undergone previous tympanostomy tube placement, and have experienced (1) at least 3 episodes of acute otitis media during the preceding 6 months, or at least 4 episodes during the preceding 12 months including at least 1 episode during the preceding 6 months, with at least 1 of the episodes having been documented with a recorded description of symptoms and tympanic membrane findings or confirmed by tympanometry, tympanocentesis, or myringotomy; or (2) middleear effusion in 1 or both ears extending over at least 180 days during the preceding year and documented by at least Figure. Flow Diagram Showing Progress Through the 2 Trials Adenoidectomy (n = 100) Allocated (n = 79) Allocated (n = 21) Period (n = 79) Year 1 (n = 0) Year 2 (n = 1) Year 3 (n = 9) Year 1 (n = 7) Year 2 (n = 12) Year 3 (n = 9) 1 Year (n = 72) 2 Years (n = 59) 3 Years (n = 41) Eligible for 3-Way Trial (n = 304) Randomization (N = 304) (n = 103) Allocated (n = 89) Allocated (n = 14) Period (n = 89) Year 1 (n = 0) Year 2 (n = 1) Year 3 (n = 7) Year 1 (n = 12) Year 2 (n = 4) Year 3 (n = 1) 1 Year (n = 77) 2 Years (n = 72) 3 Years (n = 64) (n = 101) Allocated (n = 98) Allocated (n = 3) Period (n = 98) Year 1 (n = 2) Year 2 (n = 3) Year 3 (n = 6) Year 1 (n = 10) Year 2 (n = 13) Year 3 (n = 7) 1 Year (n = 86) 2 Years (n = 70) 3 Years (n = 57) 2 clinical observations at least 6 months apart, the most recent by a study-team clinician and/or confirmed by tympanometry. Of 2122 children evaluated, 582 met the eligibility criteria (FIGURE). Of these, 17 had disqualifying medical conditions and 104 were not enrolled because their parents withheld consent for them to be assigned randomly. The remaining 461 children were stratified into 3 age categories (age 3 and 4, 5 and 6, and 7 to 15 years) and further classified by means of clinical and radiographic cri- Eligible Patients (N = 582) Not Randomized (n = 121) Disqualifying Medical Conditions (n = 17) Parents Withheld Consent (n = 104) Eligible for 2-Way Trial (n = 157) (n = 77) Allocated (n = 65) Allocated (n = 12) Period (n = 65) Year 1 (n = 1) Year 2 (n = 1) Year 3 (n = 5) Year 1 (n = 14) Year 2 (n = 4) Year 3 (n = 6) Randomization (N = 157) 1 Year (n = 50) 2 Years (n = 45) 3 Years (n = 34) (n = 80) Allocated (n = 79) Allocated (n = 1) Period (n = 79) Year 1 (n = 2) Year 2 (n = 0) Year 3 (n = 4) Year 1 (n = 8) Year 2 (n = 7) Year 3 (n = 4) 1 Year (n = 69) 2 Years (n = 62) 3 Years (n = 54) In the course of follow-up in the 3-way trial, adenoidectomy was elected for 3 control subjects and adenotonsillectomy for 8 control subjects. Surgery was performed on 3 subjects during the first, 7 subjects during the second, and 1 subject during the third follow-up year. In the 2-way trial, adenoidectomy was elected for 1 control subject and adenotonsillectomy for 16 control subjects. Surgery was performed on 7 subjects during the first, 3 subjects during the second, and 7 subjects during the third follow-up year. In the 2-way trial, 1 subject assigned to undergo adenotonsillectomy was found to have scant adenoid tissue and underwent tonsillectomy only. 946 JAMA, September 8, 1999 Vol 282, No American Medical Association. All rights reserved.

3 teria 21 as to whether they had adenoidal nasal obstruction. The children were then assigned randomly, within age and nasal obstruction categories, within 1 of 2 clinical trials. In 1 trial, children without apparent tonsil-related indications for tonsillectomy were assigned, in balanced blocks of 6 subjects, to 1 of 3 treatment groups: adenoidectomy, T&A, or control (the 3-way trial). In the other trial, children whose tonsils appeared potentially obstructing or who had a history of recurrent throat infection that met or exceeded entry criteria used in previously reported 20 or concurrent 22 tonsillectomy trials were assigned, in balanced blocks of 4 subjects, to 1 of 2 treatment groups: T&A or control (the 2-way trial). Separate, computergenerated random number lists were used for the assignments. Parents were advised that children assigned to control status could subsequently receive surgery at parental request provided that the children continued to meet trial eligibility criteria. To maximize equivalency of subjects baseline status, we required that all subjects be free of otitis media at their trial starting point (ie, the time from which outcome events were counted). Subjects who had otitis media at assignment received standardized antimicrobial treatment, as described below. Subjects assigned to undergo adenoidectomy or T&A were scheduled for surgery on the earliest date feasible. In those in whom middle-ear effusion was present at the time of surgery, myringotomy and aspiration of effusion also were performed. All operations were performed or supervised by a study-team otolaryngologist; standardsurgicaltechniqueswereused. 17 For all surgical subjects the trial starting point was the day after surgery. For control subjects who were effusion-free at assignment, the trial starting point was the following day. For those with effusion at assigment, the starting point was the first effusion-free day, computed as described below. subjects in whom effusionhadbeenpresentfor90daysorlonger without improvement underwent myringotomy and aspiration, and their trial starting point was the following day. Follow-up procedures have been described previously. 17,20 These included biweekly inquiries about day-to-day status and clinical assessments by studyteam pediatric nurse practitioners and/or pediatricians using standardized procedures and algorithms at 6-week intervals; at the time of acute illnesses (a study-team member was on call at all hours); and for episodes of otitis media, at 1- to 4-week intervals until resolution. Pneumatic otoscopes with airtight lens assemblies were used for examining the tympanic membrane. When the membrane was intact, the diagnosis of otitis media and its classification as either acute or otitis media with effusion were based on criteria reported previously. 23 In brief, otitis media was classified as acute when, in addition to middle-ear effusion, a child gave evidence of recent ear pain and/or showed marked redness or distinct fullness or bulging of the tympanic membrane. When a tympanostomy tube or preexisting perforation was present, otitis media evidenced by otorrhea through the tube or the perforation was classified as acute if accompanied by pain or fever, and otherwise as secondary otorrhea. Doubtful otoscopic diagnoses were decided by a study-team pediatrician or, if still doubtful, by a studyteam otolaryngologist on the basis of otomicroscopic examination. The accuracy of the study team s otoscopic assessments has been reported. 23 Tympanometry was performed at most visits. Tympanograms were classified and interpreted according to criteria reported previously. 24,25 When otoscopic and tympanometric findings appeared discrepant, examinations were repeated and the final otoscopic (or rarely, otomicroscopic) diagnosis was used to classify middle-ear status. Audiometry was performed by a certified audiologist at the time of trial entry, at the first postsurgical visit, during and following episodes of otitis media as deemed clinically advisable, and at maximum intervals of 6 months. For each subject we estimated the cumulative proportions of days on which unilateral and bilateral otitis media, respectively, were present, based on diagnoses at individual visits and interpolations for intervals between visits provided that the intervals did not exceed 90 days when the otitis status on the 2 visits was the same or 60 days when the status differed. All days during intervals that exceeded those limits were classified as otitis-unknown. In all subjects, each new episode of otitis media of any type was treated with an antimicrobial in conventional dosage for 10 days to 6 weeks, depending on recent clinical course and response to treatment. Amoxicillin was used whenever feasible; second-line drugs mainly used were erythromycin-sulfisoxazole and amoxicillin-clavulanate potassium. When middle-ear effusion persisted for 90 days without improvement, myringotomy with aspiration was performed. When effusion recurred within 6 months after myringotomy and persisted for 60 days without improvement, myringotomy with tube placement was performed. Secondary otorrhea was treated with an antimicrobial orally for up to 2 weeks, and if persistent thereafter, with polymyxin B-neomycin-hydrocortisone ototopical suspension. The primary outcome measure was the the number of episodes of acute otitis media within a follow-up year. Secondary measures were the estimated proportion of time with otitis media, the numbers of myringotomies and tube procedures, and the numbers of days, respectively, on which ear pain occurred and antimicrobial treatment was received. Sample-size calculation was deferred until experience could be gained concerning the occurrence rate of episodes of acute otitis media. An interim analysis after 3 years indicated that 15% of control subjects had remained free of such episodes during their first follow-up year. On an assumption that a corresponding value of 40% in surgical subjects (ie, a difference of 25%) would constitute a clinically important difference and setting 2-tailed at.05 and at.20, we estimated that 57 subjects per treatment group in each of the 2 trials would be required. 26 For this degree of difference to justify undertaking sur American Medical Association. All rights reserved. JAMA, September 8, 1999 Vol 282, No

4 gery in comparably affected children, we set as a further requirement that the difference be sustained for 2 years. Outcome data for control subjects withdrawn from control status to receive surgery were analyzed in 2 modes: in one mode, events that followed surgery were included and charged to subjects original status as controls; in the other mode, such events were excluded. All statistical tests were 2-tailed. Mean rates of occurrence of episodes of acute otitis media were compared by assuming a Poisson probability distribution 27 and applying a generalized linear model. 28 A weighted regression model, with weights equal to the lengths of observed time, was used to compare mean proportions of time with otitis media. Regression models also were used in comparisons between treatment groups to adjust for betweengroup imbalances in subject characteristics. Times to occurrence of first, second, and third episodes of acute otitis media and first accumulation of 30, 60, and 90 days of otitis media were summarized in life-table analyses and compared using the log-rank test 29,30 and an extension of the proportional hazards model for multiple recurrences. 31 Analysis of hearing data obtained after subjects trial starting points was limited to each subject s first audiogram when middle-ear effusion was present and first audiogram when middle-ear effusion was absent. RESULTS Of the 461 enrolled children, 304 were eligible for the 3-way trial and 157 for the 2-way trial (Figure). A total of 47 subjects assigned to surgical treatment groups were withdrawn from the trials without undergoing surgery, in some instances because their parents lacked insurance coverage and were unwilling to incur the resultant costs (later, arrangements were made to waive costs for such subjects). Four subjects assigned to control status were also withdrawn. To conserve resources, these 51 withdrawn subjects were discharged from the study. Accordingly, follow-up data were available for 410 subjects: 266 in the 3-way trial and 144 in the 2-way trial. Of the 410 subjects, 354 (86.3%) were followed up for at least 1 year, 308 (75.1%) for at least 2 years, and 250 (61.0%) for 3 years. The main reason for failure to complete the trial, apart from loss to follow-up, was termination of the study. Selected demographic and clinical characteristics of subjects in the 2 trials are summarized in TABLE 1. Of the 410 children, 374 (91.2%) were eligible on the basis of recurrent acute otitis media, 22 (5.4%) on the basis of persistent middle-ear effusion, and 14 (3.4%) on the basis of both conditions. However, of the 374 subjects enrolled on the basis of recurrent acute otitis media only, 119 (31.8%) had prior histories of middleear effusion of at least 2 months duration and 189 (50.5%) had middle-ear effusion at entry that, in many instances, had not been previously diagnosed. The only significant between-group difference in characteristics occurred in the 2-way trial, in which the T&A group contained proportionately more girls and fewer boys than the control group (40% vs 58%; P =.04). In the 3-way trial, primarily in the T&A group, socioeconomic status was higher among subjects who completed 3 years of follow-up than among subjects who did not. Otherwise there were no significant differences in characteristics in either trial between subjects who completed and subjects who did not complete 3 years of follow-up, or between subjects whose parents accepted initial assignment and subjects discharged without follow-up because of noncompliance with initial assignment. The median and mean intervals from assignment to starting point in the 3-way trial were 73 and 84.0 days, respectively, among adenoidectomy subjects; 60 and 66.4 days, respectively, among T&A subjects; and 8 and 22.6 days, respectively, among control subjects. Corresponding values in the 2-way trial were 60 and 63.3 days, respectively, among T&A subjects; and 0 and 19.0 days, respectively, among control subjects. In analyses for the outcomes presented here, illnesses and treatments that followed surgery in subjects withdrawn from control status to receive surgery were charged to subjects original status as controls. Analyses that excluded such events gave similar results. Similar results also were obtained in analyses that excluded the 22 subjects eligible for the trials only on the basis of persistent otitis media with effusion. Differences in outcome between the groups in the 3-way trial were generally small. As shown in TABLE 2, the mean rate of episodes of acute otitis media in adenoidectomy subjects was actually higher than in control subjects in the second follow-up year. In T&A subjects the rate was lower than in control subjects in the first follow-up year and for the 3 follow-up years combined (P =.009, data notshown).themeanratealsowaslower than in adenoidectomy subjects in the first follow-up year (P =.03, not shown) and for the 3 follow-up years combined (P =.04, data not shown). As shown in TABLE 3, both adenoidectomy subjects and T&A subjects had, on average, less estimated time with otitis media than control subjects in the first follow-up year but not thereafter. The first-year difference between T&A and control subjects also was responsible for a difference between these 2 groups for the 3-year follow-up period as a whole (P =.04, data not shown). The results of life-table analyses were consistent with these results. Data concerning the remaining outcome measures are summarized in TABLE 4. During the first follow-up year T&A subjects received, on average, less antimicrobial treatment than control subjects; no other betweengroup differences during the 3-year follow-up period were significant. Differences in outcome in the 2-way trial again were generally small. As shown in Table 2, differences favoring T&A subjects over control subjects in the mean rate of episodes of acute otitis media were not significant in any individual follow-up year, but for the 3 follow-up years combined the difference was significant (P =.005, data not shown). Table 3 shows that T&A subjects had, on average, less estimated time with otitis media than control sub- 948 JAMA, September 8, 1999 Vol 282, No American Medical Association. All rights reserved.

5 jects during the first follow-up year; this resulted in a difference between the 2 groups for the 3 follow-up years combined (P =.02, data not shown). The results of life-table analyses were consistent with these results. Data for the remaining outcome measures are summarized in Table 4. During the first and second follow-up years, T&A subjects received less antimicrobial treatment than control subjects, but no other differences during the 3-year follow-up period were significant. In both the 3-way and 2-way trials, among control subjects who eventually underwent surgery, mean rates of acute otitis media and estimated proportions of time with otitis media during the segments of follow-up years that preceded the surgery were modestly higher than the corresponding wholeyear values among control subjects who remained under surveillance without change in status. Accordingly, had the Table 1. Distribution of Selected Demographic and Clinical Characteristics of Subjects According to Trial and Treatment Group Characteristic* Adenoidectomy (n = 79) 3-Way Trial, No. (%) 2-Way Trial, No. (%) (n = 89) (n = 98) (n = 65) (n = 79) Age, y (41.8) 40 (44.9) 45 (45.9) 18 (27.7) 16 (20.3) (40.5) 34 (38.2) 35 (35.7) 26 (40.0) 34 (43.0) (17.7) 15 (16.9) 18 (18.4) 21 (32.3) 29 (36.7) Sex Male 52 (65.8) 48 (53.9) 49 (50.0) 26 (40.0) 46 (58.2) Female 27 (34.2) 41 (46.1) 49 (50.0) 39 (60.0) 33 (41.8) Race White 76 (96.2) 83 (93.3) 88 (89.8) 63 (96.9) 71 (89.9) Other 3 (3.8) 6 (6.7) 10 (10.2) 2 (3.1) 8 (10.1) Entry criterion met Recurrent AOM only 72 (91.1) 80 (89.9) 86 (87.8) 64 (98.5) 72 (91.1) Persistent MEE only 3 (3.8) 6 (6.7) 9 (9.2) 0 (0.0) 4 (5.1) Both recurrent AOM and persistent MEE 4 (5.1) 3 (3.4) 3 (3.1) 1 (1.5) 3 (3.8) Age at onset of otitis media, y 1 37 (46.8) 42 (47.2) 44 (44.9) 18 (27.7) 35 (44.3) (30.4) 29 (32.6) 27 (27.6) 26 (40.0) 20 (25.3) 3 18 (22.8) 17 (19.1) 27 (27.6) 19 (29.2) 23 (29.1) Unknown 0 (0.0) 1 (1.1) 0 (0.0) 2 (3.1) 1 (1.3) MEE at time of assignment None 29 (36.7) 37 (41.6) 49 (50.0) 34 (52.3) 44 (55.7) Unilateral 14 (17.7) 23 (25.8) 21 (21.4) 14 (21.5) 22 (27.8) Bilateral 36 (45.6) 29 (32.6) 28 (28.6) 17 (26.2) 13 (16.5) Baseline hearing sensitivity in ear without effusion, db HL (70.9) 64 (71.9) 84 (85.7) 53 (81.5) 73 (92.4) (5.1) 2 (2.2) 4 (4.1) 0 (0.0) 2 (2.5) Not available 19 (24.1) 23 (25.8) 10 (10.2) 12 (18.5) 4 (5.1) Nasal obstruction attributable to large adenoids Any 21 (26.6) 25 (28.1) 27 (27.6) 22 (33.8) 23 (29.1) None 58 (73.4) 64 (71.9) 71 (72.4) 43 (66.2) 56 (70.9) Upper-respiratory allergy according to specified algorithm Definite or probable 14 (17.7) 8 (9.0) 19 (19.4) 7 (10.8) 18 (22.8) Possible or unlikely 65 (82.3) 81 (91.0) 79 (80.6) 58 (89.2) 61 (77.2) Siblings Any 53 (67.1) 66 (74.2) 70 (71.4) 50 (76.9) 64 (81.0) None 26 (32.9) 23 (25.8) 28 (28.6) 15 (23.1) 15 (19.0) Parents socioeconomic status Executive or professional 11 (13.9) 19 (21.3) 25 (25.5) 10 (15.4) 13 (16.5) Otherwise employed 58 (73.4) 58 (65.2) 58 (59.2) 44 (67.7) 56 (70.9) Disabled, public assistance, unemployed, or other 10 (12.7) 12 (13.5) 15 (15.3) 11 (16.9) 10 (12.7) *AOM indicates acute otitis media; MEE, middle-ear effusion; and db HL, decibel hearing level. Percents do not all sum to 100 owing to rounding. Baseline was defined as within 90 days before surgery in surgical subjects and within 90 days before or after the trial starting point in control subjects, provided that in each case at least 1 ear was effusion-free. The value shown is the pure-tone average hearing threshold (500, 1000, and 2000 Hz). When both ears were effusion-free the value is that for the better-hearing ear. Based on combined clinical and radiographic assessment. 21 Algorithm available from the authors American Medical Association. All rights reserved. JAMA, September 8, 1999 Vol 282, No

6 surgery not been performed and had these higher values been maintained for the remainders of the follow-up years in question, the resulting calculated whole-year values in control subjects would have been marginally higher than those shown in Tables 2 and 3. Among surgical and control subjects in both trials who were lost to follow-up, rates of acute otitis media and estimated proportions of time with otitis media during the segments of follow-up years that preceded the loss to follow-up differed relatively little, and in no consistent direction, from the corresponding whole-year values among subjects who remained under surveillance. Outcomes were generally less favorable in younger than in older subjects and in subjects with bilateral effusion at the time of assignment than in subjects with unilateral or no effusion. However, surgical-vs-control outcomes did not change substantially after adjusting individually for age group, sex, middle-ear effusion status at assignment, baseline presence of nasal obstruction attributable to large adenoids, probable presence of upper respiratory allergy, and parents socioeconomic status. Analysis indicated that hearing acuity was related consistently only to whether otitis media was present and not to subjects treatment groups. When middle-ear effusion was absent, group mean pure-tone averages ranged from 3.3 to 5.7 db hearing level, and when effusion was present, from 7.5 db to 17.4 db hearing level. Of the 261 subjects who underwent surgery, 30 (11.5%) developed perioperative or postoperative complications (TABLE 5). Complications were more common with T&A than with adenoidectomy. The mean reported duration of postoperative sore throat in adenoidectomy subjects was 1.1 days (range, 0-7 days), and in T&A subjects, 5.8 days (range, 0-21 days). In the course of antimicrobial treatment erythematous rashes occurred in 6 adenoidectomy sub- Table 2. Distribution of Subjects in the 3-Way and 2-Way Trials According to Number of Episodes of Acute Otitis Media,* by Whole Year of Follow-up, and Treatment Group Follow-up Year Treatment Group (No. of Subjects) No. of Episodes, No. (%) of Subjects Difference, Surgical vs, in % of Subjects With No Episodes (95% CI) 3-Way Trial Total Unilateral No. of Episodes, Episodes % Range 1 Adenoidectomy (61) 19 (31.1) 10 (16.4) 15 (24.6) 17 (27.9) 9.6 ( 5.1 to 24.4) (71) 26 (36.6) 16 (22.5) 19 (26.8) 10 (14.1) 15.1 (0.7 to 29.5) Episodes per Subject, No. Mean Rate of Occurrence P Values (79) 17 (21.5) 23 (29.1) 14 (17.7) 25 (31.6) NA NA 2 Adenoidectomy (53) 14 (26.4) 19 (35.8) 8 (15.1) 12 (22.6) 10.9 ( 28.0 to 6.2) (67) 23 (34.3) 24 (35.8) 9 (13.4) 11 (16.4) 3.0 ( 19.7 to 13.8) (59) 22 (37.3) 16 (27.1) 12 (20.3) 9 (15.3) NA NA 3 Adenoidectomy (34) 12 (35.3) 11 (32.4) 6 (17.6) 5 (14.7) 0.9 ( 22.0 to 20.3) (58) 21 (36.2) 17 (29.3) 12 (20.7) 8 (13.8) 0 ( 18.4 to 18.5) (47) 17 (36.2) 14 (29.8) 6 (12.8) 10 (21.3) NA NA 2-Way Trial 1 (44) 13 (29.5) 17 (38.6) 4 (9.1) 10 (22.7) 7.1 ( 9.6 to 23.9) (67) 15 (22.4) 16 (23.9) 11 (16.4) 25 (37.3) NA NA 2 (40) 20 (50.0) 10 (25.0) 8 (20.0) 2 (5.0) 11.8 ( 8.3 to 31.9) (55) 21 (38.2) 23 (41.8) 7 (12.7) 4 (7.3) NA NA 3 (23) 15 (65.2) 7 (30.4) 0 (0) 1 (4.3) 17.5 ( 6.9 to 41.9) (44) 21 (47.7) 10 (22.7) 10 (22.7) 3 (6.8) NA NA *The number of acute episodes for each subject was calculated by totaling episodes that presented acutely and episodes defined as new because ear pain or otoscopic findings either supervened in the course of otitis media with effusion, persisted or recurred at least 10 days after the subject completed at least 75% of a 10-day course of antimicrobial treatment for acute otitis media, or developed more than 30 days after the onset of an episode of acute otitis media for which less treatment had been received. Not included in the table are data derived from experiences of less than a whole year (ie, 12 calendar months) of follow-up (although those data are included in analyses described in the text for the 3 follow-up years combined). Follow-up was considered satisfactory if intervals between visits did not exceed 90 days when the otitis status on successive visits was the same, or 60 days when the status differed. All days during intervals that exceeded those limits were classified as otitis-unknown. Data for each follow-up year are limited to subjects with no more than 65 otitis-unknown days in that year. CI indicates confidence interval; NA, not applicable. Many of the unilateral episodes were associated with otitis media with effusion in the opposite ear. Weighted by the number of days classifiable for each subject as otitis-present or otitis-absent. Based on a comparison of mean rates of occurrence between the designated surgical group and the control group in both trials. 950 JAMA, September 8, 1999 Vol 282, No American Medical Association. All rights reserved.

7 jects, 4 T&A subjects, and 7 control subjects; serum sickness occurred in 1 T&A subject and 1 control subject. COMMENT Most previously reported randomized trials of adenoid-tonsil surgery for otitis media had as their main entry criterion persistent otitis media with effusion, and most tested the efficacy of adenoidectomy and not of T&A. Only the trials reported by Rynnel-Dagööetal 32 and by ourselves 17 included recurrent acute otitis media as an entry criterion, and only the trials reported by McKee, 7 Maw, 8 and Maw and Herod 9 compared the efficacy of adenoidectomy with that of T&A. Rynnel-Dagöö etal 32 found adenoidectomy inefficacious. McKee, 7 whose trial excluded children with recurrent or chronic otitis media because those conditions were considered absolute indications for adenoidectomy, found the incidence of otitis media (type not specified) during the 2-year follow-up period lower in the adenoidectomy group than in the T&A group but not significantly so. The trials reported by Maw 8 and Maw and Herod 9 found adenoidectomy and T&A equally efficacious in clearance of middle-ear effusion; neither trial described the occurrence of acute otitis media. Limitations of these trials, as discussed previously, 17 included nonstringent eligibility criteria, limited methods for detection and follow-up of otitis media, failure to specify use or nonuse of antimicrobial treatment for recurrences of otitis media, and failure to consider the possibility of a type II error. Our previous trials, 17 involving children who had undergone tympanostomy tube placement and who, after tube extrusion, had again developed otitis media, showed adenoidectomy to have been effective in these children for 2 years in reducing the occurrence of otitis media. The effect was greater with regard to time with middle-ear effusion than with regard to the occurrence rate of acute otitis media and seemed large enough overall to be considered clinically important. The present trials were designed with 3 considerations in mind. First, to test the efficacy of adenoid-tonsil surgery in children less severely affected with otitis media than those in our earlier trials and to avoid the potentially confounding influence of tubes, we designed the trials to be tubeless to the extent feasible by enrolling only children who had not previously undergone tube placement and, after enrollment, by limiting first surgical interventions for persistent middle-ear effusion to myringotomy and aspiration alone. Second, we wished to test the efficacy of adenoidtonsil surgery in children who had Table 3. Distribution of Subjects in the 3-Way and 2-Way Trials According to Estimated Proportion of Days on Which Otitis Media Was Present,* by Whole Year of Follow-up, and Treatment Group Follow-up Year Treatment Group, No. of Subjects Mean No. of Days Classifiable as Otitis Present or Otitis Absent % of Days Classified as Otitis Present, No. (%) of Subjects Mean (SD) % of Total Days per Year Classified as Otitis Present P Value 95% Confidence Interval Way Trial 1 Adenoidectomy (61) (19.7) 11 (18.0) 22 (36.1) 7 (11.5) 9 (14.8) 22.4 (21.6) % to 15.0% (71) (18.3) 17 (23.9) 24 (33.8) 12 (16.9) 5 (7.0) 18.6 (19.1) % to 18.2% (79) (7.6) 14 (17.7) 23 (29.1) 17 (21.5) 19 (24.1) 29.9 (23.7) NA NA 2 Adenoidectomy (53) (17.0) 14 (26.4) 17 (32.1) 7 (13.2) 6 (11.3) 20.0 (19.8) % to 7.8% (67) (25.4) 12 (17.9) 19 (28.4) 14 (20.9) 5 (7.5) 20.4 (20.5) % to 7.1% (59) (20.3) 14 (23.7) 15 (25.4) 11 (18.6) 7 (11.9) 20.3 (20.6) NA NA 3 Adenoidectomy (34) (23.5) 8 (23.5) 8 (23.5) 6 (17.6) 4 (11.8) 19.3 (20.6) % to 6.2% (58) (29.3) 13 (22.4) 13 (22.4) 9 (15.5) 6 (10.3) 18.5 (20.9) % to 5.9% (47) (31.9) 9 (19.1) 14 (29.8) 4 (8.5) 5 (10.6) 16.6 (19.6) NA NA 2-Way Trial 1 (44) (20.5) 13 (29.5) 12 (27.3) 8 (18.2) 2 (4.5) 16.3 (16.6) % to 13.7% (67) (7.5) 14 (20.9) 27 (40.3) 13 (19.4) 8 (11.9) 23.4 (18.2) NA NA 2 (40) (47.5) 6 (15.0) 9 (22.5) 4 (10.0) 2 (5.0) 11.9 (18.1) % to 6.9% (55) (23.6) 20 (36.4) 13 (23.6) 8 (14.5) 1 (1.8) 12.2 (13.4) NA NA 3 (23) (47.8) 5 (21.7) 5 (21.7) 1 (4.3) 1 (4.3) 9.8 (14.1) % to 6.5% (44) (34.1) 14 (31.8) 12 (27.3) 3 (6.8) 0 (0) 9.7 (11.0) NA NA *Proportions were calculated on the basis of diagnoses at individual visits and interpolations for intervals between visits, provided that the intervals did not exceed 90 days when the otitis status on successive vists was the same or 60 days when the status differed. All days during intervals that exceeded those limits were classified as otitis-unknown. Calculations excluded otitis-unknown days from both the numerator and the denominator. Not included in the table are data derived from experiences of less than a whole year (ie, 12 calendar months) of follow-up (although those data are included in analyses described in the text for the 3 follow-up years combined). Data for each follow-up year also are limited to subjects with no more than 65 otitis unknown days in that year. Percents do not all sum to 100 owing to rounding. Weighted by the number of days classifiable for each subject as otitis-present or otitis-absent. Based on a comparison between the designated surgical group and the control group in the 3-way trial, and between the adenotonsillectomy group and the control group in the 2-way trial, in regard to the mean percentage of days classified as otitis-present. NA indicates not applicable. Confidence interval indicates the difference between the designated surgical group and the control group in the 3-way trial, and between the adenotonsillectomy group and the control group in the 2-way trial, in the mean percentage of days classified as otitis-present American Medical Association. All rights reserved. JAMA, September 8, 1999 Vol 282, No

8 Table 4. Days With Ear Pain, Days With Antimicrobial Treatment, and Myringotomy Procedures in Subjects, According to Treatment Group 1 2 have led to less vigilance and less detection of illness among surgical subjects than among control subjects, which would have resulted in an overstatement of the efficacy of surgery. The possibility of observer bias was minimized by the adjunctive use of tympanometry. We think that the potential bias introduced by differences between surgical and control subjects in times to starting points was limited in effect and less consequential than the bias that might have resulted had we not ensured initial effusion-free status in all subjects. Finally, as noted previously, our calculations suggest that bias resulting from the withdrawal of certain subjects from control status in order to undergo surgery or from the loss of subjects to follow-up did not affect trial outcomes substantially. In the present trials, subjects illnesses might have been minimized as a consequence of the trials unusually close monitoring and prompt and sustained treatment. Accordingly, it seems possible that in nonresearch settings the degree of benefit afforded by surgery might differ from that found in our trials. How should these findings be applied? Our study sample seemed similar to children generally who are considered candidates for adenoidectomy or T&A because of histories of recurrent acute otitis media. Given that we found both operations to have limited efficacy and in view of their not inconsid- (n = 71), 3-Way Trial (n = 67) Adenoidectomy Adenoidectomy Outcome Measure (n = 61) (n = 79) (n = 53) (n = 59) Days with ear pain, mean No. per subject (range)* 7.0 (0-37) 7.3 (0-41) 8.1 (0-57) 6.8 (0-43) 4.9 (0-32) 6.8 (0-50) No. (%) of subjects with 10 d 14 (23) 17 (24) 17 (22) 13 (25) 11 (16) 10 (17) 50.2 (0-177) 38.1 (0-220) 61.9 (0-174) 44.6 (0-152) 38.6 (0-167) 44.0 (0-124) Days with antimicrobial treatment, mean No. per subject (range)* No. (%) of subjects with 30 d 40 (66) 33 (46) 57 (72) 30 (57) 31 (46) 32 (54) No. of myringotomy procedures (No. with 2 (1) 2 (2) 8 (3) 1 (1) 2 (0) 4 (2) tympanostomy tube[s]) *For subjects with fewer than 365 days of reportage in a follow-up year, the No. of days was standardized on the basis of 365 days. During the first, second, and third follow-up years, respectively, the mean No. of days of reportage in the 3-way trial were 352, 346, and 348 in adenoidectomy subjects; 352, 349, and 354 in adenotonsillectomy subjects; and 350, 349, and 350 in control subjects. The mean No. of days of reportage in the 2-way trial were 350, 346, 354 in adenotonsillectomy subjects and 353, 352, and 351 in control subjects. group vs control group, P.001 in the 3-way trial; P.01 in the 2-way trial. group vs control group, P =.002 in the 3-way trial; P =.03 in the 2-way trial. Limited to procedures performed after the trial starting point. Bilateral myringotomy was counted as a single procedure. Both procedures were performed on the same subject. Table 5. Perioperative and Postoperative Complications in the 2 Trials troublesome histories specifically of recurrent acute otitis media, whether or not they also had had persistent middle-ear effusion. Finally, in children with either recurrent acute otitis media, or persistent otitis media with effusion, or both, we wished to compare the efficacy of adenoidectomy with that of T&A. To meet these objectives and at the same time avoid mixing children who might differ prognostically, separate 3-way and 2-way trials were necessary. In both of these trials, the efficacy of adenoid-tonsil surgery proved to be quite modest with respect to both the occurrence of acute otitis media and the proportion of time spent with otitis media. However, within those bounds, in the No. (%) of Subjects by Operation Adenoidectomy Complication (n = 83) (n = 178)* Incipient malignant hyperthermia 1 (1.2) 1 (0.6) Retained in hospital 1 additional day 0 (0.0) 11 (6.2) and/or readmitted to hospital Hemorrhage after discharge from hospital 0 (0.0) 4 (2.2) Postoperative pneumonia 1 (1.2) 0 (0.0) Postoperative velopharyngeal insufficiency Transient ( 42 d) 2 (2.4) 9 (5.1) Persistent (9 mo) 0 (0.0) 1 (0.6) Total 4 (4.8) 26 (14.6) *One subject was found at surgery to have scant adenoid tissue and underwent tonsillectomy only. Numbers do not sum to 100 owing to rounding. Retained or readmitted due to fever, poor fluid intake orally, vomiting, and/or dehydration. In 3 subjects, hemorrhage prompted return visits to hospital with 2 subjects readmitted (in 1 case, twice). Subject eventually underwent pharyngeal flap procedure. 3-waytrialT&Aappearednarrowlymore efficacious than adenoidectomy. In neither trial did efficacy reach the level we initially posed as necessary to justify surgeryincomparablyaffectedchildren. The rate of surgical complications in the 2 trials was not inconsiderable. In both our trials, failure to comply with treatment assignment occurred more often among subjects assigned to undergo surgery than among those assigned to control status(figure). If such failure to comply involved less severely affected subjects disproportionately, the resulting bias might have led to an understatement of the efficacy of surgery by trial findings. Conversely, assumptions by parents that surgery was efficacious might 952 JAMA, September 8, 1999 Vol 282, No American Medical Association. All rights reserved.

9 and Whole Year of Follow-up, 2-Way Trial Adenoidectomy (n = 34) (n = 58) (n = 47) (n = 44) (n = 67) (n = 40) (n = 55) (n = 23) (n = 44) 5.4 (0-27) 4.7 (0-26) 6.1 (0-59) 11.1 (0-57) 11.7 (0-71) 7.4 (0-43) 6.6 (0-40) 4.5 (0-17) 7.6 (0-52) 4 (12) 9 (16) 8 (17) 18 (41) 27 (40) 11 (28) 12 (22) 3 (13) 12 (27) 46.1 (0-136) 31.6 (0-102) 42.1 (0-141) 39.0 (0-134) 59.5 (0-167) 28.6 (0-122) 37.1 (0-109) 31.0 (0-95) 31.0 (0-109) 16 (47) 26 (45) 24 (51) 24 (55) 49 (73) 14 (35) 33 (60) 11 (48) 16 (36) 0 2 (0) 3 (2) 1 (1) 8 (4) 2 (2) 2 (1) 0 2 (2) erable risks, morbidity, and costs, we believe that neither operation ordinarily should be considered as an initial intervention in such children. Instead we believe that nonsurgical management 33 should be attempted first, with tube placement to be considered later as the preferred first surgical recourse if the burden of illness becomes intolerable, 34 and with adenoidectomy reserved for those who develop recurrent otitis media after tubal extrusion. 17 Our finding that T&A appeared narrowly more efficacious than adenoidectomy prompts 2 further questions: whether the occurrence of otitis media is related to infection not only in the nasopharynx but also in the oropharynx; and relatedly, whether children, such as those in our earlier trials, 17 who have undergone tube placement and who continue to develop otitis media after tube extrusion might benefit more from T&A than from adenoidectomy alone. The latter question could be answered only by a randomized clinical trial in which such children undergo either adenoidectomy or T&A, but the additional risks posed by the addition of tonsillectomy to the procedure would, in our judgment, outweigh any potential benefit. Funding/Support: This research was supported by grant NS from the National Institute of Neurological and Communicative Disorders and Stroke and by grant DC from the National Institute on Deafness and Other Communication Disorders. Inpatient charges and professional fees to subjects parents who lacked insurance coverage were waived by the Children s Hospital of Pittsburgh and the Departments of Anesthesiology and Otolaryngology. Previous Presentation: This work was presented, in part, at the Sixth International Congress of Pediatric Otorhinolaryngology; May 30, 1994; Rotterdam, the Netherlands. Acknowledgment: We are indebted to the many Children s Hospital of Pittsburgh house officers and Pittsburgh-area practitioners who referred patients for the study; to Kenneth D. Rogers, MD, and Floyd H. Taylor, ScD, who assisted with study design and planning; and to Sylvan E. Stool, MD, who served as otolaryngological consultant and supervisor. Regrettably, space limitations preclude a complete listing of the many other staff members who assisted in the study; some of them have been acknowledged previously. 17 REFERENCES 1. Hall MJ, Kozak LJ, Gillum BS. National survey of ambulatory surgery: Stat Bull Metrop Insur Co. July-September 1997;78(3): Paradise JL. Adenoidectomy and adenotonsillectomy for recurrent or persistent otitis media. Pediatr Res. 1992;31:99A. 3. Harvey W. On Excision of the Enlarged Tonsil and Its Consequences in Cases of Deafness. London, England: Henry Renshaw; 1850: Meyer W. On adenoid vegetations in the nasopharyngeal cavity. Medico-chirurgical Trans (London). 1870;53: Crowe SJ, Watkins, et al. Relation of tonsillar and nasopharyngeal infections to general systemic disorders. Bull Johns Hopkins Hosp. 1917;28: Kaiser AD. Results of tonsillectomy. JAMA. 1930; 95: McKee WJE. The part played by adenoidectomy in the combined operation of tonsillectomy with adenoidectomy. Br J Prev Soc Med. 1963;17: Maw AR. Chronic otitis media with effusion (glue ear) and adenotonsillectomy. BMJ. 1983;287: Maw AR, Herod F. Otoscopic, impedance, and audiometric findings in glue ear treated by adenoidectomy and tonsillectomy. Lancet. 1986;1: Hoekelman RA, Friedman SB, Nelson NM, Seidel HM, eds. Primary Pediatric Care. 2nd ed. St Louis, Mo: Mosby Year Book; 1992: Arnold JE. The ear. In: Behrman RE, Kliegman RM, Arvin AA, eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, Pa: WB Saunders Co; 1996: Paradise JL. Tonsillectomy and adenoidectomy. In: Bluestone CD, Stool SE, Kenna MA, eds. Pediatric Otolaryngology. Vol 2. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1996: Wiatrak BJ, Woolley AL. Pharyngitis and adenotonsillar disease. In: Cummings CW et al, eds. Otolaryngology Head and Neck Surgery. Vol 5. 3rd ed. St Louis, Mo: Mosby Year Book; 1998; Clinical Indicators Compendium: Guidelines for Tonsillectomy, Adenoidectomy,. Alexandria, Va: American Academy of Otolaryngology Head and Neck Surgery Inc; Paradise JL. Why T&A remains moot. Pediatrics. 1972;49: Paradise JL. Clinical trials of tonsillectomy and adenoidectomy. South Med J. 1976;69: Paradise JL, Bluestone CD, Rogers KD, et al. Efficacy of adenoidectomy for recurrent otitis media in children previously treated with tympanostomy-tube placement. JAMA. 1990;263: Paradise JL. Pittsburgh tonsillectomy and adenoidectomy study. Ann Otol Rhinol Laryngol. 1975; 84(pt 2, suppl 19): Paradise JL, Bluestone CD. Toward rational indications for tonsil and adenoid surgery. Hosp Pract. 1976;11(2): Paradise JL, Bluestone CD, Bachman RZ, et al. Efficacy of tonsillectomy for recurrent throat infection in severely affected children. N Engl J Med. 1984; 310: Paradise JL, Bernard BS, Colborn DK, Janosky JE. Assessment of adenoidal obstruction in children. Pediatrics. 1998;101: Paradise JL, Bluestone CD, Rogers KD, et al. Comparative efficacy of tonsillectomy for recurrent throat infection in more vs less severely affected children [abstract]. Pediatr Res. 1992;31:126A. 23. Paradise JL. On classifying otitis media as suppurative or nonsuppurative, with a suggested clinical schema. J Pediatr. 1987;111: Paradise JL, Smith CG, Bluestone CD. Tympanometric detection of middle-ear effusion in infants and young children. Pediatrics. 1976;58: Smith CG, Paradise JL, Young TI. Modified schema for classifying positive-pressure tympanograms. Pediatrics. 1982;69: Fleiss JL. Statistical Methods for Rates and Proportions. New York, NY: John Wiley & Sons; Breslow NE, Day NE. Statistical methods in cancer research, II: the design and analysis of cohort studies. IARC Sci Publ. 1987;82: Baker RJ, Nelder JA. The Generalized Linear Interactive Modeling (GLIM) System. Oxford, England: Royal Statistical Society; 1985: Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50: Peto R, Peto J. Asymptotically efficient rank invariant test procedures. J R Stat Soc [A]. 1972;135: Andersen PK, Gill RD. Cox s regression model counting process. Ann Stat. 1982;10: Rynnel-Dagöö B, Ahlbom A, Schiratzki H. Effects of adenoidectomy: a controlled two-year followup. Ann Otol Rhinol Laryngol. 1978;87: Paradise JL. Managing otitis media: a time for change. Pediatrics. 1995;96: Casselbrant ML, Kaleida PH, Rockette HE, et al. Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent acute otitis media. Pediatr Infect Dis J. 1992;11: American Medical Association. All rights reserved. JAMA, September 8, 1999 Vol 282, No