兒童急性中耳炎治療

1、Treatment of Acute Otitis Media in Children under 2 Years of Age,2012-3-15,,,,本人制作，僅供分享學(xué)習(xí)討論之用,2,SOURCE INFORMATION,N Engl J Med, 2011, 364:105-115(had been cited by 16 articles)From the Department of Pediatrics, Univer

2、sity of Pittsburgh School of Medicine, USA.Correspondence author: Dr. Hoberman E-mail:hoberman@chp.edu.,3,,,美國科學(xué)信息所（ISI）公布,4,Introduction of The New England Journal of Medicine (NEJM),1812年創(chuàng)刊，由美國麻州醫(yī)學(xué)協(xié)會所出版的同行評審性質(zhì)之綜合性醫(yī)學(xué)期

3、刊。全科醫(yī)學(xué)周刊，每年52期 出版風(fēng)格：重要的研究成果、臨床發(fā)現(xiàn)以及觀點(diǎn)。注重文章的實(shí)用性，多為指導(dǎo)臨床實(shí)踐。 嚴(yán)格的審稿程序，稿件的處理流程通常需10—12周。來稿的刊用率約為7%。,5,BACKGROUND,Acute otitis media(AOM) is the most frequently diagnosed illness in children in the US.Most children have rout

4、inely been treated with antimicrobial drugs in the US.,1.Tahtinen PA, et al. A placebo-controlled trial of antimicrobial treatment for acute otitis media. N Engl J Med 2011;364:116-126 2.Klein JO. Is acute otitis media

5、a treatable disease? N Engl J Med 2011;364:168-169,6,A watchful-waiting strategy has long been applied in several countries to minimize the use of antimicrobial drugs. -Netherlands and Scotland4,5 -USA,2004

6、,6,7 -Canada 8,4.Appelman CL, et al. Otitis media acuta: NHG-standaard (eerste herziening). Huisarts Wet 1999;42:362-366 5.Scottish Intercollegiate Guidelines Network. Diagnosis and management of childhood otit

7、is media in primary care. Guideline no. 66. Edinburgh: Royal College of Physicians in Edinburgh, 2003. 8.Forgie S, Zhanel G, Robinson J. Management of acute otitis media. Paediatr Child Health (Oxford) 2009;14:457-464,7

8、,AOM in children aged 6 to 23 months is “nonsevere” 6(mild otalgia and T≤ 39℃ during the preceding 24 hours) Diagnosis of AOM is uncertain.7,Indications of Watchful Waiting,6.Kaleida PH, et al. Amoxicillin or myringotom

9、y or both for acute otitis media: results of a randomized clinical trial. Pediatrics 1991;87:466-474 7.American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute o

10、titis media. Pediatrics 2004;113:1451-1465,8,The watchful waiting strategy has been based on the results of clinical trials3 that showed relatively high rates of spontaneous improvement in children with acute otitis medi

11、a.,Fundament,3.Rosenfeld RM, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: metaanalysis of 5400 children from thirty-three randomized trials. J Pediatr 1994;124:355-367,9,Limitations of earlier

12、trials : -The lack of stringent diagnostic criteria; -The inclusion of few very young children; -Antimicrobial drug had limited efficacy or was administered in suboptimal doses.9,9.Paradise JL. Short-course anti

13、microbial treatment for acute otitis media: not best for infants and young children. JAMA 1997;278:1640-1642,To choose amoxicillin–clavulanate(the most effective treatment for AOM) 7,10 in this study.,10.Hoberman A, et

14、al. Large dosage amoxicillin/clavulanate, compared with azithromycin, for the treatment of bacterial acute otitis media in children. Pediatr Infect Dis J 2005;24:525-532,10,Rates of spontaneous improvement similar to the

15、 rates seen in those studies among children receiving placebo have not been found uniformly.6 Therefore, for children with AOM, the circumstances in which immediate antimicrobial treatment is the preferred strategy have

16、 remained unclear.,11,OBJECTIVES,To evaluate the extent to which antimicrobial treatment(Amoxicillin-clavulanate) and placebo treatment affect the course of both symptoms and signs of AOM in children aged 6 to 23 months

17、.,12,METHODS,Eligibility and EnrollmentRandomizationAssessment of SymptomsOtoscopic Examination, Overall Assessment, and ManagementOutcomesStatistical Analysis,13,1.Eligibility and Enrollment,From November 2006 to M

18、arch 2009 at the Children's Hospital of Pittsburgh and Armstrong Pediatrics, Pennsylvania. The study protocol was approved by the institutional review board at the University of Pittsburgh; written informed consent

19、was obtained from a parent of each enrolled child. The protocol is available with the full text of this article at NEJM.org.,14,Inclusion Criteria,Eligible children (1) will be aged 6 to 23 months, (2) have received pneu

20、mococcal conjugate vaccine, and (3) have evidence of AOM defined as: Recent (within 48 hours), onset of signs and symptoms and a score of ≥ 3 on the AOM-SOS scale. Presence of middle-ear effusionModerate or marked bul

21、ging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.,15,AOM-SOS,The Acute Otitis Media Severity of Symptoms (AOM-SOS) scale11,12 The AOM-SOS scale consists of

22、 seven items: tugging of ears, crying, irritability, difficulty sleeping, diminished activity, diminished appetite, and fever. As “none,” “a little,” or “a lot,” with corresponding scores of 0, 1, and 2scores range fro

23、m 0 to 14, with higher scores indicating greater severity of symptoms,11.Shaikh N, et al. Development and preliminary evaluation of a parent-reported outcome instrument for clinical trials in acute otitis media. Pediatr

24、Infect Dis J 2009;28:5-8 12.Shaikh N, et al. Responsiveness and construct validity of a symptom scale for acute otitis media. Pediatr Infect Dis J 2009;28:9-12,16,,AOM-SOS,17,Exclusion Criteria,Children(1) had another a

25、cute illness (e.g., pneumonia) or a chronic illness (e.g., cystic fibrosis), (2)were allergic to amoxicillin, (3)had received more than one dose of an antimicrobial drug within the previous 96 hours, (4)had had otalgia f

26、or longer than 48 hours, or (5)had perforation of the tympanic membrane.,18,Exclusion Criteria(protocol),(1)certain signs or symptoms (e.g., toxic appearance, otalgia >48 hours, spontaneous perforation of the tympanic

27、 membrane and drainage or temperature ≥105?F); (2) clinical or anatomical characteristics that might obscure response to treatment (e.g., tympanostomy , submucous cleft palate, high-arched palate, or Down's syndrome

28、); (3) underlying systemic problems that might obscure response to infection (e.g., serious underlying disease [e.g.,cystic fibrosis, neoplasm, juvenile diabetes]), concomitant infection, known renal insufficiency, know

29、n hepatic insufficiency, history of immune dysfunction, chronic gastrointestinal conditions , malignancy;,19,,(4) sensorineural hearing loss;(5) comedications (e.g., systemic corticosteroids at any point while enrolled

30、in the study, more than one dose of systemic antimicrobial therapy within 96 hours, any investigational drug or vaccine; (6) hypersensitivity to penicillin, amoxicillin or amoxicillin-clavulanate, or phenylketonuria or

31、known hypersensitivity to aspartame; (7) unable to complete the study protocol or not having access to a telephone; and (8) current enrollment in another study or previously enrolled in this study.,aspartame阿司帕坦; pheny

32、lketonuria苯丙酮酸尿,20,2.Randomization,Stratification according to history of recurrent AOM (defined as ≥3 episodes in 6 months or ≥4 episodes in 1 year ) and according to their exposure or nonexposure to three or more child

33、ren for at least 10 hours per week. At each study site, within each stratum, we randomly assigned children in blocks of four, in a 1:1 ratio,21,,Amoxicillin–clavulanate (Augmentin ES, GlaxoSmithKline), 90/6.4mg/kg/day i

34、n 2 divided doses for 10 days.Placebo was similar to Amoxicillin–clavulanate in appearance and taste. The parents were unaware of the children's group assignments.Parents prepared acetaminophen as needed for the r

35、elief of symptoms.,22,3.Assessment of Symptoms,Structured interview by telephone every day until the first follow-up visit and in person at each visit. Parents record their child's AOM-SOS scores and other pertinen

36、t clinical information in a diary twice a day for 3 days and once a day thereafter.,23,4.Otoscopic Examination, Overall Assessment, and Management,Otoscopy on day 1, day 4-5, day 10-12, day 21-25.,Slight,Otoscopic Photog

37、raphs,Moderate,marked,bulging of tympanic membrane,24,Overall Assessment,To categorize clinical success or clinical failure at each visit.Clinical failure at or before the day 4–5 visit: a lack of substantial improvemen

38、t in symptoms, a worsening of signs on otoscopic examination, or both. Clinical failure at the day 10–12 visit : the failure to achieve complete or nearly complete resolution of symptoms and of otoscopic signs.,13.Kalei

39、da PH. Assessment of otoscopists' accuracy regarding middle-ear effusion: otoscopic validation. Am J Dis Child 1992;146:433-435,25,Management for clinical failure cases,A standardized 10-day regimen of orally adminis

40、tered amoxicillin, at a dose of 90mg/kg/day, and cefixime, at a dose of 8mg/kg/day. Once a child had met the criteria for clinical failure, he or she remained in that category for the analyses.,26,,Relapse at the day 21

41、–25 visit: the reappearance of AOM in a child who had previously been categorized as having met the criteria for clinical success.,27,,To obtain nasopharyngeal specimens from the children for culturing, at study entry an

42、d at the day 10–12 and day 21–25 visits.,28,5.Outcomes,The primary outcome measures A.The time to resolution of symptoms: -The time to the first recording of an AOM-SOS score of 0 or 1 -The time to the second

43、of two successive recordings of that score.B.The symptom burden over time: -The mean AOM-SOS score of each day over the first 7 days of follow-up -The groups' weighted mean scores for that period.,29,,The s

44、econdary outcomes:Overall clinical efficacyThe occurrence of adverse eventsNasopharyngeal colonization ratesThe use of acetaminophenThe use of health care resources.,30,6.Statistical Analysis,Sample estimates: a sam

45、ple of 120 children in each study group. All the analyses were based on the intention-to-treat principle, were performed with the use of two-sided tests, and included adjustment for the study stratification variables.,3

46、1,,To compare the time to the resolution of symptoms between the study groups using life-table plots, and to conduct tests of equal hazard functions using a proportional-hazards model. To compare the mean AOM-SOS scores

47、 in the two groups at individual assessments each day over the first 7 days of follow-up using generalized estimating equations, and the groups' weighted mean scores for that period using regression analysis.,32,,For

48、 analyses of clinical success or failure, we used logistic regression. To determine whether variables were prognostic or effect modifiers, we used the proportional-hazards model or logistic-regression models. To used M

49、cNemar's test for analyses of nasopharyngeal colonization rates.,33,RESULTS,1.Study Population2.Efficacy of Treatment -Symptomatic Response -Clinical Failure -Prognostic Factors and Effect Modifiers

50、-Relapse and Residual Middle-Ear Effusion3.Nasopharyngeal Colonization and Other Outcomes4.Complications and Adverse Events,34,1.Study Population,1385 Children were assessed for eligibility,887 Were not eligible,498 W

51、ere eligible,291 Underwent randomization,207 Had parent who declined participation,144 Were assigned to and received amoxicillin–clavulanate,147 Were assigned to and received placebo,,,,,,,,,,,35,36,Selected Demographic

52、and Clinical Characteristics(1),1.Age at entry 6–11 mo 12–17 mo 18–23 mo2.Sex Male Female3.Race White Black Other,4.Maternal level of education Less than high school High-school graduate

53、 College graduate5.Type of health insurance Private Medicaid6.Exposure to other children Yes No,37,7.AOM-SOS score(1)Baseline score3–56–89–1112–14(2)Mean baseline score (±SD)8.Laterality of ac

54、ute otitis mediaBilateralUnilateral,9.Degree of tympanic membrane bulging in worse ear SlightModerateMarked,Selected Demographic and Clinical Characteristics(2),There were no significant differences in characteris

55、tics between the two study groups.,38,,,There were no significant differences in characteristics between the two study groups.,39,,There were no significant differences between enrolled children and children whose parent

56、s withheld consent or between the children in the two study groups. There were no significant correlation between children's AOM-SOS scores at entry and the degree of bulging of their affected tympanic membranes.,40

57、,2.Efficacy of Treatment: 2.1Symptomatic Response,The proportion of children in whom symptoms had not resolved,41,Day2 Day4 Day7Group A 35% 61% 80%Group B 28% 54% 74%P=0.14 for the overall comparison,Rate

58、s of the first recording of a score of 0 or 1,,,,Group A : children who were treated with amoxicillin–clavulanateGroup B: children who were treated with placebo,42,,,43,Day2 Day4 Day7Group A 20% 41% 67%Group B

59、 14% 36% 53%P=0.04 for the overall comparison,Rates of two successive recordings of a score of 0 or 1,In 54% of the instances in which scores fell to 0 or 1, a subsequent score was higher than 1.,,,,44,,,45,The me

60、an AOM-SOS scores over the first 7 days were lower in the amoxicillin–clavulanate group than in the placebo group at each time point (P=0.02) and at the 10–12 day visit (1.59±0.21 vs. 2.46±0.20; P=0.003).,Group

61、 A Group B P Value*Score≤8 2.21±0.16 2.58±0.19 0.14Score ＞8 3.59±0.27 4.50±0.28 0.02,* Initial AOM-SOS score at trial entry,,,,The 7-day weighted mean score,46,The 7-day weighted m

62、ean (±SE) score was lower in the amoxicillin–clavulanate group than in the placebo group (2.79±0.16 vs. 3.42±0.18; P=0.01).,47,Group A Group B P Value*Day4-5 4% 23% <0.

63、001Day10-12 16% 51% <0.001,* At or before the day(n),,,,Rates of clinical failure at different time,2.2Clinical Failure,48,n of C.F. n of a score≥2 % #*Day4-5 39 3

64、3 85%Day10-12 95 60 63%,*At or before the day(n)C.F. denotes clinical failure#No difference between the proportions.,,,Proportions of a score≥2 in all clinical f

65、ailure at different time,,49,No child was categorized as having met the criteria for clinical failure on the basis of symptoms alone.,Mean scores of clinical failure and not clinical failure at different time,Mean score

66、of C.F. Mean score of not C.F.At day4-5 5.0±3.2 2.2±2.3At day10-12 3.7±3.3 1.2±1.8,,,,C.F. denotes clinical failure,50,2.3 Prognostic Factors and Ef

67、fect Modifiers,At day 10 to 12Children’s exposure or nonexposure, (P=0.007)Children with higher AOM-SOS scores at entry and with lower scores (P=0.004) Children with bilateral AOM with unilateral AOM (P=0.002)Childre

68、n with more bulging of the tympanic membrane and with less bulging (P<0.001),51,,,,,52,At day 10–12 , the rates of clinical failure in severe and nonsevere conditions initially,Group A Group B * Severe